Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions

AbstractOur recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. Mief2, Eif3h, Cux1, and Atp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.

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Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex

International Journal of Molecular Sciences ◽

10.3390/ijms222413201 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13201

Author(s):

Songphon Kanlayaprasit ◽

Surangrat Thongkorn ◽

Pawinee Panjabud ◽

Depicha Jindatip ◽

Valerie W. Hu ◽

...

Keyword(s):

Transcription Factors ◽

Prefrontal Cortex ◽

Bisphenol A ◽

Molecular Mechanisms ◽

Autism Spectrum ◽

Postmortem Brain ◽

Dependent Manner ◽

Distribution Analysis ◽

Docking Analysis ◽

Specific Effects

Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome–interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring’s prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring’s prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

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Faculty Opinions recommendation of Oxytocin pretreatment decreases oxytocin-induced myometrial contractions in pregnant rats in a concentration-dependent but not time-dependent manner.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1160663.622055 ◽

2009 ◽

Author(s):

Phyllis Leppert

Keyword(s):

Time Dependent ◽

Dependent Manner ◽

Pregnant Rats

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Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

Current Neurovascular Research ◽

10.2174/1567202616666190131155834 ◽

2019 ◽

Vol 16 (1) ◽

pp. 3-11

Author(s):

Luisa Halbe ◽

Abdelhaq Rami

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Cell Damage ◽

Protective Mechanism ◽

Unfolded Proteins ◽

Neuronal Viability ◽

Hippocampal Cell ◽

Trigger Cell Death ◽

Autophagy Inhibition

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

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Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder

Journal of Child Neurology ◽

10.1177/0883073815609150 ◽

2015 ◽

Vol 31 (5) ◽

pp. 629-635 ◽

Cited By ~ 39

Author(s):

Fatih Kardas ◽

Ayse Kacar Bayram ◽

Esra Demirci ◽

Leyla Akin ◽

Sevgi Ozmen ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Bisphenol A ◽

Children With Autism ◽

Autism Spectrum ◽

Spectrum Disorder

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Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction

Reproductive Toxicology ◽

10.1016/s0890-6238(02)00006-0 ◽

2002 ◽

Vol 16 (2) ◽

pp. 117-122 ◽

Cited By ~ 211

Author(s):

Shizuka Honma ◽

Atsuko Suzuki ◽

David L. Buchanan ◽

Yoshinao Katsu ◽

Hajime Watanabe ◽

...

Keyword(s):

Bisphenol A ◽

Female Mouse ◽

Low Dose ◽

In Utero ◽

Dose Effect ◽

In Utero Exposure

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Abstract 107: Apocynin Attenuates Isoproterenol-induced Myocardial Injury: Implications For Targeting Nadph Oxidase In Myocardial Fibrogenesis

Circulation Research ◽

10.1161/res.113.suppl_1.a107 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Yu Chen ◽

Jingang Cui ◽

Qinbo Yang ◽

Chenglin Jia ◽

Minqi Xiong ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Myocardial Fibrosis ◽

Myocardial Injury ◽

Oxidase Inhibitor ◽

Ros Generation ◽

Dependent Manner ◽

Expression Of Genes ◽

Therapeutic Development ◽

Myocardial Injuries

Myocardial fibrosis results from cardiac injuries caused by various pathophysiological mechanisms including myocardial infarction, leading to destruction of myocardial architecture and progressive cardiac dysfunction. Oxidative stress is likely involved in myocardial ischemic injury and the subsequent tissue remodeling mediated by myocardial fibrogenesis. Our current study aimed to evaluate the implication of NADPH oxidase in overproduction of reactive oxygen species and its contribution to the pathogenesis of myocardial fibrogenesis after ischemic injuries. The effects of Apocynin, a selective NADPH oxidase inhibitor, were evaluated in the mouse model of isoproterenol-induced myocardial injury by histopathological approaches and whole-genome gene expression profiling. The results demonstrated that Apocynin was able to inhibit the development of ISO-induced myocardial necrotic lesions and fibrogenesis in a dose-dependent manner. Moreover, the preventive effects of Apocynin on myocardial injuries were associated with suppressed expression of genes implicated in inflammation responses and extracellular matrix, which were remarkably upregulated by isoproterenol administration. In summary, o ur study provides proof-of-concept for the involvement of NADPH oxidase-mediated ROS generation in myocardial ischemic injuries and fibrogenesis, which will benefit the mechanism-based therapeutic development targeting NADPH oxidase and oxidative stress in treating myocardial fibrosis and related disorders.

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