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Fatehfar S, Sameei P, Abdollahzade N, Chodari L, Saboory E, Roshan-Milani S. Maternal Treadmill Exercise and Zinc Supplementation Alleviate Prenatal Stress-Induced Cognitive Deficits and Restore Neurological Biomarkers in Offspring: A Study on Male Rats Aged 30 and 90 Days. Dev Neurobiol 2025; 85:e22964. [PMID: 40195087 DOI: 10.1002/dneu.22964] [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] [Received: 06/22/2024] [Revised: 02/25/2025] [Accepted: 03/04/2025] [Indexed: 04/09/2025]
Abstract
The detrimental effects of prenatal stress (PS) on offspring's neurological and behavioral outcomes are well documented. However, strategies to mitigate these effects are underexplored. This study examines whether prenatal zinc supplementation and treadmill exercise can modulate PS-induced cognitive impairments and neurobiological markers in young and adult male rat offspring, leveraging the established neuroprotective potential of both physical activity and zinc. Pregnant rats were divided into five groups: control, stress, stress + exercise, stress + zinc, and stress + exercise + zinc, with all rats except the control group subjected to restraint stress (gestational days 15-19). Pregnant rats in the exercise groups underwent forced exercise, whereas those in the zinc groups received oral zinc sulfate throughout the pregnancy. At postnatal days 30 and 90, the cognitive function of male offspring was evaluated using the Morris water maze (MWM) test, and the hippocampal gene expression levels of caspase-3, brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) were measured using reverse transcription-polymerase chain reaction (RT-PCR). PS impaired cognitive functions, increased caspase-3 expression, and decreased BDNF and GFAP expression levels in adult rats. Prenatal exercise was found to mitigate PS-induced cognitive deficits primarily through enhancing GFAP expression, whereas prenatal zinc improved PS-induced cognitive impairments mainly through reduced caspase-3 and increased BDNF expression. The combined effect of exercise and zinc was not additive on cognitive functions and biomarkers. Physical activity may alleviate PS-induced cognitive deficits by modulating astrocytic factors, whereas zinc may exert its effects by inhibiting apoptosis via a BDNF-dependent pathway. Further targeted research is necessary to confirm these relationships.
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Affiliation(s)
- Sina Fatehfar
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Parsa Sameei
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Naseh Abdollahzade
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Leila Chodari
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ehsan Saboory
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shiva Roshan-Milani
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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Sameei P, Fatehfar S, Abdollahzadeh N, Chodari L, Saboory E, Roshan-Milani S. The effects of forced exercise and zinc supplementation during pregnancy on prenatally stress-induced behavioral and neurobiological consequences in adolescent female rat offspring. Dev Psychobiol 2023; 65:e22411. [PMID: 37607889 DOI: 10.1002/dev.22411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 04/10/2023] [Accepted: 06/23/2023] [Indexed: 08/24/2023]
Abstract
Prenatal manipulations can lead to neurobehavioral changes in the offspring. In this study, individual and combined effects of forced exercise and zinc supplementation during pregnancy on prenatally restraint stress (PRS)-induced behavioral impairments, neuro-inflammatory responses, and oxidative stress have been investigated in adolescent female rat offspring. Pregnant rats were divided into five groups: control; restraint stress (RS); RS + exercise stress (RS + ES), RS + zinc supplementation (RS + Zn); and RS + ES + Zn. All the pregnant rats (except control) were exposed to RS from gestational days 15 to 19. Pregnant rats in ES groups were subjected to forced treadmill exercise (30 min/daily), and in Zn groups to zinc sulfate (30 mg/kg/orally), throughout the pregnancy. At postnatal days 25-27, anxiety-like and stress-coping behaviors were recorded, and the gene expressions of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and the concentration of total antioxidant capacity were measured in the prefrontal cortex. PRS significantly enhanced anxiety, generated passive coping behaviors, increased IL-1β and TNF-α expression, and decreased the antioxidant capacity. ES potentiated while zinc reversed PRS-induced behavioral impairments. Prenatal zinc also restored the anti-inflammatory and antioxidant capacity but had no effect on additive responses imposed by the combination of RS and ES. Suppression of PRS-induced behavioral and neurobiological impairments by zinc suggests the probable clinical importance of zinc on PRS-induced changes on child temperament.
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Affiliation(s)
- Parsa Sameei
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Sina Fatehfar
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Naseh Abdollahzadeh
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Leila Chodari
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Ehsan Saboory
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shiva Roshan-Milani
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Lee K, Mills Z, Cheung P, Cheyne JE, Montgomery JM. The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders. Pharmaceuticals (Basel) 2022; 16:ph16010001. [PMID: 36678498 PMCID: PMC9866730 DOI: 10.3390/ph16010001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly modulated by zinc, which is co-released with glutamate and concentrates in postsynaptic spines. Both NMDARs and zinc have been strongly linked to autism spectrum disorders (ASDs), suggesting that NMDARs are an important player in the beneficial effects observed with zinc in both animal models and children with ASDs. Significant evidence is emerging that these beneficial effects occur via zinc-dependent regulation of SHANK proteins, which form the backbone of the postsynaptic density. For example, dietary zinc supplementation enhances SHANK2 or SHANK3 synaptic recruitment and rescues NMDAR deficits and hypofunction in Shank3ex13-16-/- and Tbr1+/- ASD mice. Across multiple studies, synaptic changes occur in parallel with a reversal of ASD-associated behaviours, highlighting the zinc-dependent regulation of NMDARs and glutamatergic synapses as therapeutic targets for severe forms of ASDs, either pre- or postnatally. The data from rodent models set a strong foundation for future translational studies in human cells and people affected by ASDs.
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Estrada‐Ortiz N, Starokozhko V, van Steenwijk H, van der Heide C, Permentier H, van Heemskerk L, Prins GH, Heegsma J, Faber KN, Bressers S, Steiblen G, de Groot A, Groome S, van Miert E, Groothuis G, de Graaf IAM. Disruption of vitamin A homeostasis by the biocide tetrakis(hydroxymethyl) phosphonium sulphate in pregnant rabbits. J Appl Toxicol 2022; 42:1921-1936. [PMID: 35857281 PMCID: PMC9804500 DOI: 10.1002/jat.4364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 06/29/2022] [Accepted: 07/09/2022] [Indexed: 01/05/2023]
Abstract
The biocide tetrakis(hydroxymethyl)phosphonium sulphate (THPS) and other members of the tetrakis(hydroxymethyl) phosphonium salts (THPX) family are associated with liver toxicity in several mammalian species and teratogenicity in rabbits. Malformations include skeletal changes and abnormalities in eye development and are very similar to those seen with vitamin A deficiency or excess. For this reason, it was hypothesized that teratogenicity of THPS(X) might be attributed to disturbances in retinol availability and/or metabolism as a result of maternal toxicity, for example, either due to insufficient dietary intake by the mothers or due to liver toxicity. Therefore, in the present study, liver toxicity and vitamin A homeostasis were studied in pregnant rabbits that were exposed to 13.8 or 46.0 mg/kg THPS during organogenesis and in precision-cut liver slices of rats and rabbits exposed to 0-70 μM THPS. Results show that in vivo exposure to THPS leads to a marked reduction of food intake, increased plasma concentrations of γ-glutamytransferase, degenerative changes in the liver and to changes in retinoid content in liver and plasma in the rabbits during organogenesis. In addition, THPS, both in vivo and ex vivo, caused a change in expression of proteins related to vitamin A metabolism and transport. Together, these observations could explain the birth defects observed in earlier teratogenicity studies.
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Affiliation(s)
- Natalia Estrada‐Ortiz
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Viktoriia Starokozhko
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Hidde van Steenwijk
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Cor van der Heide
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Hjalmar Permentier
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Lisanne van Heemskerk
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Grietje Harmanna Prins
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Janette Heegsma
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medi‐cal Center GroningenGroningenThe Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of GroningenUniversity Medi‐cal Center GroningenGroningenThe Netherlands
| | | | - Guy Steiblen
- Solvay, Toxicological and Environmental Risk Assessment UnitGenasFrance
| | - Antoinette de Groot
- Solvay, Toxicological and Environmental Risk Assessment UnitBruxellesBelgium
| | | | - Erik van Miert
- Solvay, Toxicological and Environmental Risk Assessment UnitBruxellesBelgium
| | - Geny Groothuis
- Groningen Research Institute of Pharmacy (GRIP)University of GroningenGroningenThe Netherlands
| | - Inge Anne Maria de Graaf
- University Medical Center Groningen, Surgical Research LaboratoryUniversity of GroningenGroningenThe Netherlands,School of Science and EngineeringUniversity of GroningenGroningenThe Netherlands
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Alsufiani HM, Alkhanbashi AS, Laswad NAB, Bakhadher KK, Alghamdi SA, Tayeb HO, Tarazi FI. Zinc deficiency and supplementation in autism spectrum disorder and Phelan-McDermid syndrome. J Neurosci Res 2022; 100:970-978. [PMID: 35114017 DOI: 10.1002/jnr.25019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 12/02/2021] [Accepted: 01/07/2022] [Indexed: 01/05/2023]
Abstract
Approximately 1 in 36 children are diagnosed with autism spectrum disorder (ASD). The disorder is four times more common in males than in females. Zinc deficiency and mutations in SHANK2 and SHANK3 (members of a family of excitatory postsynaptic scaffolding proteins) are all risk factors that may contribute to the pathophysiology of the disease. The presence of shankopathies (loss of one copy of the SHANK3 gene) can lead to the development of Phelan-McDermid syndrome (PMDS)-a rare genetic disorder characterized by developmental delay, intellectual disability, poor motor tone, and ASD-like symptoms. We reviewed the relationship between zinc, ASD, and PMDS as well as the effect of zinc supplementation in improving symptoms of ASD and PMDS based on 22 studies published within 6 years (2015-2020). Zinc deficiency (assessed by either dietary intake, blood, hair, or tooth matrix) was shown to be highly prevalent in ASD and PMDS patients as well as in preclinical models of ASD and PMDS. Zinc supplements improved the behavioral deficits in animal models of ASD and PMDS. Clinical trials are still needed to validate the beneficial therapeutic effects of zinc supplements in ASD and PMDS patients.
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Affiliation(s)
- Hadeil M Alsufiani
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Alaa S Alkhanbashi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Norah A Bin Laswad
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khulood K Bakhadher
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shareefa A Alghamdi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Haythum O Tayeb
- Division of Neurology, Department of Internal Medicine, The Neuroscience Research Unit, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Frank I Tarazi
- Department of Psychiatry and Neuroscience, Harvard Medical School and McLean Hospital, Belmont, Massachusetts, USA
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Mousaviyan R, Davoodian N, Alizadeh F, Ghasemi-Kasman M, Mousavi SA, Shaerzadeh F, Kazemi H. Zinc Supplementation During Pregnancy Alleviates Lipopolysaccharide-Induced Glial Activation and Inflammatory Markers Expression in a Rat Model of Maternal Immune Activation. Biol Trace Elem Res 2021; 199:4193-4204. [PMID: 33400154 DOI: 10.1007/s12011-020-02553-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/22/2022]
Abstract
Maternal immune activation (MIA) model has been profoundly described as a suitable approach to study the pathophysiological mechanisms of neuropsychiatric disorders, including schizophrenia. Our previous study revealed that prenatal exposure to lipopolysaccharide (LPS) induced working memory impairments in only male offspring. Based on the putative role of prefrontal cortex (PFC) in working memory process, the current study was conducted to examine the long-lasting effect of LPS-induced MIA on several neuroinflammatory mediators in the PFC of adult male pups. We also investigated whether maternal zinc supplementation can alleviate LPS-induced alterations in this region. Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on gestation days 15/16 and supplemented with ZnSO4 (30 mg/kg) throughout pregnancy. At postnatal day 60, the density of both microglia and astrocyte cells and the expression levels of IL-6, IL-1β, iNOS, TNF-α, NF-κB, and GFAP were evaluated in the PFC of male pups. Although maternal LPS treatment increased microglia and astrocyte density, number of neurons in the PFC of adult offspring remained unchanged. These findings were accompanied by the exacerbated mRNA levels of IL-6, IL-1β, iNOS, TNF-α, NF-κB, and GFAP as well. Conversely, prenatal zinc supplementation alleviated the mentioned alterations induced by LPS. These findings support the idea that the deleterious effects of prenatal LPS exposure could be attenuated by zinc supplementation during pregnancy. It is of interest to suggest early therapeutic intervention as a valuable approach to prevent neurodevelopmental deficits, following maternal infection. Schematic diagram describing the experimental timeline. On gestation days (GD) 15 and 16, pregnant dams were administered with intraperitoneal injections of either LPS (0.5 mg/kg) or vehicle and supplemented with ZnSO4 (30 mg/kg) throughout pregnancy by gavage. The resulting offspring were submitted to qPCR, immunostaining, and morphological analysis at PND 60. Maternal zinc supplementation alleviated increased expression levels of inflammatory mediators and microglia and astrocyte density induced by LPS in the PFC of treated offspring. PND postnatal day, PFC prefrontal cortex.
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Affiliation(s)
- Ronak Mousaviyan
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nahid Davoodian
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
- Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Faezeh Alizadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Neuroscience Reesearch Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Seyed Abdollah Mousavi
- Pathology Department, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fatemeh Shaerzadeh
- Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL, 32610, USA
| | - Haniyeh Kazemi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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Zinc, but not paracetamol, prevents depressive-like behavior and sickness behavior, and inhibits interferon-gamma and astrogliosis in rats. Brain Behav Immun 2020; 87:489-497. [PMID: 32006614 DOI: 10.1016/j.bbi.2020.01.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/20/2019] [Accepted: 01/28/2020] [Indexed: 12/12/2022] Open
Abstract
Considering all mental and addictive disorders, depression is the most responsible for years of life lost due to premature mortality and disability. Antidepressant drugs have limited effectiveness. Depression can be triggered by immune/inflammatory factors. Zinc and paracetamol interfere with immune system and have demonstrated beneficial effects on depression treatment when administered concomitant with antidepressant drugs. The objective of this study was to test zinc and/or paracetamol as treatments of depressive-like behavior, sickness behavior, and anxiety in rats, as well as to understand the central and peripheral mechanisms involved. Sickness behavior and depressive-like behavior were induced in rats with repetitive lipopolysaccharide (LPS, 1 mg/kg for two consecutive days) administrations. Rats received zinc and/or paracetamol for three consecutive days. Sickness behavior (daily body weight and open field general activity); anxiety (light-dark test); depressive-like/antidepressant behavior (forced swim test); plasma corticosterone and interferon (IFN)-gamma levels; and glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH) brain expression were evaluated. LPS induced sickness behavior and depressive-like behavior, as well as elevated IFN-gamma levels and increased GFAP expression. Zinc prevented both behavioral and biochemical impairments. Paracetamol and zinc + paracetamol association induced only slight beneficial effects. Anxiety, corticosterone, and TH do not seem be related with depression and the other behavioral and neuroimmune changes. In conclusion, zinc treatment was beneficial for sickness behavior and depressive-like behavior without concomitant administration of antidepressants. IFN-gamma and GFAP were linked with the expression of sickness behavior and depressive-like behavior and were also involved with the antidepressant effects. Therefore, zinc, IFN-gamma, and GFAP pathways should be considered for depression treatment.
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Alizadeh F, Davoodian N, Kazemi H, Ghasemi-Kasman M, Shaerzadeh F. Prenatal zinc supplementation attenuates lipopolysaccharide-induced behavioral impairments in maternal immune activation model. Behav Brain Res 2019; 377:112247. [PMID: 31545978 DOI: 10.1016/j.bbr.2019.112247] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/05/2019] [Accepted: 09/16/2019] [Indexed: 11/16/2022]
Abstract
Maternal infection during pregnancy is considered a key risk factor for developing schizophrenia in offspring. There is evidence that maternal exposure to infectious agents is associated with fetal zinc deficiency. Due to the essential role of zinc in brain function and development, in the present study, we activated maternal immune system using lipopolysaccharide (LPS) as a model of schizophrenia to examine whether zinc supplementation throughout pregnancy can reverse LPS-induced deleterious effects. To test the hypothesis, pregnant rats were treated with intraperitoneal injection of either saline or LPS (0.5 mg/kg) at gestational day 15 and 16, and zinc supplementation (30 mg/kg) was administered throughout pregnancy by gavage. At postnatal day 60, Y-maze was used to evaluate working memory of offspring. Moreover, the expression levels of catechol O-methyltransferase (COMT) and glutamate decarboxylase 67 (GAD67) were measured in the frontal cortex of the brain samples. Only male offspring prenatally exposed to LPS showed a significant impairment in working memory. In addition, prenatal LPS exposure causes a moderate decrease in GAD67 expression level in the male pups, while COMT expression was found unchanged. Interestingly, zinc supplementation restored the alterations in working memory as well as GAD67 mRNA level in the male rats. No alteration was detected for neither working memory nor COMT/GAD67 genes expression in female offspring. This study demonstrates that zinc supplementation during pregnancy can attenuate LPS-induced impairments in male pups. These results support the idea to consume zinc supplementation during pregnancy to limit neurodevelopmental deficits induced by infections in offspring.
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Affiliation(s)
- Faezeh Alizadeh
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nahid Davoodian
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Haniyeh Kazemi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Maryam Ghasemi-Kasman
- Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Fatemeh Shaerzadeh
- Department of Neuroscience, University of Florida College of Medicine and McKnight Brain Institute, Gainesville, FL, 32610, USA
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Tellez-Merlo G, Morales-Medina JC, Camacho-Ábrego I, Juárez-Díaz I, Aguilar-Alonso P, de la Cruz F, Iannitti T, Flores G. Prenatal immune challenge induces behavioral deficits, neuronal remodeling, and increases brain nitric oxide and zinc levels in the male rat offspring. Neuroscience 2019; 406:594-605. [DOI: 10.1016/j.neuroscience.2019.02.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 12/11/2018] [Accepted: 02/12/2019] [Indexed: 12/20/2022]
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Cezar LC, Kirsten TB, da Fonseca CCN, de Lima APN, Bernardi MM, Felicio LF. Zinc as a therapy in a rat model of autism prenatally induced by valproic acid. Prog Neuropsychopharmacol Biol Psychiatry 2018; 84:173-180. [PMID: 29481896 DOI: 10.1016/j.pnpbp.2018.02.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 02/05/2018] [Accepted: 02/17/2018] [Indexed: 01/18/2023]
Abstract
Autism is characterized by numerous behavioral impairments, such as in communication, socialization and cognition. Recent studies have suggested that valproic acid (VPA), an anti-epileptic drug with teratogenic activity, is related to autism. In rodents, VPA exposure during pregnancy induces autistic-like effects. Exposure to VPA may alter zinc metabolism resulting in a transient deficiency of zinc. Therefore, we selected zinc as a prenatal treatment to prevent VPA-induced impairments in a rat model of autism. Wistar female rats received either saline solution or VPA (400 mg/kg, i.p) on gestational day (GD) 12.5. To test the zinc supplementation effect, after 1 h of treatment with saline or VPA, a dose of zinc (2 mg/kg, s.c.) was injected. The offspring were tested for abnormal communication behaviors with an ultrasound vocalization task on postnatal day (PND) 11, repetitive behaviors and cognitive ability with a T-maze task on PND 29, and social interaction with a play behavior task on PND 30. Tyrosine hydroxylase protein (TH) expression was evaluated in the striatum. Prenatal VPA decreased ultrasonic vocalization, induced repetitive/restricted behaviors and cognitive inflexibility, impaired socialization, and reduced striatal TH levels compared with control group. Zinc treatment reduced VPA-induced autistic-like behaviors. However, we found no evidence of an effect of zinc on the VPA-induced reduction in TH expression. The persistence of low TH expression in the VPA-Zn group suggests that Zn-induced behavioral improvement in autistic rats may not depend on TH activity.
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Affiliation(s)
- Luana Carvalho Cezar
- University of São Paulo, School of Veterinary Medicine, Department of Pathology, Sao Paulo, Brazil.
| | - Thiago Berti Kirsten
- Paulista University, Environmental and Experimental Pathology, Sao Paulo, Brazil
| | | | | | | | - Luciano Freitas Felicio
- University of São Paulo, School of Veterinary Medicine, Department of Pathology, Sao Paulo, Brazil
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Nuttall JR. The plausibility of maternal toxicant exposure and nutritional status as contributing factors to the risk of autism spectrum disorders. Nutr Neurosci 2015; 20:209-218. [DOI: 10.1080/1028415x.2015.1103437] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Johnathan R. Nuttall
- Departments of Nutrition and Environmental Toxicology, University of California Davis, Davis, CA, USA
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Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring. PLoS One 2015. [PMID: 26218250 PMCID: PMC4517817 DOI: 10.1371/journal.pone.0134565] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.
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Maternal zinc deficiency during pregnancy elevates the risks of fetal growth restriction: a population-based birth cohort study. Sci Rep 2015; 5:11262. [PMID: 26053136 PMCID: PMC4459238 DOI: 10.1038/srep11262] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 05/20/2015] [Indexed: 02/07/2023] Open
Abstract
We investigated the association between maternal zinc level during pregnancy and the risks of low birth weight (LBW) and small for gestational age (SGA) infants in a large population-based birth cohort study. In this study, 3187 pregnant women were recruited. For serum zinc level, 2940 pregnant women were sufficient (≥56 μg/dL) and 247 deficient (<56 μg/dL). Of interest, 7.3% newborns were with LBW among subjects with low zinc level (RR: 3.48; 95% CI: 2.03, 5.96; P < 0.001). Adjusted RR for LBW was 3.41 (95% CI: 1.97, 5.91; P < 0.001) among subjects with low zinc level. Moreover, 15.0% newborns were with SGA among subjects with low zinc level (RR: 1.98; 95% CI: 1.36, 2.88; P < 0.001). Adjusted RR for SGA was 1.93 (95% CI: 1.32, 2.82; P < 0.001) among subjects with low zinc level. A nested case-control study within above cohort showed that maternal serum zinc level was lower in SGA cases as compared with controls. By contrast, maternal serum C-reactive protein, TNF-α and IL-8 levels were significantly higher in SGA cases than that of controls. Moreover, nuclear NF-κB p65 was significantly up-regulated in placentas of SGA cases as compared with controls. Taken together, maternal zinc deficiency during pregnancy elevates the risks of LBW and SGA infants.
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14
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Prenatal zinc prevents communication impairments and BDNF disturbance in a rat model of autism induced by prenatal lipopolysaccharide exposure. Life Sci 2015; 130:12-7. [DOI: 10.1016/j.lfs.2015.02.027] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 02/11/2015] [Accepted: 02/26/2015] [Indexed: 12/21/2022]
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Kirsten TB, Galvão MC, Reis-Silva TM, Queiroz-Hazarbassanov N, Bernardi MM. Zinc prevents sickness behavior induced by lipopolysaccharides after a stress challenge in rats. PLoS One 2015; 10:e0120263. [PMID: 25775356 PMCID: PMC4361539 DOI: 10.1371/journal.pone.0120263] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
Sickness behavior is considered part of the specific beneficial adaptive behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, sickness behavior should be momentarily abrogated to prioritize survival behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced sickness behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced sickness behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent sickness behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.
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Affiliation(s)
- Thiago B. Kirsten
- Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil
- Environmental and Experimental Pathology, Paulista University, São Paulo, Brazil
| | - Marcella C. Galvão
- Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil
| | - Thiago M. Reis-Silva
- Department of Pathology, School of Veterinary Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Maria M. Bernardi
- Environmental and Experimental Pathology, Paulista University, São Paulo, Brazil
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Kim J, Kim S, Jeon S, Hui Z, Kim Y, Im Y, Lim W, Kim C, Choi H, Kim O. Anti-inflammatory effects of zinc in PMA-treated human gingival fibroblast cells. Med Oral Patol Oral Cir Bucal 2015; 20:e180-7. [PMID: 25662537 PMCID: PMC4393980 DOI: 10.4317/medoral.19896] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 10/21/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Abnormal cellular immune response has been considered to be responsible for oral lesions in recurrent aphthous stomatitis. Zinc has been known to be an essential nutrient metal that is necessary for a broad range of biological activities including antioxidant, immune mediator, and anti-inflammatory drugs in oral mucosal disease. The objective of this study was to investigate the effects of zinc in a phorbol-12-myristate-13-acetate (PMA)-treated inflammatory model on human gingival fibroblast cells (hGFs). STUDY DESIGN Cells were pre-treated with zinc chloride, followed by PMA in hGFs. The effects were assessed on cell viability, cyclooxygenease-1,2(COX-1,2) protein expression, PGE2 release, ROS production and cytokine release, Results: The effects were assessed on cell viability, COX1/2 protein expression, PGE2 release, ROS production, cytokine release. The results showed that, in the presence of PMA, zinc treatment leads to reduce the production of ROS, which results in decrease of COX-2 expression and PGE2 release. CONCLUSIONS Thus, we suggest that zinc treatment leads to the mitigation of oral inflammation and may prove to be an alternative treatment for recurrent aphthous stomatitis.
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Affiliation(s)
- Jisun Kim
- Department of Oral Pathology, Dental Science Research Institute and Medical Research, Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Bug-Gu, Gwangju, 500-757, Korea,
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Pujol Lopez Y, Steinbusch HWM, Rutten B, Kenis G, van den Hove DL, Myint AM. Effects of subcutaneous LPS injection on gestational length and intrauterine and neonatal mortality in mice. Neuroimmunomodulation 2015; 22:274-8. [PMID: 25613151 DOI: 10.1159/000368554] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 09/18/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Infection during pregnancy can predispose offspring to develop various psychiatric disorders such as depression in later life. In order to investigate the potential mechanisms underlying these associations, animal models of maternal infection have been employed. As such, lipopolysaccharide (LPS) has been commonly used to mimic a bacterial infection in pregnant mice. OBJECTIVE The original aim of our study was to investigate the effects of different doses of subcutaneous LPS administration on affective behavior in adult mouse offspring. In the present paper, however, we report that subcutaneous LPS administration has a profound impact on gestational length, litter size, and perinatal mortality in the offspring, even at a relatively low dose. METHODS Pregnant mice were randomly divided into 3 groups, receiving either a high (2 mg/kg) or a low (0.5 mg/kg) dose of LPS or phosphate-buffered saline by means of subcutaneous injection. Subsequently, the effects on gestational length, litter size, and perinatal mortality in the offspring were assessed. RESULTS After subcutaneous injection with a high dose of LPS, we observed a significant decrease in gestational length and an increase in neonatal mortality. When the low dose was administered, a tendency towards a reduced litter size was observed, most likely reflecting increased intrauterine mortality in response to prenatal maternal LPS exposure. CONCLUSIONS We showed that subcutaneous administration of 2 mg/kg LPS to pregnant mice in the last phase of gestation should be avoided because of high offspring mortality rates, whereas subcutaneous injection of 0.5 mg/kg LPS seems to result in reabsorption of the fetuses.
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Affiliation(s)
- Yara Pujol Lopez
- School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre+, Maastricht, The Netherlands
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Galvão MC, Chaves-Kirsten GP, Queiroz-Hazarbassanov N, Carvalho VM, Bernardi MM, Kirsten TB. Prenatal zinc reduces stress response in adult rat offspring exposed to lipopolysaccharide during gestation. Life Sci 2015; 120:54-60. [DOI: 10.1016/j.lfs.2014.10.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 10/14/2014] [Accepted: 10/21/2014] [Indexed: 12/31/2022]
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Zhao M, Chen YH, Chen X, Dong XT, Zhou J, Wang H, Wu SX, Zhang C, Xu DX. Folic acid supplementation during pregnancy protects against lipopolysaccharide-induced neural tube defects in mice. Toxicol Lett 2014; 224:201-8. [DOI: 10.1016/j.toxlet.2013.10.021] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 10/18/2013] [Accepted: 10/21/2013] [Indexed: 01/23/2023]
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20
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Chen YH, Zhao M, Chen X, Zhang Y, Wang H, Huang YY, Wang Z, Zhang ZH, Zhang C, Xu DX. Zinc supplementation during pregnancy protects against lipopolysaccharide-induced fetal growth restriction and demise through its anti-inflammatory effect. THE JOURNAL OF IMMUNOLOGY 2012; 189:454-63. [PMID: 22661087 DOI: 10.4049/jimmunol.1103579] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
LPS is associated with adverse developmental outcomes, including preterm delivery, fetal death, teratogenicity, and intrauterine growth restriction (IUGR). Previous reports showed that zinc protected against LPS-induced teratogenicity. In the current study, we investigated the effects of zinc supplementation during pregnancy on LPS-induced preterm delivery, fetal death and IUGR. All pregnant mice except controls were i.p. injected with LPS (75 μg/kg) daily from gestational day (GD) 15 to GD17. Some pregnant mice were administered zinc sulfate through drinking water (75 mg elemental Zn per liter) throughout the pregnancy. As expected, an i.p. injection with LPS daily from GD15 to GD17 resulted in 36.4% (4/11) of dams delivered before GD18. In dams that completed the pregnancy, 63.2% of fetuses were dead. Moreover, LPS significantly reduced fetal weight and crown-rump length. Of interest, zinc supplementation during pregnancy protected mice from LPS-induced preterm delivery and fetal death. In addition, zinc supplementation significantly alleviated LPS-induced IUGR and skeletal development retardation. Further experiments showed that zinc supplementation significantly attenuated LPS-induced expression of placental inflammatory cytokines and cyclooxygenase-2. Zinc supplementation also significantly attenuated LPS-induced activation of NF-κB and MAPK signaling in mononuclear sinusoidal trophoblast giant cells of the labyrinth zone. It inhibited LPS-induced placental AKT phosphorylation as well. In conclusion, zinc supplementation during pregnancy protects against LPS-induced fetal growth restriction and demise through its anti-inflammatory effect.
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Affiliation(s)
- Yuan-Hua Chen
- Department of Toxicology, Anhui Medical University, Hefei 230032, China
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Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice. Infect Immun 2012; 80:2121-32. [PMID: 22473610 DOI: 10.1128/iai.06295-11] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress, and subsequent apoptosis of placental trophoblasts. PCR array analysis of 84 oxidative stress-related genes demonstrated that 27 genes were upregulated at least 2-fold and that 9 genes were downregulated at least 2-fold in the T. gondii infection group compared with levels in the control group. The expression of NADPH oxidase 1 (Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress (ERS) markers, followed by cleavage of caspase-12, activation of ASK1/JNK, and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway, and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The upregulation of Nox1 was contact dependent and preceded the increase in levels of ERS markers and the activation of the proapoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase-12, CHOP, and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts.
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Prenatal exposure to lipopolysaccharide results in neurodevelopmental damage that is ameliorated by zinc in mice. Brain Behav Immun 2012; 26:326-36. [PMID: 22024135 DOI: 10.1016/j.bbi.2011.10.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Revised: 09/22/2011] [Accepted: 10/09/2011] [Indexed: 01/24/2023] Open
Abstract
There is converging evidence that during pregnancy a maternal immune response to infection can cause neurodevelopmental damage. Lipopolysaccharide (LPS)-mediated induction of metallothionein (MT) and subsequent hypozincaemia has been linked to fetal brain damage. Our group has demonstrated that Zn, when co-administered with LPS in early pregnancy in mice (gestation day (GD) 8), prevents fetal malformations and neurodevelopmental deficits in offspring. Others demonstrating fetal brain lesions have administered LPS much later in gestation (after GD 16), when the influence of LPS-mediated MT-induction on maternal plasma Zn levels, and the effect of Zn co-administration with LPS, are unknown. The aims of this study are firstly to examine whether LPS causes MT induction and maternal hypozincaemia in mid-to-late pregnancy, and secondly to determine if histochemical markers of inflammatory damage in fetal brain are affected by LPS and whether this damage can be alleviated with Zn treatment. Pregnant mice were injected with LPS (5 mg/kgbodywt.) or saline vehicle on GD 16 and then humanely killed at 8, 16 and 24 h for Zn and MT measurements, or concomitantly injected subcutaneously with Zn (2 mg/kgbodywt.) or saline and then killed on GD 18 and immunohistochemistry performed on fetal brain. Maternal hepatic MT was markedly induced after LPS-challenge and this was associated with a 38% reduction in maternal plasma Zn concentrations. Coincidentally, the fetuses of LPS-treated dams showed astrogliosis, extensive cell death and an increased number of cells producing TNF-α which was prevented with concomitant Zn treatment. These results support the premise that in mid-to-late pregnancy, an infection-mediated activation of a maternal immune response can cause MT induction that redistributes Zn in the mother, restricting fetal Zn supply, causing neurodevelopmental damage.
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23
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Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development. ACTA ACUST UNITED AC 2010; 89:313-25. [DOI: 10.1002/bdrb.20264] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Boksa P. Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav Immun 2010; 24:881-97. [PMID: 20230889 DOI: 10.1016/j.bbi.2010.03.005] [Citation(s) in RCA: 469] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 03/09/2010] [Accepted: 03/10/2010] [Indexed: 12/31/2022] Open
Abstract
Epidemiological studies with human populations indicate associations between maternal infection during pregnancy and increased risk in offspring for central nervous system (CNS) disorders including schizophrenia, autism and cerebral palsy. Since 2000, a large number of studies have used rodent models of systemic prenatal infection or prenatal immune activation to characterize changes in brain function and behavior caused by the prenatal insult. This review provides a comprehensive summary of these findings, and examines consistencies and trends across studies in an effort to provide a perspective on our current state of understanding from this body of work. Results from these animal modeling studies clearly indicate that prenatal immune activation can cause both acute and lasting changes in behavior and CNS structure and function in offspring. Across laboratories, studies vary with respect to the type, dose and timing of immunogen administration during gestation, species used, postnatal age examined and specific outcome measure quantified. This makes comparison across studies and assessment of replicability difficult. With regard to mechanisms, evidence for roles for several acute mediators of effects of prenatal immune activation has emerged, including circulating interleukin-6, increased placental cytokines and oxidative stress in the fetal brain. However, information required to describe the complete mechanistic pathway responsible for acute effects of prenatal immune activation on fetal brain is lacking, and no studies have yet addressed the issue of how acute prenatal exposure to an immunogen is transduced into a long-term CNS change in the postnatal animal. Directions for further research are discussed.
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Affiliation(s)
- Patricia Boksa
- Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, Verdun, Quebec, Canada.
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25
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Chen X. Protective effects of quercetin on liver injury induced by ethanol. Pharmacogn Mag 2010; 6:135-41. [PMID: 20668581 PMCID: PMC2900062 DOI: 10.4103/0973-1296.62900] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2009] [Revised: 01/08/2010] [Accepted: 05/05/2010] [Indexed: 01/01/2023] Open
Abstract
Quercetin, a natural compound of multiple origins, has broad biopharmacological effects, such as antioxidant, directly scavenging free radical, and hepatoprotectivity effects. This study is designed to investigate the interveneous effect of quercetin on liver injury induced by ethanol in rats. The rats that were orally treated with 50% ethanol for continuous ten days, which resulted in cell necrosis, fibrosis and inflammatory infiltration, were included in this study. Higher contents of AST, ALT ADH, γ-GT, TG in plasma and MDA in liver tissue, and lower content of GSH in liver tissue were highlighted in ethanol-treated rats when compared with healthy ones. The levels of cytokines such as IL-1β, IL-1, IL-6, IL-8, and TNF-α in rats plasma were also significantly enhanced, and level of IL-10 was obviously lowered through ethanol treatment. By preventive and synchronism treatment with quercetin for fourteen days, the contents of AST, ALT ADH, γ-GT, TG and MDA, and levels of IL-1β, IL-1, IL-6, IL-8, and TNF-α were significantly reduced, whereas GSH and level of IL-10 were obviously increased. It may be deduced that quercetin, by multiple mechanisms interplay, demonstrated somewhat protective effect on liver injury induced by ethanol in rats.
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Affiliation(s)
- Xi Chen
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, 151 Malianwa North Road, Haidian District, Beijing 100193, PR China
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26
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Peculiarities of the Molecular Structure and Functions of Metallothioneins in the Central Nervous System. NEUROPHYSIOLOGY+ 2010. [DOI: 10.1007/s11062-010-9113-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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27
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Meyer U, Feldon J. Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol 2010; 90:285-326. [DOI: 10.1016/j.pneurobio.2009.10.018] [Citation(s) in RCA: 261] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2009] [Revised: 09/30/2009] [Accepted: 10/14/2009] [Indexed: 12/17/2022]
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Osswald J, Carvalho AP, Claro J, Vasconcelos V. Effects of cyanobacterial extracts containing anatoxin-a and of pure anatoxin-a on early developmental stages of carp. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2009; 72:473-8. [PMID: 18640721 DOI: 10.1016/j.ecoenv.2008.05.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Revised: 05/19/2008] [Accepted: 05/23/2008] [Indexed: 05/23/2023]
Abstract
This study compares the effects of pure anatoxin-a and cyanobacterial extracts of an anatoxin-a producing strain on early stages of development of carp. Carp eggs were exposed from 2:30 h to 4 days post-fertilization to different ecologically relevant concentrations of anatoxin-a, provided as pure toxin or contained in the cyanobacterial extracts. Data on time to mortality, mortality rate, time to hatching, hatching rate, skeletal malformations rate, and larval standard length were registered until 8 days post-fertilization. At any tested concentration of anatoxin-a, the pure toxin was almost harmless to carp early stages of development, contrarily to cell extracts that were highly toxic. Only an adverse effect on the larval length was found at the highest concentration of pure toxin, while increasing concentrations of cell extracts caused increasing adverse effects in all the analyzed parameters. Anatoxin-a producing cyanobacteria should be regarded as putative modulators of aquatic ecosystems communities.
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Affiliation(s)
- J Osswald
- Interdisciplinary Centre of Marine and Environmental Research (CIMAR/CIIMAR), University of Porto, Rua dos Bragas 289, 4050-123 Porto, Portugal
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DeSesso JM, Watson RE, Keen CL, Hazelden KP, Haws LC, Li AA. Analysis and integration of developmental neurotoxicity and ancillary data into risk assessment: a case study of dimethoate. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2009; 72:94-109. [PMID: 19034799 DOI: 10.1080/15287390802477452] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Dimethoate is an organophosphate (OP) pesticide used to control a wide variety of insects on agricultural crops and ornamentals. To ensure that dimethoate is used safely, it is important to determine exposure levels that protect against adverse effects at all life stages, including the developing fetus, infant, and child. Based on an analysis of a developmental neurotoxicity (DNT) study, a cholinesterase (ChE) sensitivity study, a cross-fostering study, and several single- and multigenerational reproductive toxicity studies, two potential critical endpoints for dimethoate were identified: brain ChE inhibition (ChEI) in adult females, and pup mortality. An initial evaluation concluded that pup mortality was a preferable endpoint, based on an increased number of pup deaths born to dams dosed with > or =3 mg/kg dimethoate via oral gavage. Closer examination, however, revealed that the pup deaths were clustered in a small number of litters in which the dams providing postnatal care exhibited maternal care deficits. When the data were analyzed using the dam as the unit of statistical significance, a significant increase in the average litter proportion of pup deaths was observed only when the dams were dosed postnatally with 6 mg/kg dimethoate while they were raising the pups. Gestational exposure (i.e., during pregnancy only) to 6 mg/kg dimethoate exerted no effect on pup survival. This leads to the conclusion that it is postnatal exposure of the nursing dams that is associated with pup mortality. Furthermore, a previous benchmark dose (BMD) meta-analysis approach revealed that BMDL(10) for adult females (the lower 95% bound of the dose resulting in a 10% reduction in the parameter of interest) for ChEI was > 3-fold lower than the BMDL(10) for pup mortality (0.19 and 0.68 mg/kg, respectively). Overall, this study underscores the importance of using the dam as the unit of statistical significance when assessing data collected in the perinatal period, and it is concluded that adult brain ChEI is the correct critical endpoint for assessing risk of dimethoate toxicity.
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Zhao L, Chen YH, Wang H, Ji YL, Ning H, Wang SF, Zhang C, Lu JW, Duan ZH, Xu DX. Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice. Toxicol Sci 2008; 103:149-57. [PMID: 18281254 DOI: 10.1093/toxsci/kfn027] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including embryonic resorption, fetal death and growth retardation, and preterm delivery. In the present study, we showed that an ip injection with LPS daily from gestational day (gd) 8 to gd 12 resulted in the incidence of external malformations. The highest incidence of malformed fetuses was observed in fetuses from dams exposed to 20 microg/kg LPS, in which 34.9% of fetuses per litter were externally malformed. In addition, 17.4% of fetuses per litter in 30 microg/kg group and 12.5% of fetuses per litter in 10 microg/kg group were externally malformed. Importantly, external malformations were also observed in fetuses from dams exposed to only two doses of LPS (20 microg/kg, ip) on gd 8, in which 76.5% (13/17) of litters and 39.1% of fetuses per litter were affected. LPS-induced teratogenicity seemed to be associated with oxidative stress in fetal environment, measured by lipid peroxidation, nitrotyrosine residues, and glutathione (GSH) depletion in maternal liver, embryo, and placenta. alpha-Phenyl-N-t-butylnitrone (PBN, 100 mg/kg, ip), a free radical spin-trapping agent, abolished LPS-induced lipid peroxidation, nitrotyrosine residues, and GSH depletion. Consistent with its antioxidant effects, PBN decreased the incidence of external malformations. Taken together, these results suggest that reactive oxygen species might be, at least partially, involved in LPS-induced teratogenesis.
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Affiliation(s)
- Lei Zhao
- Department of Toxicology, Anhui Medical University, Hefei 230032, China
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Hill DA, Reese CT, Clarke D, Martin TV. Exposure to chlorinated biphenyls causes polymorphonucleocytes to induce progenitor cell toxicity in culture. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2007; 3:23-30. [PMID: 16823073 PMCID: PMC3785676 DOI: 10.3390/ijerph2006030003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Progenitor cells (PC) are the precursors for many developmental structures and are sensitive to a variety of toxic agents including the environmental contaminants, polychlorinated biphenyls (PCBs). The mechanism(s) that contributes to the development of PCB-induced progenitor cell-related fetotoxicities are not completely understood. However, several studies have demonstrated an important role for neutrophils (polymorphonucleocytes) in the development of PCB induced toxicities. Our recent findings have indicated that conditioned medium collected from PC (CMPC) exposed to a single dose of the PCB mixture, Aroclor 1248, can activate isolated neutrophil populations. Because of our recent findings, this study was conducted to determine if conditioned medium from PC treated with a PCB mixture causes neutrophils to injure PC in culture. Isolated PC were cultured and treated with different concentrations of Aroclor 1248 for 24 hours. The resulting PC-derived conditioned media was collected and its affect on neutrophil activity was analyzed. Conditioned medium from PC treated with Aroclor 1248 was chemotactic for neutrophils. The conditioned medium from Aroclor 1248 treated-PC also stimulated neutrophils to release super oxide anion, cathepsin G and elastase into culture medium. Furthermore, the conditioned medium from Aroclor 1248 treated- PC was able to stimulate neutrophils to cause progenitor cell toxicity in co-cultures. The conditioned medium from Aroclor 1248 treated-PC was not toxic to individual neutrophil cultures or PC cultures. Moreover, the addition of a protease inhibitor to the co-cultures containing neutrophils and PC, afforded protection against neutrophil-induced cytotoxicity of PC. These data suggest that a PCB mixture can cause progenitor cells to produce a factor(s) that activates neutrophils and stimulates them to damage PC populations in culture.
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Affiliation(s)
- Dwayne A Hill
- Department of Biology, School of Computer, Mathematical and Natural Sciences, Morgan State University, Baltimore, Maryland 21251, USA.
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Bolkent S, Arda-Pirincci P, Bolkent S, Yanardag R, Tunali S, Yildirim S. Influence of zinc sulfate intake on acute ethanol-induced liver injury in rats. World J Gastroenterol 2006; 12:4345-51. [PMID: 16865776 PMCID: PMC4087745 DOI: 10.3748/wjg.v12.i27.4345] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of metallothionein and proliferating cell nuclear antigen (PCNA) on the morphological and biochemical effects of zinc sulfate in ethanol-induced liver injury.
METHODS: Wistar albino rats were divided into four groups. Group I; intact rats, group II; control rats given only zinc, group III; animals given absolute ethanol, group IV; rats given zinc and absolute ethanol. Ethanol-induced injury was produced by the 1 mL of absolute ethanol, administrated by gavage technique to each rat. Animals received 100 mg/kg per day zinc sulfate for 3 d 2 h prior to the administration of absolute ethanol.
RESULTS: Increases in metallothionein immunoreactivity in control rats given only zinc and rats given zinc and ethanol were observed. PCNA immunohistochemistry showed that the number of PCNA-positive hepatocytes was increased significantly in the livers of rats administered ethanol + zinc sulfate. Acute ethanol exposure caused degenerative morphological changes in the liver. Blood glutathione levels decreased, serum alkaline phosphatase and aspartate transaminase activities increased in the ethanol group when compared to the control group. Liver glutathione levels were reduced, but lipid peroxidation increased in the livers of the group administered ethanol as compared to the other groups. Administration of zinc sulfate in the ethanol group caused a significant decrease in degenerative changes, lipid peroxidation, and alkaline phosphatase and aspartate transaminase activities, but an increase in liver glutathione.
CONCLUSION: Zinc sulfate has a protective effect on ethanol-induced liver injury. In addition, cell proliferation may be related to the increase in metallothionein immunoreactivity in the livers of rats administered ethanol + zinc sulfate.
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Affiliation(s)
- Sema Bolkent
- Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Cerrahpasa 34098, Istanbul, Turkey.
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Abstract
Maternal infection during the first trimester of pregnancy has been associated with preterm birth, spontaneous abortion, growth retardation, and congenital anomalies. Previously, our group has shown that subcutaneous injection of zinc prevents endotoxin [lipopolysaccharide (LPS)]-induced teratogenicity. The purpose of this study was to investigate whether increasing or decreasing dietary zinc alters the teratogenic effects of LPS. Female C57BL6 mice were mated and fed diets containing 5, 35, or 100 mg/kg zinc. On gestational day (GD) 8, pregnant dams were injected with either LPS (0.5 mg/kg s.c.) or saline and killed on GD18. LPS-treated fetuses from dams fed 5 and 35 mg/kg zinc diet had a significantly higher number of abnormalities per litter (2- and 1- fold saline controls, respectively) compared with those from LPS + zinc supplemented dams, which were not significantly different from the saline control groups. The beneficial effect and importance of zinc was also reflected in the larger size of fetuses (weight and crown-rump length) from the LPS + zinc-supplemented treatment group. We have demonstrated that low dietary zinc during exposure to infection (i.e. LPS) in pregnancy augments the negative impact of LPS alone, and that dietary zinc supplementation throughout pregnancy ameliorates LPS-induced teratogenicity.
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Affiliation(s)
- Joanne S C Chua
- Division of Clinical Biochemistry, Hanson Institute, Australia
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Lam PK, Torfs CP. Interaction between maternal smoking and malnutrition in infant risk of gastroschisis. ACTA ACUST UNITED AC 2006; 76:182-6. [PMID: 16498669 DOI: 10.1002/bdra.20238] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Gastroschisis is a severe birth defect characterized by a tear in the infant's abdominal wall. Young mothers have the highest risk of having an infant with gastroschisis. In an animal model, the defect resulted from exposure of pregnant mice to carbon monoxide (CO) in combination with a low protein and low zinc diet. METHODS We evaluated this model in a study of 55 infants with gastroschisis and 94 age-matched controls that included maternal interview with a food frequency questionnaire. Smoking cigarettes (> or = 1 pack/day) or marijuana (more than once) 3 months prior to pregnancy indicated CO exposure. Low protein or zinc intake and a low body mass index (BMI) indicated maternal malnutrition. RESULTS When assessed separately, high CO, low protein, low zinc, and low BMI were each significantly associated with an increased risk of gastroschisis. Although we observed significant CO-BMI and CO-zinc interactions after adjusting for income, only a combination of high CO exposure and low BMI yielded a synergistic adverse effect. Compared to the low risk of having an infant with gastroschisis for mothers who did not have low BMI and did not smoke, the risk of having an infant with gastroschisis was 16.3 times (95% CI, 2.49-113.4) higher for mothers who did not have low BMI but smoked, and 19.7 times (95% CI, 4.33-89.6) higher for mothers who did not smoke but had low BMI. However, the risk was 26.5 times (95% CI, 7.85-89.4) higher for mothers who had low BMI and smoked. CONCLUSIONS Our results suggest that young mothers are at increased risk of having an infant with gastroschisis if they smoke and are also malnourished.
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Affiliation(s)
- Phung K Lam
- Department of Medicine, University of California-San Diego, San Diego, California 92103-8374, USA.
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Tekesin I, Wallwiener D, Schmidt S. The value of quantitative ultrasound tissue characterization of the cervix and rapid fetal fibronectin in predicting preterm delivery. J Perinat Med 2005; 33:383-91. [PMID: 16238532 DOI: 10.1515/jpm.2005.070] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To evaluate clinical risk factors, cervical fetal fibronectin (fFN), cervical length, and mean gray value assessment in predicting of preterm delivery (PTD) in patients with signs and/or symptoms of preterm labor (PTL). STUDY DESIGN One hundred and seventeen women with PTL between 24 and 34 weeks of gestation were included. Cervical swabs were tested for fFN using the rapid fFN assay. When 2-dimensional transvaginal ultrasound measurement of cervical length was completed, a region of interest (ROI) of constant size was defined in the midsection of the posterior wall, and the tissue-specific gray scale was determined. The end point were PTDs at <34 and <37 weeks of gestation. RESULTS In univariate analysis, the three strongest predictors of spontaneous preterm birth <34 weeks were positive fFN (relative risk [RR] 8.9; 95% confidence interval [CI] 2.6-30.1), cervical length < or =2.5 cm (RR 6.9; 95% CI 1.6-29.7), and a low mean gray value of < or =5.97 (RR 7.9; 95% CI 2.3-27.2). Predictors significantly associated with spontaneous PTD at less than 37 weeks of gestation included previous PTD in multiparas (RR 3.9; 95% CI 1.6-9.5), positive fFN (RR 7.6; 95% CI 3.8-15.3), cervical length < or =2.5 cm (RR 2.6; 95% CI 1.4-5.1) and a low gray scale value of < or =6.54 (RR 4.5; 95% CI 2.3-8.9). In the final regression models used to predict spontaneous PTD <34 weeks and <37 weeks of gestation, both a positive fetal fibronectin (odds ratio [OR] 13.4; 95% CI, 2.5-72.1, P=0.003 vs. OR, 17.3; 95% CI 4.9-61.8, P<0.001) and a low gray scale value (OR 6.3 95% CI 1.3-29.4, P=0.02 vs. OR, 7.1; 95% CI 2-25.2, P=0.003) remained powerful predictors. The RRs of spontaneous PTD <37 weeks has been analyzed by a combination of these significant parameters. Low mean gray value < or =6.54 and negative fFN had a 10.3-fold (95% CI 2-74.5) increased risk of spontaneous preterm birth at <37 weeks. Combination of positive fFN and normal gray level (>6.54), had a higher increase risk of PTD (RR 18.1; 95% CI 4.4-76.7). When both factors were positive, the RR increases to 24.8 (95% CI 6.2-98.7). CONCLUSIONS Combined use of rapid fFN and cervical gray value analysis improves the diagnostic efficiency and allows identification of women at risk for preterm delivery and in need for further prophylactic/therapeutic intervention.
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Affiliation(s)
- Ismail Tekesin
- Department of Gynecology and Obstetrics, University of Tuebingen, Germany.
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