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Zhen S, Zheng L, Li Q, Yin Z, Cui H, Li Y, Wu S, Li K, Zhao Y, Liang F, Hu J. Maternal green space exposure and congenital heart defects: A population-based study. ENVIRONMENTAL RESEARCH 2025; 268:120745. [PMID: 39746627 DOI: 10.1016/j.envres.2024.120745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/07/2024] [Accepted: 12/30/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Beneficial effects of maternal green space exposure on preterm birth and low birth weight have been documented, but few studies have investigated its protective effect on fetal congenital heart defects (CHDs). Our study aimed to investigate the association between maternal green space exposure and CHDs, and quantify the potential benefits of reducing the risk of fetal CHDs by achieving the target of green space coverage. METHODS The study included 4160 births with CHDs and 567,483 births without birth defects born from 2014 to 2019 in 14 cities in Liaoning Province, China. Maternal green space exposure, including periconception period (3 months before conception to 3 months into pregnancy), preconception period (3 months before conception), and the first trimester (3 months into pregnancy), was assessed using satellite-based normalized difference vegetation index (NDVI). Logistic regression models were used to estimate the associations between maternal green space exposure and the risk of fetal CHDs. RESULTS A 0.1-unit increase in maternal green space exposure during the periconception was significantly associated with 5% declines in the risk of CHDs (OR: 0.95, 95% CI: 0.92, 0.98). Exposure-response association suggested that continuous improvements in maternal green space exposure during the periconception had a greater protective impact on the risk of total CHDs, while attenuated benefits were identified in the area where NDVI is around 0.23. Assuming causality, 5.06% (95% CI: 1.72%, 8.28%) of the annual rate of CHDs could be avoided by increasing NDVI exposure to 0.23 during periconception period in the areas where NDVI is below 0.23. In addition, rural residents, and mothers who have parity twice or more, were more prone to the protective effect of green space exposure. CONCLUSIONS Our study provides evidence that maternal green space exposure is a protective factor against the risk of fetal CHDs. The findings suggest that prioritizing green space in public policy can be an effective health-promoting measure.
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Affiliation(s)
- Shihan Zhen
- School of Public Health and Emergency Management, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Lu Zheng
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang, 110004, China; Health Sciences Institute, China Medical University, Shenyang, 110122, China
| | - Qian Li
- School of Public Health and Emergency Management, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Zhouxin Yin
- School of Public Health and Emergency Management, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Hong Cui
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, 110004, China
| | - Yan Li
- Liaoning Provincial Hospital for Women and Children, Shenyang, 110005, China
| | - Shuqi Wu
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang, 110004, China; Health Sciences Institute, China Medical University, Shenyang, 110122, China
| | - Kecheng Li
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang, 110004, China; Health Sciences Institute, China Medical University, Shenyang, 110122, China
| | - Ying Zhao
- Liaoning Provincial Hospital for Women and Children, Shenyang, 110005, China.
| | - Fengchao Liang
- School of Public Health and Emergency Management, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
| | - Jiajin Hu
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang, 110004, China; Health Sciences Institute, China Medical University, Shenyang, 110122, China.
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Zhen S, Li N, Li Y, Li Q, Zheng L, Yin Z, Dou Y, Wu S, Liu Y, Zhang X, Yang X, Wang Y, Ge W, Gao X, Yang J, Liang F, Hu J, Zhao Y. Maternal exposure to fine particulate matter before and during pregnancy, and the risk of birth defects: A population-based study. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 289:117408. [PMID: 39626490 DOI: 10.1016/j.ecoenv.2024.117408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 01/26/2025]
Abstract
Although epidemiological evidence has linked maternal exposure to air pollution with adverse birth outcomes, the association between exposure to fine particulate matter (PM2.5) and the risk of total birth defects in highly polluted developing regions remains limited. The objective of this study was to assess the relationship between maternal exposure to PM2.5 before and during pregnancy and the occurrence of birth defects. This study included 16,080 births with birth defects and 567,483 controls born between 2014 and 2019 in 14 cities in Liaoning Province, China. The assessment of exposure was conducted using satellite-based PM2.5 data at a spatial resolution of 1 km. Participants were classified into four subgroups based on their exposure to PM2.5 before and during pregnancy. The association between maternal exposure to PM2.5, and the risk of birth defects, was estimated using logistic regression models. For each 10 μg/m³ increase in PM2.5, the odds ratios of birth defects were 1.68 (95% CI: 1.65, 1.70) and 2.41 (95% CI: 2.36, 2.45) during the preconception period and pregnancy, respectively. We observed a J-shaped association between maternal PM2.5 exposure during both the preconception period and pregnancy and the risk of total birth defects. Mothers exposed to elevated levels of PM2.5 during both the preconception period and pregnancy exhibited the highest risk of total birth defects (odds ratio: 4.43, 95% CI: 4.17, 4.71). Our findings illustrated that maternal exposure to PM2.5 before and during pregnancy was associated with increased risks of birth defects and underscored the potential health benefits of reducing air pollution exposure during the preconception period and pregnancy.
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Affiliation(s)
- Shihan Zhen
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China
| | - Na Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, China Medical University, Shenyang 110004, China
| | - Yan Li
- Liaoning Provincial Hospital for Women and Children, Shenyang 110005, China
| | - Qian Li
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China
| | - Lu Zheng
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Zhouxin Yin
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yan Dou
- Department of Epidemiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Shuqi Wu
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Yilin Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, China Medical University, Shenyang 110004, China; Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiaoyan Zhang
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Xinyue Yang
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Ye Wang
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Wenxiu Ge
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Xiaoyu Gao
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Jing Yang
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China
| | - Fengchao Liang
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Jiajin Hu
- Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang 110004, China; Health Sciences Institute, China Medical University, Shenyang 110122, China.
| | - Ying Zhao
- Liaoning Provincial Hospital for Women and Children, Shenyang 110005, China.
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Sinkey RG, Ogunsile FJ, Kanter J, Bean C, Greenberg M. Society for Maternal-Fetal Medicine Consult Series #68: Sickle cell disease in pregnancy. Am J Obstet Gynecol 2024; 230:B17-B40. [PMID: 37866731 PMCID: PMC10961101 DOI: 10.1016/j.ajog.2023.10.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Pregnant individuals with sickle cell disease have an increased risk of maternal and perinatal morbidity and mortality. However, prepregnancy counseling and multidisciplinary care can lead to favorable maternal and neonatal outcomes. In this consult series, we summarize what is known about sickle cell disease and provide guidance for sickle cell disease management during pregnancy. The following are Society for Maternal-Fetal Medicine recommendations.
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Zhao JH, Ma S, Li CY, Zhang HC, Zhao LJ, Zhang ZY. Clinically approved small-molecule drugs for the treatment of rheumatoid arthritis. Eur J Med Chem 2023; 256:115434. [PMID: 37148849 DOI: 10.1016/j.ejmech.2023.115434] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/25/2023] [Accepted: 04/28/2023] [Indexed: 05/08/2023]
Abstract
Rheumatoid arthritis (RA) is a persistent autoimmune ailment that is typified by the development of pannus, proliferation of synovial lining cells, microvascular neogenesis, infiltration of interstitial inflammatory cells, and destruction of cartilage and bone tissue. The disease not only imposes physical pain and economic burden on patients, but also results in a significant decline in their quality of life, rendering it a leading cause of disability. General treatment and drugs are commonly employed to alleviate the condition and symptoms of RA. Cyclooxygenase (COX), janus kinase (JAK), glucocorticoid receptor (GR) et al. have been identified as the main therapeutic targets for RA. This article provides a comprehensive review of the clinical applications and synthetic routes of 26 representative drugs for the treatment of RA, with the aim of facilitating the discovery of more effective new drugs for the treatment of this debilitating disease.
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Affiliation(s)
- Jian-Hui Zhao
- Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Shuai Ma
- Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Chao-Yuan Li
- Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Hong-Chao Zhang
- Department of Orthopedics, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Li-Jie Zhao
- The Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States; School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, 450001, China.
| | - Zi-Yan Zhang
- Department of Orthopedics, The second Hospital, Jilin University, Changchun, 130021, China.
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Brain Structural and Functional Alterations in Mice Prenatally Exposed to LPS Are Only Partially Rescued by Anti-Inflammatory Treatment. Brain Sci 2020; 10:brainsci10090620. [PMID: 32906830 PMCID: PMC7564777 DOI: 10.3390/brainsci10090620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/30/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Aberrant immune activity during neurodevelopment could participate in the generation of neurological dysfunctions characteristic of several neurodevelopmental disorders (NDDs). Numerous epidemiological studies have shown a link between maternal infections and NDDs risk; animal models of maternal immune activation (MIA) have confirmed this association. Activation of maternal immune system during pregnancy induces behavioral and functional alterations in offspring but the biological mechanisms at the basis of these effects are still poorly understood. In this study, we investigated the effects of prenatal lipopolysaccharide (LPS) exposure in peripheral and central inflammation, cortical cytoarchitecture and behavior of offspring (LPS-mice). LPS-mice reported a significant increase in interleukin-1β (IL-1β) serum level, glial fibrillary acidic protein (GFAP)- and ionized calcium-binding adapter molecule 1 (Iba1)-positive cells in the cortex. Furthermore, cytoarchitecture analysis in specific brain areas, showed aberrant alterations in minicolumns’ organization in LPS-mice adult brain. In addition, we demonstrated that LPS-mice presented behavioral alterations throughout life. In order to better understand biological mechanisms whereby LPS induced these alterations, dams were treated with meloxicam. We demonstrated for the first time that exposure to LPS throughout pregnancy induces structural permanent alterations in offspring brain. LPS-mice also present severe behavioral impairments. Preventive treatment with meloxicam reduced inflammation in offspring but did not rescue them from structural and behavioral alterations.
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6
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Liu FH, Dai HX, Gong TT, Zhang JY, Li J, Chen ZJ, Li LL, Chen YL, Liu S, Jiang CZ, Huang YH, Zhao YH, Wu QJ. Maternal preconception and first trimester exposure to PM 10 and the risk of oral clefts in offspring: a population-based, case-control study. Occup Environ Med 2020; 77:721-727. [PMID: 32737151 DOI: 10.1136/oemed-2020-106434] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 06/10/2020] [Accepted: 06/22/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Current literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PM10) and the risk of oral cleft (OC). METHODS We conducted a case-control study involving 3086 OC cases and 7950 controls, registered in the Maternal and Child Health Certificate Registry in Liaoning Province between 2010 and 2015. PM10 concentrations were obtained from the Environment Protection Bureau. The exposure windows included the 3 months before pregnancy, the first trimester and the individual months. Unconditional logistic regression model was performed to estimate the OR and 95% CI for the association between PM10 exposure and the risk of OC, cleft lip only (CLO), cleft palate only (CPO), and cleft lip and palate (CLP). RESULTS Maternal PM10 exposure was positively associated with an increased risk for OC during the 3 months preconception (per 10 µg/m3 increment: OR=1.04, 95% CI 1.01 to 1.07; highest vs lowest quartile: OR=1.23, 95% CI 1.04 to 1.45) and the first trimester (per 10 µg/m3 increment: OR=1.05, 95% CI 1.02 to 1.08; highest vs lowest quartile: OR=1.37, 95% CI 1.15 to 1.64). Analyses based on individual months presented similar positive associations, particularly in the second month of pregnancy (OR=1.77, 95% CI 1.51 to 2.09) for highest versus lowest quartile. In the subtype analysis, stronger associations were observed for CLO, whereas there was negligible evidence for CPO and CLP. Sensitivity analyses using propensity score matching generated similar findings. CONCLUSIONS Our study provides evidence that PM10 exposure during the 3 months preconception and the first trimester increases the risk of OC.
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Affiliation(s)
- Fang-Hua Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Hui-Xu Dai
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ting-Ting Gong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jia-Yu Zhang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jing Li
- Department of Science and Education, Shenyang Maternity and Child Health Hospital, Shenyang, China
| | - Zong-Jiao Chen
- Department of Atmospheric Environment Monitoring, Liaoning Eco-environmental Monitoring Center, Shenyang, China
| | - Li-Li Li
- Department of Children's Health Prevention, Shenyang Maternity and Child Health Hospital, Shenyang, China
| | - Yan-Ling Chen
- Office of Institution, Liaoning Women and Children's Health Hospital, Shenyang, China
| | - Shu Liu
- Department of Atmospheric Environment Monitoring, Liaoning Eco-environmental Monitoring Center, Shenyang, China
| | - Cheng-Zhi Jiang
- School of Environmental and Chemical Engineering, Shenyang Ligong University, Shenyang, Liaoning, China
| | - Yan-Hong Huang
- Department of Ophthalmology, Shenyang Women's and Children's Hospital, Shenyang, China
| | - Yu-Hong Zhao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qi-Jun Wu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China .,Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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7
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Duff MR, Gabel SA, Pedersen LC, DeRose EF, Krahn JM, Howell EE, London RE. The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase. J Med Chem 2020; 63:8314-8324. [PMID: 32658475 DOI: 10.1021/acs.jmedchem.0c00546] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although nonsteroidal anti-inflammatory drugs (NSAIDs) target primarily cyclooxygenase enzymes, a subset of NSAIDs containing carboxylate groups also has been reported to competitively inhibit dihydrofolate reductase (DHFR). In this study, we have characterized NSAID interactions with human DHFR based on kinetic, NMR, and X-ray crystallographic methods. The NSAIDs target a region of the folate binding site that interacts with the p-aminobenzoyl-l-glutamate (pABG) moiety of folate and inhibit cooperatively with ligands that target the adjacent pteridine-recognition subsite. NSAIDs containing benzoate or salicylate groups were identified as having the highest potency. Among those tested, diflunisal, a salicylate derivative not previously identified to have anti-folate activity, was found to have a Ki of 34 μM, well below peak plasma diflunisal levels reached at typical dosage levels. The potential of these drugs to interfere with the inflammatory process by multiple pathways introduces the possibility of further optimization to design dual-targeted analogs.
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Affiliation(s)
- Michael R Duff
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United States
| | - Scott A Gabel
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Lars C Pedersen
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Eugene F DeRose
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Juno M Krahn
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, Durham, North Carolina 27709, United States
| | - Elizabeth E Howell
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, United States
| | - Robert E London
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, Durham, North Carolina 27709, United States
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Zhang Y, Fang XM, Chen GX. Clinical use of low-dose aspirin for elders and sensitive subjects. World J Clin Cases 2019; 7:3168-3174. [PMID: 31667166 PMCID: PMC6819284 DOI: 10.12998/wjcc.v7.i20.3168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 09/28/2019] [Accepted: 10/15/2019] [Indexed: 02/05/2023] Open
Abstract
The use of low-dose aspirin (LDA) has been a common preventive measure to reduce the risk of cardiovascular events. This is attributed to aspirin's ability to inhibit platelet activation. On the other hand, the use of LDA in human subjects has been associated with the development of gastrointestinal injuries like ulcer and bleeding, especially for those sensitive subjects such as elder human subjects. This opinion review will summarize the recent clinical reports regarding the use of LDA and the development of gastrointestinal conditions in China. Based on these reports, it seems that the use of LDA is commonly associated with gastrointestinal injuries, and stopping its use leads to recovery in elderly subjects. Therefore, we would like to suggest that gastroduodenal health and conditions should be seriously taken into consideration when LDA is recommended to the elderly, or other alternative means to reduce the risk of cardiovascular events such as nutritional interventions should be suggested.
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Affiliation(s)
- Yan Zhang
- Department of Gastroenterology, Affiliated Puren Hospital of Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Xiang-Ming Fang
- Department of Gastroenterology, Affiliated Puren Hospital of Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
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Analysis of exposure margins in developmental toxicity studies for detection of human teratogens. Regul Toxicol Pharmacol 2019; 105:62-68. [DOI: 10.1016/j.yrtph.2019.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 03/19/2019] [Accepted: 04/07/2019] [Indexed: 12/17/2022]
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10
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Seeni I, Ha S, Nobles C, Liu D, Sherman S, Mendola P. Air pollution exposure during pregnancy: maternal asthma and neonatal respiratory outcomes. Ann Epidemiol 2018; 28:612-618.e4. [PMID: 30153910 PMCID: PMC6232679 DOI: 10.1016/j.annepidem.2018.06.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/01/2018] [Accepted: 06/05/2018] [Indexed: 01/24/2023]
Abstract
PURPOSE Maternal asthma increases adverse neonatal respiratory outcomes, and pollution may further increase risk. Air quality in relation to neonatal respiratory health has not been studied. METHODS Transient tachypnea of the newborn (TTN), asphyxia, and respiratory distress syndrome (RDS) were identified using medical records among 223,375 singletons from the Consortium on Safe Labor (2002-2008). Community Multiscale Air Quality models estimated pollutant exposures. Multipollutant Poisson regression models calculated adjusted relative risks of outcomes for interquartile range increases in average exposure. Maternal asthma and preterm delivery were evaluated as effect modifiers. RESULTS TTN risk increased after particulate matter (PM) less than or equal to 10-micron exposure during preconception and trimester one (9-10%), and whole-pregnancy exposure to PM less than or equal to 2.5 microns (PM2.5; 17%) and carbon monoxide (CO; 10%). Asphyxia risk increased after exposure to PM2.5 in trimester one (48%) and whole pregnancy (84%), CO in trimester two and whole pregnancy (28-32%), and consistently for ozone (34%-73%). RDS risk was associated with increased concentrations of nitrogen oxides (33%-42%) and ozone (9%-21%) during all pregnancy windows. Inverse associations were observed with several pollutants, particularly sulfur dioxide. No interaction with maternal asthma was observed. Restriction to term births yielded similar results. CONCLUSIONS Several pollutants appear to increase neonatal respiratory outcome risks.
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Affiliation(s)
- Indulaxmi Seeni
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research, Bethesda, MD
| | - Sandie Ha
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research, Bethesda, MD; University of California, Merced, Social Sciences and Management Building, Merced, CA
| | - Carrie Nobles
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research, Bethesda, MD
| | - Danping Liu
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research, Bethesda, MD; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Biostatistics Branch, Rockville, MD
| | | | - Pauline Mendola
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Division of Intramural Population Health Research, Bethesda, MD.
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Zhao J, Zhang B, Yang S, Mei H, Qian Z, Liang S, Zhang Y, Hu K, Tan Y, Xian H, Belue R, Jordan SS, Xu S, Zheng T, Du Y. Maternal exposure to ambient air pollutant and risk of oral clefts in Wuhan, China. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 238:624-630. [PMID: 29614471 DOI: 10.1016/j.envpol.2018.03.053] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 02/26/2018] [Accepted: 03/15/2018] [Indexed: 06/08/2023]
Abstract
Maternal exposure to ambient air pollution has been related to oral clefts in offspring; however, the epidemiologic evidence is equivocal. Especially, the association between high levels of exposure to ambient air pollution during pregnancy and oral clefts remains unclear. The objective of this study was to evaluate whether high levels of maternal exposure to PM2.5, PM10, O3, CO and SO2 are related to increased risk of oral clefts in Wuhan, China. A population-based study was conducted using cohort of 105,927 live-born infants, fetal deaths, and stillbirths during a two-year period from 2011 to 2013. For each participant, weekly and monthly averages of daily mean concentrations for each pollutant were estimated. Multiple logistic regression analyses were constructed to quantify the adjusted odds ratios (aORs) for the relationship between each air pollutant and oral clefts while controlling for key covariates. Using monthly averages, a cleft lip with or without cleft palate (CLP) was associated with PM2.5 (aORs 2nd month = 1.34, CI:1.19-1.49; aORs 3rd month=1.14, CI:1.02-1.28), PM10 (aORs 2nd month = 1.11, CI:1.00-1.23) and CO (aORs 2nd month = 1.31, CI:1.14-1.51; aORs 3rd month = 1.17, CI:1.03-1.33). A cleft palate only (CPO) was associated with PM2.5 (aORs 2nd month = 1.24, CI: 1.03-1.48), and O3 (aORs 2nd month = 1.21, CI: 1.03-1.42; aORs 3rd month = 1.18, CI: 1.02-1.37). Our findings reveal an association between air pollutants exposure and the risk of oral clefts. Future studies are needed to confirm these associations, and clarify the causality related to specific pollutants during the most relevant vulnerable exposure time windows for oral clefts during pregnancy.
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Affiliation(s)
- Jinzhu Zhao
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China; Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, 430030, China
| | - Bin Zhang
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, 430030, China
| | - Shaoping Yang
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, 430030, China
| | - Hui Mei
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, 430030, China
| | - Zhengmin Qian
- Department of Epidemiology & Biostatistics, College for Public Health and Social Justice, Saint Louis University, Saint Louis, MO, USA
| | - Shengwen Liang
- Wuhan Environmental Monitoring Center, Wuhan, Hubei Province, 430000, China
| | - Yiming Zhang
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, 430030, China
| | - Ke Hu
- Wuhan Environmental Monitoring Center, Wuhan, Hubei Province, 430000, China
| | - Yafei Tan
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, 430030, China
| | - Hong Xian
- Department of Epidemiology & Biostatistics, College for Public Health and Social Justice, Saint Louis University, Saint Louis, MO, USA
| | - Rhonda Belue
- Department of Health Management and Policy, College for Public Health and Social Justice, Saint Louis University, Saint Louis, MO, USA
| | - Savannah S Jordan
- Department of Epidemiology & Biostatistics, College for Public Health and Social Justice, Saint Louis University, Saint Louis, MO, USA
| | - Shunqing Xu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Tongzhang Zheng
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA
| | - Yukai Du
- Department of Maternal and Child Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
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Daston GP, Beekhuijzen M. Is omphalocele a non-specific malformation in New Zealand White rabbits? Reprod Toxicol 2018; 78:29-39. [PMID: 29550350 DOI: 10.1016/j.reprotox.2018.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 03/09/2018] [Accepted: 03/13/2018] [Indexed: 10/17/2022]
Abstract
We evaluated the incidence of omphalocele, a malformation that occurs sporadically in many studies. We assembled data on external malformations using all treatment groups from every study published in three major journals over the past 35 years using New Zealand White rabbits. Fifty-eight papers were included: 4905 litters and 36,977 fetuses. Omphalocele was reported in 43% and was among the most common defects, occurring at a rate of 1.10% (litter) and 0.16% (fetus). The defect did not appear to be treatment-related, although it may have been in two studies, based on rate and dose-responsiveness. Removing these two studies from the analysis, the defect was still prevalent (0.77% litter, 0.11% fetal incidence). Three studies evaluated the effects of food restriction and omphalocele was observed with food restriction in two of them, suggesting that decreased maternal weight gain or food consumption may be causal. Otherwise, it appears to be spontaneous and common.
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Clark RL. Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester. Birth Defects Res 2017. [DOI: 10.1002/bdr2.1035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Demirel C, Kilciksiz SC, Gurgul S, Erdal N, Yigit S, Tamer L, Ayaz L. Inhibition of Radiation-Induced Oxidative Damage in the Lung Tissue: May Acetylsalicylic Acid Have a Positive Role? Inflammation 2016; 39:158-165. [PMID: 26276129 DOI: 10.1007/s10753-015-0234-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The lung is relatively sensitive to irradiation. It is shown that acetylsalicylic acid (ASA) might reduce oxidative injury and that it has a place in protection from cancer. The aim of this study is to evaluate the potential radioprotective effects of ASA. Whole-body irradiation (6 Gy, single dose) was applied to the rats. Glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels in the lung tissue were measured. Control (C), Radiation (R), Radiation + ASA (R + ASA; received irradiation and 25 mg/kg of ASA intraperitoneally (i.p.)), and Radiation + Amifostine (R + WR-2721; received irradiation and 200 mg/kg of WR-2721 i.p.) groups were used. The MPO levels decreased statistically significantly in the group administered ASA. Histopathologically, a radioprotective effect of ASA was more evident in the R + ASA group. ASA is an agent which has not been used as a radioprotector in the clinic yet, and it is worth supporting with more advanced studies.
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Affiliation(s)
- Can Demirel
- Department of Biophysics, Faculty of Medicine, Gaziantep University, 27310, Gaziantep, Turkey.
| | | | - Serkan Gurgul
- Department of Biophysics, Faculty of Medicine, Gaziosmanpaşa University, 60000, Tokat, Turkey
| | - Nurten Erdal
- Department of Biophysics, Faculty of Medicine, Mersin University, 33169, Mersin, Turkey
| | - Seyran Yigit
- Department of Pathology, Izmir Atatürk Training and Research Hospital, 35000, Izmir, Turkey
| | - Lulufer Tamer
- Department of Biochemistry, Faculty of Medicine, Mersin University, 33169, Mersin, Turkey
| | - Lokman Ayaz
- Department of Biochemistry, Faculty of Pharmacy, University of Trakya, 22000, Edirne, Turkey
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Burdan F. Developmental effects of propyphenazone in analgesic and antipyretic combination with caffeine or paracetamol. Hum Exp Toxicol 2016; 23:235-44. [PMID: 15222401 DOI: 10.1191/0960327104ht439oa] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The aim of the study was to determine the influence of an over-the-counter (OTC) mixture of propyphenazone with caffeine or paracetamol on prenatal development. Propyphenazone:caffeine and propyphenazone:paracetamol mixtures were prepared with constant 3:1 and 3:5 ratios, respectively. Three dose levels of each of the mixtures were administered separately in Tween-80 water suspension once a day to pregnant Wistar rats on gestation days 8-14. The low dose was similar to the OTC preparations, 2.1 mg/kg of propyphenazone, 0.7 mg/kg of caffeine or 3.5 mg/kg of paracetamol. The middle dose was 21.0, 7.0 or 35.0 mg/kg, and the highest 210.0, 70.0 or 350.0 mg/kg for propyphenazone, caffeine or paracetamol, respectively. On day 21 of gestation the fetuses were delivered by hysterectomy. Dead or live fetuses, resorptions and the number of implantation sites were counted. Live fetuses were examined for external, visceral and skeletal malformation. Postimplantation mortality was calculated. Dose-dependent effects in the middle and high dose groups on fetal body weight/length and placental weight were found. No increase in external or internal congenital anomalies was found in any of the mixture-exposed groups. Prenatal coadministration of propyphenazone with caffeine or paracetamol caused intrauterine growth retardation but did not increase external or internal congenital anomalies. The risk of midline defects (umbilical hernia and gastroschisis) is discussed.
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Affiliation(s)
- F Burdan
- Experimental Teratology Unit of the Human Anatomy Department, Medical University of Lublin, PL-20074 Lublin, Poland.
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Zhu Y, Zhang C, Liu D, Grantz KL, Wallace M, Mendola P. Maternal ambient air pollution exposure preconception and during early gestation and offspring congenital orofacial defects. ENVIRONMENTAL RESEARCH 2015; 140:714-20. [PMID: 26099933 PMCID: PMC4498658 DOI: 10.1016/j.envres.2015.06.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 05/08/2015] [Accepted: 06/02/2015] [Indexed: 05/09/2023]
Abstract
BACKGROUND Maternal air pollution exposure has been related to orofacial clefts but the literature is equivocal. Potential chronic preconception effects have not been studied. OBJECTIVES Criteria air pollutant exposure during three months preconception and gestational weeks 3-8 was studied in relation to orofacial defects. METHODS Among 188,102 live births and fetal deaths from the Consortium on Safe Labor (2002-2008), 63 had isolated cleft palate (CP) and 159 had isolated cleft lip with or without cleft palate (CL ±CP). Exposures were estimated using a modified Community Multiscale Air Quality model. Logistic regression with generalized estimating equations adjusted for site/region and maternal demographic, lifestyle and clinical factors calculated the odds ratio (OR) and 95% CI per interquartile increase in each pollutant. RESULTS Preconception, carbon monoxide (CO; OR=2.24; CI: 1.21, 4.16) and particulate matter (PM) ≤10 µm (OR=1.72; CI: 1.12, 2.66) were significantly associated with CP, while sulfur dioxide (SO2) was associated with CL ±CP (OR=1.93; CI: 1.16, 3.21). During gestational weeks 3-8, CO remained a significant risk for CP (OR=2.74; CI: 1.62, 4.62) and nitrogen oxides (NOx; OR=3.64; CI: 1.73, 7.66) and PM ≤2.5 µm (PM2.5; OR=1.74; CI: 1.15, 2.64) were also related to the risk. Analyses by individual week revealed that positive associations of NOx and PM2.5 with CP were most prominent from weeks 3-6 and 3-5, respectively. CONCLUSIONS Exposure to several criteria air pollutants preconception and during early gestation was associated with elevated odds for CP, while CL ±CP was only associated with preconception SO2 exposure.
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Affiliation(s)
- Yeyi Zhu
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Danping Liu
- Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Katherine L Grantz
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Maeve Wallace
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Pauline Mendola
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA.
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AroER tri-screen™ is a novel functional assay to estimate both estrogenic and estrogen precursor activity of chemicals or biological specimens. Breast Cancer Res Treat 2015; 151:335-45. [PMID: 25962693 DOI: 10.1007/s10549-015-3398-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 04/18/2015] [Indexed: 01/17/2023]
Abstract
The purpose of the study is to define AroER tri-screen's utility for identifying endocrine-disrupting chemicals (EDCs) that target aromatase and/or estrogen receptor (ER), and to measure the total estrogenic activity in biological specimens. ER-positive, aromatase-expressing MCF-7 breast cancer cells were stably transfected with an estrogen responsive element (ERE)-driven luciferase reporter plasmid to yield a new high-throughput screening platform-the AroER tri-screen. AroER tri-screen was capable of identifying estrogen precursors, such as cortodoxone, which function as estrogens through a two-step conversion process in aromatase-expressing tissue. Furthermore, the system proved useful for assessing EDC activity in biologically relevant samples. Estimating these activities is critical because natural estrogens and estrogenic EDCs are important factors in ER-positive breast cancer risk. As our research demonstrates, incorporating functionally active aromatase into the AroER tri-screen produces a powerful and unique tool to (1) identify new EDCs targeting aromatase and/or ER; (2) discover novel EDCs activated by aromatase; and (3) estimate overall estrogenic activities in biological samples as a potential intermediate risk factor for breast cancer.
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Case-control analysis of maternal prenatal analgesic use and cardiovascular malformations: Baltimore-Washington Infant Study. Am J Obstet Gynecol 2014; 211:404.e1-9. [PMID: 24681289 DOI: 10.1016/j.ajog.2014.03.054] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/25/2014] [Accepted: 03/21/2014] [Indexed: 11/20/2022]
Abstract
OBJECTIVE We sought to assess maternal prenatal use of analgesics and risk of cardiovascular malformations (CVM) in the offspring. STUDY DESIGN Data from the Baltimore-Washington Infant Study, a population-based case-control investigation of CVM, were used to examine selected isolated CVM diagnoses and maternal analgesic use during the periconceptional period (3 months before and after conception). We compared case and control infants on frequency of maternal use of analgesics and estimated adjusted odds ratios (adjORs) and 95% confidence intervals (CI) with logistic regression models for specific CVM phenotypes. RESULTS Frequency of periconceptional use of any analgesic was 52% among control mothers and 53% among case mothers. Analyses by CVM diagnoses identified an association of tetralogy of Fallot with maternal acetaminophen use (adjOR, 1.6; 95% CI, 1.1-2.3) and dextrotransposition of the great arteries with intact ventricular septum with maternal nonsteroidal antiinflammatory drug use (adjOR, 3.2; 95% CI, 1.2-8.7). CONCLUSION Analgesic use during the periconceptional period was not associated with CVM in the aggregate or with most phenotypes of CVM examined. Associations with 2 phenotypes of CVM may have occurred by chance. These findings warrant corroboration and further study, including further evaluation of the observed associations, the dose of analgesic taken, more specific timing of analgesic use, and indications for use.
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David ND, Mauro MDO, Gonçalves CA, Pesarini JR, Strapasson RLB, Kassuya CAL, Stefanello MÉA, Cunha-Laura AL, Monreal ACD, Oliveira RJ. Gochnatia polymorpha ssp. floccosa: bioprospecting of an anti-inflammatory phytotherapy for use during pregnancy. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:370-9. [PMID: 24727192 DOI: 10.1016/j.jep.2014.04.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 03/19/2014] [Accepted: 04/03/2014] [Indexed: 05/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gochnatia polymorpha ssp. floccosa is used in folk medicine to treat inflammation and infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly consumed medications during pregnancy in women with inflammatory diseases. However, the relationship between the use of NSAIDs and the risk of miscarriage and birth defects and/or benefits is not fully understood. Thus, an investigation regarding the use of Gochnatia polymorpha during gestation is of relevance for developing safe anti-inflammatory drugs for use during pregnancy. MATERIALS AND METHODS The pregnant females were randomly divided into 5 groups. Control group received a hydroalcoholic solution (1.2%), via gavage, for at least 15 days prior to mating and throughout the gestational period. The pre-treatment group received Gochnatia polymorpha ethanol extract (GPEE), via gavage, at a dose of 100mg/kg body weight (b.w.) for at least 15 days prior to mating and up to the appearance of the vaginal plug. The organogenesis group received GPEE at a dose of 100mg/kg (b.w.), via gavage, on the 5-15th gestacional day. The pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, throughout the gestational period (from the 1st to the 18th day of pregnancy). The pre+pregnancy group received GPEE at a dose of 100mg/kg (b.w.), via gavage, for at least 15 days prior to mating and throughout the entire gestational period. The clinical signals of maternal toxicity and teratogenesis were evaluated. Additional assays to evaluate chronic inflammation, antigenotoxicity and immunomodolatory activity were performed. RESULTS AND CONCLUSIONS The results indicated that GPEE does not interfere with reproductive performance or embryo-fetal development but does correlate with reduced weight and fetal length. The extract was not teratogenic or mutagenic or an immunomodulator. However, GPEE did exhibit effective anti-inflammatory activity. Based on this study, it can be inferred that GPEE is an important, safe anti-inflammatory agent for use during pregnancy according to the experimental design we utilized, which opens up possibilities for the bioprospecting of a new anti-inflammatory phytotherapy for use during pregnancy.
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Affiliation(s)
- Natan de David
- Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica (CeTroGen), Núcleo de Hospital Universitário (NHU), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil; Programa de Mestrado em Farmácia, Centro de Ciências Biológicas e da Saúde (CCBS), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil
| | - Mariana de Oliveira Mauro
- Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica (CeTroGen), Núcleo de Hospital Universitário (NHU), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil; Programa de Pós-graduação em Biotecnologia e Biodiversidade - Rede Pró Centro-Oeste, Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil
| | - Caroline Amélia Gonçalves
- Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica (CeTroGen), Núcleo de Hospital Universitário (NHU), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil
| | - João Renato Pesarini
- Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica (CeTroGen), Núcleo de Hospital Universitário (NHU), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil; Programa de Pós-graduação em Saúde e Desenvolvimento na Região Centro-Oeste, Faculdade de Medicina "Dr. Hélio Mandetta" (FAMED), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil
| | | | | | | | - Andréa Luiza Cunha-Laura
- Programa de Mestrado em Farmácia, Centro de Ciências Biológicas e da Saúde (CCBS), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil
| | - Antônio Carlos Duenhas Monreal
- Centro de Ciências Biológicas e da Saúde (CCBS), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil
| | - Rodrigo Juliano Oliveira
- Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica (CeTroGen), Núcleo de Hospital Universitário (NHU), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil; Programa de Mestrado em Farmácia, Centro de Ciências Biológicas e da Saúde (CCBS), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil; Programa de Pós-graduação em Saúde e Desenvolvimento na Região Centro-Oeste, Faculdade de Medicina "Dr. Hélio Mandetta" (FAMED), Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, Mato Grosso do Sul, Brazil.
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Nakhai-Pour HR, Bérard A. Major malformations after first trimester exposure to aspirin and NSAIDs. Expert Rev Clin Pharmacol 2014; 1:605-16. [PMID: 24422733 DOI: 10.1586/17512433.1.5.605] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The use of aspirin and other NSAIDs during the first trimester of pregnancy is widespread, despite inconclusive evidence regarding the possible risks for the baby. We present an overview of the current evidence relating to the associations between aspirin or NSAID use during the first trimester of pregnancy and the risk of congenital malformations. We systematically searched Medline, Embase, the Cochrane Library and the reference lists of all relevant articles from 1966 to March 2008 that examined the association between aspirin and NSAID use during the first trimester of pregnancy and the risk of congenital malformations in humans. We analyzed 30 studies that met the predefined inclusion criteria: 22 case-control studies, seven cohort studies and one randomized, controlled trial. There are not enough human data available to assess the effect of high-dose aspirin and NSAIDs in pregnant women, such as those used in the treatment of rheumatoid arthritis, osteoarthritis and pain relief. This review suggests that the exposure to aspirin or NSAIDs during the first trimester of pregnancy is associated with an increased risk of gastroschisis (aspirin), cardiac malformations (NSAIDs) and orofacial malformations (naproxen).
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Affiliation(s)
- Hamid Reza Nakhai-Pour
- Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada and Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada
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Soh MC, Nelson-Piercy C. Update of the management of rheumatoid arthritis in pregnancy. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/eog.11.77] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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van Gelder MM, van Rooij IA, de Jong-van den Berg LT, Roeleveld N. Teratogenic Mechanisms Associated with Prenatal Medication Exposure. Therapie 2014; 69:13-24. [DOI: 10.2515/therapie/2014003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 10/18/2013] [Indexed: 12/31/2022]
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Çolakoğlu S, Aktaş A, Raimondo S, Türkmen AP, Altunkaynak BZ, Odacı E, Geuna S, Kaplan S. Effects of prenatal exposure to diclofenac sodium and saline on the optic nerve of 4- and 20-week-old male rats: a stereological and histological study. Biotech Histochem 2013; 89:136-44. [DOI: 10.3109/10520295.2013.827741] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Brown SA, Seifert SA, Rayburn WF. Management of envenomations during pregnancy. Clin Toxicol (Phila) 2013; 51:3-15. [DOI: 10.3109/15563650.2012.760127] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Overturf MD, Overturf CL, Baxter D, Hala DN, Constantine L, Venables B, Huggett DB. Early life-stage toxicity of eight pharmaceuticals to the fathead minnow, Pimephales promelas. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2012; 62:455-64. [PMID: 22048524 DOI: 10.1007/s00244-011-9723-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 10/17/2011] [Indexed: 05/13/2023]
Abstract
Human pharmaceuticals are routinely being detected in the environment, and there is growing concern about whether these drugs could elicit effects on aquatic organisms. Regulatory paradigms have shifted accordingly, with a greater emphasis on chronic toxicity data compared with acute data. The Organisation for Economic Co-operation and Development 210 Early Life Stage Test has been proposed as a good measure of the potential for pharmaceuticals to elicit chronic toxicity. To begin building a data set regarding the early life-stage toxicity of pharmaceuticals to fish, fathead minnows (FHM) were exposed to amiodarone, carbamazepine, clozapine, dexamethasone, fenofibrate, ibuprofen, norethindrone, or verapamil. Survival and growth were used to assess chronic toxicity in FHM at 28 days posthatch. Exposure of FHM to carbamazepine, fenofibrate, and ibuprofen resulted in no significant adverse effects at the concentrations tested. FHM survival was not impacted by verapamil exposure; however, growth was significantly decreased at 600 μg/L. Dexamethasone-exposed FHM showed a significant decrease in survival at a concentration of 577 μg/L; however, growth was not impacted at the concentration tested. Norethindrone exposure resulted in a significant decrease in survival and dry weight at 14.8 and 0.74 μg/L, respectively. Exposure to amiodarone and clozapine resulted in a significant decrease in survival and a significant increase in growth at concentrations of 1020 and 30.8 μg/L, respectively. Although the effect levels derived in this study are greater then concentrations observed in the environment, these data suggest that synthetic progestins may require additional research.
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Affiliation(s)
- M D Overturf
- Department of Biology, University of North Texas, Denton, TX 76203, USA
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Spezielle Arzneimitteltherapie in der Schwangerschaft. ARZNEIMITTEL IN SCHWANGERSCHAFT UND STILLZEIT 2012. [PMCID: PMC7271212 DOI: 10.1016/b978-3-437-21203-1.10002-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Developmental outcome after exposure to cyclooxygenase inhibitors during pregnancy and lactation. Reprod Toxicol 2011; 32:407-17. [DOI: 10.1016/j.reprotox.2011.09.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 09/01/2011] [Accepted: 09/28/2011] [Indexed: 11/21/2022]
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Wilffert B, Altena J, Tijink L, van Gelder MMHJ, de Jong-van den Berg LTW. Pharmacogenetics of drug-induced birth defects: what is known so far? Pharmacogenomics 2011; 12:547-58. [PMID: 21521026 DOI: 10.2217/pgs.10.201] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A literature review was performed to collect information on the role of pharmacogenetics in six proposed teratogenic mechanisms associated with drug use during pregnancy: folate antagonism, oxidative stress, angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism, cyclooxygenase-1 and -2 inhibition, 5-hydroxytryptamine-reuptake inhibition and drug transporters in the placenta. Data on the direct relationship between pharmacogenetics and drug-induced birth defects were found for folate metabolism, oxidative stress caused by phenytoin exposure and drug transporters in the placenta. Although no specific data to support pharmacogenetic-related birth defects were found for the NSAIDs, paroxetine and fluoxetine, it might be expected that polymorphisms modify their teratogenic effects. The usually low prevalence of drug-induced malformations impedes the demonstration of the contribution of pharmacogenetics. Large-scale studies, preferably case-control studies, are needed.
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Affiliation(s)
- Bob Wilffert
- Unit of Pharmacoepidemiology & Pharmacoeconomics, Department of Pharmacy, University of Groningen, Groningen 9713AV, The Netherlands.
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van Gelder MMHJ, Roeleveld N, Nordeng H. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and the risk of selected birth defects: a prospective cohort study. PLoS One 2011; 6:e22174. [PMID: 21789231 PMCID: PMC3138772 DOI: 10.1371/journal.pone.0022174] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 06/19/2011] [Indexed: 12/18/2022] Open
Abstract
Background Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs. Methods and Findings We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0–12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4–1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9–15.7). Conclusions Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded.
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Affiliation(s)
- Marleen M H J van Gelder
- Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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32
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Van Dorp DR, Malleis JM, Sullivan BP, Klein MD. Teratogens inducing congenital abdominal wall defects in animal models. Pediatr Surg Int 2010; 26:127-39. [PMID: 19756655 DOI: 10.1007/s00383-009-2482-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2009] [Indexed: 02/04/2023]
Abstract
Congenital abdominal wall defects are common anomalies which include gastroschisis, omphalocele and umbilical cord hernia. Recent reports indicate that gastroschisis is increasing in prevalence, whereas omphalocele has remained steady, suggesting that environmental factors may play a part in their pathogenesis. The aim of this study is to review animal teratogen studies resulting in abdominal wall defects to investigate their possible causes. Each report was examined not only for the teratogens causing the defects, but also to carefully identify the defect occurring and its correlation with the known clinical anomalies. We found many discrepancies between the nomenclature used by animal teratology investigators and that used by clinicians. We were able to confirm the induction of gastroschisis by 22 teratogens, omphalocele by 9 teratogens and umbilical cord hernia by 8. There is no doubt that environmental factors may be responsible, at least in part, for all three of the clinical abdominal wall defects. Future studies should take care to appreciate the differences between these anomalies and describe them in detail, so that accurate and meaningful conclusions can be obtained.
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Affiliation(s)
- Dennis R Van Dorp
- Departments of Surgery, Wayne State University and Children's Hospital of Michigan, Michigan, USA
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33
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Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 2010; 115:3997-4005. [PMID: 20110424 DOI: 10.1182/blood-2009-04-216069] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
During embryonic development, lymph sacs form from the cardinal vein, and sprout centrifugally to form mature lymphatic networks. Separation of the lymphatic from the blood circulation by a hitherto unknown mechanism is essential for the homeostatic function of the lymphatic system. O-glycans on the lymphatic endothelium have recently been suggested to be required for establishment and maintenance of distinct blood and lymphatic systems, primarily by mediating proper function of podoplanin. Here, we show that this separation process critically involves platelet activation by podoplanin. We found that platelet aggregates build up in wild-type embryos at the separation zone of podoplanin(+) lymph sacs and cardinal veins, but not in podoplanin(-/-) embryos. Thus, podoplanin(-/-) mice develop a "nonseparation" phenotype, characterized by a blood-filled lymphatic network after approximately embryonic day 13.5, which, however, partially resolves in postnatal mice. The same embryonic phenotype is also induced by treatment of pregnant mice with acetyl salicylic acid, podoplanin-blocking antibodies, or by inactivation of the kindlin-3 gene required for platelet aggregation. Therefore, interaction of endothelial podoplanin of the developing lymph sac with circulating platelets from the cardinal vein is critical for separating the lymphatic from the blood vascular system.
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34
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van Gelder MMHJ, van Rooij IALM, Miller RK, Zielhuis GA, de Jong-van den Berg LTW, Roeleveld N. Teratogenic mechanisms of medical drugs. Hum Reprod Update 2010; 16:378-94. [DOI: 10.1093/humupd/dmp052] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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35
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Combined administration of gonadotropin-releasing hormone, progesterone, and meloxicam is an effective treatment for the repeat-breeder cow. Theriogenology 2009; 72:542-8. [DOI: 10.1016/j.theriogenology.2009.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2009] [Revised: 04/07/2009] [Accepted: 04/12/2009] [Indexed: 02/02/2023]
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David A, Pancharatna K. Developmental anomalies induced by a non-selective COX inhibitor (ibuprofen) in zebrafish (Danio rerio). ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2009; 27:390-395. [PMID: 21783969 DOI: 10.1016/j.etap.2009.01.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2007] [Revised: 12/11/2008] [Accepted: 01/18/2009] [Indexed: 05/29/2023]
Abstract
Effects of ibuprofen (a non-selective COX inhibitor) on the embryonic development, hatching success, larval growth, behavioral pattern and survival competence were studied in Danio rerio. Embryos at 2/4 celled stage were exposed to graded doses (0, 1, 5, 10, 50 and 100μg/L distilled water) of ibuprofen in triplicate sets (n=30). The experiment was repeated thrice. The results indicate that developing embryos tolerated lower (1 and 5μg/L) doses of the drug readily but, exposure to higher doses (>10μg/L) caused retarded development, decreased hatching rate and growth, cardiac anomalies, spinal curvature, pectoral fin malformation and behavioral alterations resulting in greater mortality of experimental embryos. This study suggests that, ibuprofen which is marketed as over-the-counter (OTC) drug is embryotoxic at least at higher (>10μg/L) dose level to zebrafish embryos.
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Affiliation(s)
- Anuradha David
- Department of Zoology, Karnatak University, Dharwad-580 003, India
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Cappon GD, Fleeman TL, Cook JC, Hurtt ME. Combined Treatment Potentiates the Developmental Toxicity of Ibuprofen and Acetazolamide in Rats. Drug Chem Toxicol 2008; 28:409-21. [PMID: 16298872 DOI: 10.1080/01480540500262805] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Aspirin (ASA), an irreversible cyclooxygenase (COX) inhibitor, induces ventricular septal defect (VSD) and diaphragmatic hernia (DH) in rat fetuses when administered on gestation days (GDs) 9-10, a critical period for cardiovascular (CV) and midline development. Evaluation of a spectrum of nonsteroidal antiinflammatory drugs (NSAIDs; reversible COX inhibitors) showed that while some NSAIDs induced VSD in rats, none of the NSAIDs evaluated produced DH. In addition to inhibiting COX, ASA also inhibits carbonic anhydrase. The purpose of this study was to determine whether concurrent inhibition of COX and carbonic anhydrase would produce a teratogenic profile that includes both VSD and DH. To inhibit both COX and carbonic anhydrase, ibuprofen (COX inhibitor) and acetazolamide (carbonic anhydrase inhibitor) were coadministered on GDs 9-10. Groups of 20 female Crl:CD(SD)IGS BR rats were given either 300 mg kg(-1) day(-1) ibuprofen, 1000 mg kg(-1) day(-1) acetazolamide, or both (combination of ibuprofen and acetazolamide). Fetuses were evaluated on GD 21 for external and visceral development. Ibuprofen induced VSD in 3.7% of fetuses per litter; no defects in appendicular skeletal development were noted. Acetazolamide induced VSD in 5.9% of the fetuses per litter and appendicular defects in 41% of the fetuses per litter. Coadministration of ibuprofen and acetazolamide produced VSD in 18.7% of the fetuses per litter and appendicular defects in 77% of the fetuses per litter; however, there were no DH. Therefore, while concurrent inhibition of COX and carbonic anhydrase did not produce DH, potentiation was noted for the induction of VSD and appendicular anomalies.
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Affiliation(s)
- Gregg D Cappon
- Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
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38
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Feldkamp ML, Carey JC, Sadler TW. Development of gastroschisis: review of hypotheses, a novel hypothesis, and implications for research. Am J Med Genet A 2007; 143A:639-52. [PMID: 17230493 DOI: 10.1002/ajmg.a.31578] [Citation(s) in RCA: 131] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Gastroschisis, a ventral body wall defect, is a continuing challenge and concern to researchers, clinicians, and epidemiologists seeking to identify its cause(s) and pathogenesis. Concern has been renewed in recent years because, unlike most other birth defects, rates of gastroschisis are reportedly increasing in many developed and developing countries. No tenable explanation or specific causes have been identified for this trend. Rates of gastroschisis are particularly high among pregnancies of very young women. Such an intriguing association, not observed to this degree with other birth defects, may afford clues to the defect's cause. Understanding the causes of gastroschisis may provide insight to the defect's origin. In pursuing such causal studies, it would be helpful to understand the embryogenesis of gastroschisis. To date, four main embryologic hypotheses have been proposed: (1) Failure of mesoderm to form in the body wall; (2) Rupture of the amnion around the umbilical ring with subsequent herniation of bowel; (3) Abnormal involution of the right umbilical vein leading to weakening of the body wall and gut herniation; and (4) Disruption of the right vitelline (yolk sac) artery with subsequent body wall damage and gut herniation. Although based on embryological phenomena, these hypotheses do not provide an adequate explanation for how gastroschisis would occur. Therefore, we propose an alternative hypothesis, based on well described embryonic events. Specifically, we propose that abnormal folding of the body wall results in a ventral body wall defect through which the gut herniates, leading to the clinical presentation of gastroschisis. This hypothesis potentially explains the origin of gastroschisis as well as that of other developmental defects of the ventral wall.
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Affiliation(s)
- Marcia L Feldkamp
- Department of Pediatrics, Division of Medical Genetics, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
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Kling DE, Schnitzer JJ. Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic hernia (CDH). AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2007; 145C:139-57. [PMID: 17436305 DOI: 10.1002/ajmg.c.30129] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Congenital diaphragmatic hernia (CDH) is a congenital malformation that occurs with a frequency of 0.08 to 0.45 per 1,000 births. Children with CDH are born with the abdominal contents herniated through the diaphragm and exhibit an associated pulmonary hypoplasia which is frequently accompanied by severe morbidity and mortality. Although the etiology of CDH is largely unknown, considerable progress has been made in understanding its molecular mechanisms through the usage of genetic, teratogenic, and surgical models. The following review focuses on the teratogenic and surgical models of CDH and the possible molecular mechanisms of nitrofen (a diphenyl ether, formerly used as an herbicide) in both induction of CDH and pulmonary hypoplasia. In addition, the mechanisms of other compounds including several anti-inflammatory agents that have been linked to CDH will be discussed. Furthermore, this review will also explore the importance of vitamin A in lung and diaphragm development and the possible mechanisms of teratogen interference in vitamin A homeostasis. Continued exploration of these models will bring forth a clearer understanding of CDH and its molecular underpinnings, which will ultimately facilitate development of therapeutic strategies.
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Affiliation(s)
- David E Kling
- Massachusetts General Hospital, Department of Pediatric Surgery, Boston, MA 02114, USA.
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Flippin JL, Huggett D, Foran CM. Changes in the timing of reproduction following chronic exposure to ibuprofen in Japanese medaka, Oryzias latipes. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2007; 81:73-8. [PMID: 17166604 DOI: 10.1016/j.aquatox.2006.11.002] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2006] [Revised: 11/03/2006] [Accepted: 11/04/2006] [Indexed: 05/13/2023]
Abstract
Effluents from wastewater treatment plants and untreated sewage constitute a low concentration but continuous source of pharmaceutical products to the aquatic environment. One such drug, ibuprofen, is a non-steroidal anti-inflammatory agent that primarily acts through inhibition of cyclooxygenase (COX) activity. Oryzias latipes (Japanese medaka) were exposed for 6 weeks via water to three concentrations of ibuprofen (1-100 microg/L nominal concentrations) and a water control. Reproductive parameters, including frequency of spawning, fecundity, egg size, and rate of fertilization, were measured for each pair of adult medaka following 6 weeks of exposure. Livers homogenates from exposed individuals were assayed for COX activity and whole individuals were histologically examined for tissue damage. Increasing exposure to ibuprofen significantly increased the number of eggs per reproductive event, but decreased the number of spawning events per week. Liver tissue collected from females had less variability in COX activity with increasing concentration of ibuprofen exposure, and tended to have elevated hepatosomatic indices. No pathological damage was evident the in the gills, livers and head kidneys of animals from the highest exposure group. The results of this experiment begin to show that exposure to chronic low levels of ibuprofen alter the pattern of reproduction and may produce sex-specific responses in teleosts.
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Affiliation(s)
- Jennifer L Flippin
- Department of Biology, West Virginia University, Morgantown, WV 26506-6057, United States
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41
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Ofori B, Oraichi D, Blais L, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: A nested case-control study. ACTA ACUST UNITED AC 2006; 77:268-79. [PMID: 16929547 DOI: 10.1002/bdrb.20085] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Many women take non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy but the risks for the infant remain controversial. We carried out a study to quantify the association between those women prescribed NSAIDs in early pregnancy and congenital anomalies. METHODS A population-based pregnancy registry was built by linking data from three administrative databases in Quebec between 1997-2003. The inclusion criteria were mothers of live singleton infants, between 15-45 years of age, covered by the RAMQ drug plan > or =12 months before and during pregnancy, and prescribed an NSAID or other medications during pregnancy. We selected as cases infants with any congenital anomaly (ICD-9; 740-759) diagnosed in the first year of life. Up to 10 controls, defined as infants with no congenital anomalies detected were selected for each case. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. RESULTS Within the registry, 36,387 pregnant women met the inclusion criteria. We identified 93 births with congenital anomalies in 1056 women (8.8%) who filled prescriptions for NSAIDs in the first trimester of pregnancy, compared to 2478 in 35,331 (7%) women who did not. The adjusted OR for any congenital anomalies for women who filled a prescription for NSAIDs in the first trimester was 2.21 (95% CI = 1.72-2.85). The adjusted OR for the anomalies related to cardiac septal closure was 3.34 (95% CI = 1.87-5.98). There were no significant associations with anomalies of other major organ systems. CONCLUSIONS Our study suggests that women prescribed NSAIDs during early pregnancy may be at a greater risk of having children with congenital anomalies, specifically cardiac septal defects.
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Affiliation(s)
- Benjamin Ofori
- Research Center, Sainte-Justine Hospital, Montreal, Quebec, Canada
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Burdan F, Szumilo J, Dudka J, Korobowicz A, Klepacz R. Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors. Braz J Med Biol Res 2006; 39:925-34. [PMID: 16862284 DOI: 10.1590/s0100-879x2006000700011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2005] [Accepted: 04/05/2006] [Indexed: 11/21/2022] Open
Abstract
Ventricular septal defects (VSDs) are common congenital abnormalities which have been reported to be associated with maternal fever and various environmental factors. The aim of the present study was to evaluate the effect of prenatal exposure to cyclooxygenase (COX) inhibitors on heart defects. A retrospective statistical analysis was performed using data collected in our laboratory during various teratological studies carried out on albino CRL:(WI)WUBR Wistar strain rats from 1997 to 2004. The observations were compared with concurrent and historic control data, as well as findings from other developmental toxicological studies with selective and nonselective COX-2 inhibitors. Despite the lack of significant differences in the frequency of VSDs between drug-exposed and control groups, statistical analysis by the two-sided Mantel-Haenszel test and historical control data showed a higher incidence of heart defects in offspring exposed to nonselective COX inhibitors (30.06/10,000). Unlike other specific inhibitors, aspirin (46.26/10,000) and ibuprofen (106.95/10,000) significantly increased the incidence of the VSD when compared with various control groups (5.38-19.72/10,000). No significant differences in length or weight were detected between fetuses exposed to COX inhibitors and born with VSD and non-malformed offsprings. However, a statistically significant increase of fetal body length and decrease of body mass index were found in fetuses exposed to COX inhibitors when compared with untreated control. We conclude that prenatal exposure to COX inhibitors, especially aspirin and ibuprofen, increased the incidence of VSDs in rat offspring but was not related to fetal growth retardation.
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Affiliation(s)
- F Burdan
- Experimental Teratology Unit, Human Anatomy Department, Medical University of Lublin, Poland.
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Østensen M, Khamashta M, Lockshin M, Parke A, Brucato A, Carp H, Doria A, Rai R, Meroni P, Cetin I, Derksen R, Branch W, Motta M, Gordon C, Ruiz-Irastorza G, Spinillo A, Friedman D, Cimaz R, Czeizel A, Piette JC, Cervera R, Levy RA, Clementi M, De Carolis S, Petri M, Shoenfeld Y, Faden D, Valesini G, Tincani A. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther 2006; 8:209. [PMID: 16712713 PMCID: PMC1526635 DOI: 10.1186/ar1957] [Citation(s) in RCA: 356] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.
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Affiliation(s)
- Monika Østensen
- Department of Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Switzerland.
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Affiliation(s)
- A Mortell
- Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland
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45
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Green RF, Moore C. Incorporating genetic analyses into birth defects cluster investigations: Strategies for identifying candidate genes. ACTA ACUST UNITED AC 2006; 76:798-810. [PMID: 17036308 DOI: 10.1002/bdra.20280] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Incorporating genetic analyses into birth defect cluster investigations may increase understanding of both genetic and environmental risk factors for the defect. Current constraints of most birth defect cluster investigations make candidate gene selection the most feasible approach. Here, we describe strategies for choosing candidate genes for such investigations, which will also be applicable to more general gene-environment studies. METHODS We reviewed publicly available web-based resources for selection of candidate genes and identification of risk factors, as well as publications on different strategies for candidate gene selection. RESULTS Candidate gene selection requires consideration of available gene-disease databases, previous epidemiological studies, animal model research, linkage and expression studies, and other resources. We describe general considerations for utilizing available resources, as well as provide an example of a search for candidate genes related to gastroschisis. CONCLUSIONS Available web resources could facilitate selection of candidate genes, but selection of optimal candidates will still require a strong understanding of genetics and the pathogenesis of the defect, as well as careful consideration of previous epidemiological studies.
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Affiliation(s)
- Ridgely Fisk Green
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
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46
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Burdan F. Comparison of developmental toxicity of selective and non-selective cyclooxygenase-2 inhibitors in CRL:(WI)WUBR Wistar rats – DFU and piroxicam study. Toxicology 2005; 211:12-25. [PMID: 15863244 DOI: 10.1016/j.tox.2005.02.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2004] [Revised: 01/31/2005] [Accepted: 02/01/2005] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cyclooxygenase (COX) inhibitors are one of the most often ingested drugs during pregnancy. Unlike general toxicity data, their prenatal toxic effects were not extensively studied before. The aim of the experiment was to evaluate the developmental toxicity of the non-selective (piroxicam) and selective (DFU; 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanon) COX-2 inhibitors. METHODS Drugs were separately, orally once daily dosed to pregnant rats from day 8 to 21 (GD1=plug day). Doses were set at 0.3, 3.0 and 30.0mg/kg for piroxicam and 0.2, 2.0 and 20.0mg/kg for DFU. Fetuses were delivered on GD 21 and routinely examined. Comprehensive clinical and developmental measurements were done. The pooled statistical analysis for ventricular septal (VSD) and midline (MD) defects was performed for rat fetuses exposed to piroxicam, selective and non-selective COX-2 inhibitor based on present and historic data. RESULTS Maternal toxicity, intrauterine growth retardation, and increase of external and skeletal variations were found in rats treated with the highest dose of piroxicam. Decrease of fetal length was the only signs of the DFU developmental toxicity observed in pups exposed to the highest compound dose. Lack of teratogenicity was found in piroxicam and DFU-exposed groups. Prenatal exposure to non-selective COX inhibitors increases the risk of VSD and MD when compared to historic control but not with selective COX-2 inhibitors. CONCLUSION Both selective and non-selective COX-2 inhibitors were toxic for rats fetuses when administered in the highest dose. Unlike DFU, piroxicam was also highly toxic to the dams. Prenatal exposure to selective COX-2 inhibitors does not increase the risk of ventricular septal and midline defects in rat when compared to non-selective drugs and historic control.
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Affiliation(s)
- Franciszek Burdan
- Experimental Teratology Unit of the Human Anatomy Department, 1 Raclawickie Ave., Medical University of Lublin, PL-20950 Lublin, Poland.
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Clark RL, White TEK, A Clode S, Gaunt I, Winstanley P, Ward SA. Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. ACTA ACUST UNITED AC 2005; 71:380-94. [PMID: 15617018 DOI: 10.1002/bdrb.20027] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The artemisinins are playing an increasingly important role in treating multidrug-resistant malaria. The artemisinin, artesunate, is currently in use in Southeast Asia and is advocated for use in Africa. In these areas, more than one million people die of malaria each year, with the highest mortality occurring in children and pregnant women. To test the developmental toxicity in ICH-compliant animal studies, embryofetal development studies were conducted in rats and rabbits treated with artesunate alone or a three-drug combination (CDA) consisting of chlorproguanil hydrochloride, Dapsone, and artesunate in the ratio 1.00:1.25:2.00. Developmental toxicity seen with CDA could be attributed to the administered dose of artesunate. The hallmark effect of artesunate exposure was a dramatic induction of embryo loss, apparent as abortions in rabbits and resorptions in both rats and rabbits. In addition, low incidences of cardiovascular malformations and a syndrome of skeletal defects were induced at or close to embryolethal doses of artesunate in both rats and rabbits. The cardiovascular malformations consisted of ventricular septal and vessel defects. The skeletal syndrome consisted of shortened and/or bent long bones and scapulae, misshapen ribs, cleft sternebrae, and incompletely ossified pelvic bones. These developmental effects were observed largely in the absence of any apparent maternal toxicity. The no or low adverse effect levels were in the range of 5 to 7 mg/kg/day artesunate. Encouragingly, no adverse drug-related developmental effects have been observed in a limited number of pregnant women (more than 100 first trimester and 600 second and third trimester) treated with artemisinins, primarily artesunate. Investigations of the mechanism of developmental toxicity are ongoing to attempt to determine whether rats and rabbits are more sensitive to artemisinins than humans.
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Affiliation(s)
- Robert L Clark
- Safety Assessment, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA.
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Burdan F, Szumilo J, Klepacz R, Dudka J, Korobowicz A, Tokarska E, Cendrowska-Pinkosz M, Madej B, Klepacz L. Gastrointestinal and hepatic toxicity of selective and non-selective cyclooxygenase-2 inhibitors in pregnant and non-pregnant rats. Pharmacol Res 2004; 50:533-43. [PMID: 15458776 DOI: 10.1016/j.phrs.2004.04.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2004] [Indexed: 11/22/2022]
Abstract
The aim of the study was to evaluate the toxicity of non-selective (tolmetin, ibuprofen and piroxicam) and selective (DFU) cyclooxygenase-2 inhibitors on pregnant and non-pregnant rats. The drugs were administered orally once (DFU, piroxicam) or three times (tolmetin, ibuprofen) a day from days 8 through 21 of gestation experiment in three doses. The initial dose was similar to the human antiinflammatory one and set as 8.5 mg/kg (tolmetin, ibuprofen), 0.3 mg/kg (piroxicam) and 0.2 mg/kg (DFU). The middle dose was increased 10 times and the highest one 100 times the initial dose. The highest dose for ibuprofen was set at 200mg/kg due to high mortality. On gestation/experimental day 21 animals were sacrificed, blood was collected and abdominal organs were taken for pathological examination. Activity of alanine and asparate aminotransferases and levels of total protein and urea were determined. Stomach, small and large intestines, and liver were grossly and histologically examined. Dose-dependent mortality, signs of gastrointestinal toxicity, and significant changes of biochemical parameters were found in groups exposed to non-selective COX inhibitors in both pregnant and non-pregnant rats. Mild regressive structural hepatic changes were observed. Significant decrease of protein level in non-pregnant rats treated with high DFU dose, and occasionally observed gastrointestinal changes were the only changes noted in groups exposed to the selective COX-2 inhibitor. Tolerability of non-selective COX inhibitors was lower in both pregnant and non-pregnant groups when compared with DFU. Insignificant mortality and histological changes were noted between pregnant and non-pregnant groups.
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Affiliation(s)
- Franciszek Burdan
- Experimental Teratology Unit of the Human Anatomy Department, Medical University of Lublin, 1 Spokojna Str., PL-20074 Lublin, Poland.
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Burdan F. Developmental toxicity evaluation of ibuprofen and tolmetin administered in triple daily doses to Wistar CRL:(WI)WUBR rats. ACTA ACUST UNITED AC 2004; 71:321-30. [PMID: 15505808 DOI: 10.1002/bdrb.20018] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Ibuprofen and tolmetin are popular non-steroidal anti-inflammatory drugs. Previous animal studies taken with single daily doses showed their good prenatal tolerability. However, since both cyclooxygenase (COX) inhibitors have a short half-life, the current report presents drug developmental effects after triple daily doses administration, as they are used in human. METHODS Drugs were separately, orally dosed to pregnant rats triple daily 8 hr apart from day 8 to 21 (GD=1-plug day). The total daily doses were set at 25.5, 255.0, and 600.0 mg/kg for ibuprofen and 25.5, 255.0, and 2550.0 mg/kg for tolmetin. Fetuses were delivered on GD 21 and routinely examined. Comprehensive clinical and developmental measurements were done. RESULTS Maternal toxicity and intrauterine growth retardation were found in groups exposed to the highest doses of both drugs. An increase of external variations was reported in groups exposed to the middle and highest dose of ibuprofen and to the highest dose of tolmetin. Skeletal variations were significantly different only in litters treated with the highest doses of the drugs. Pooled statistical analysis showed a higher incidence of midline and ventricular septal (VSD) defect in rat fetuses exposed to COX inhibitors when compared with historical control data. For ibuprofen, the influence on VSD was similar to aspirin. CONCLUSION Both COX inhibitors were toxic to dams in the highest doses evaluated, which caused a significantly greater incidence of intrauterine growth retardation and developmental variations.
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Affiliation(s)
- Franciszek Burdan
- Experimental Teratology Unit of the Human Anatomy Department, Medical University of Lublin, Lublin, Poland.
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