Sex-specific impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring's prefrontal cortex.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-05-15 DOI:10.1186/s13293-024-00614-2
Songphon Kanlayaprasit, Thanit Saeliw, Surangrat Thongkorn, Pawinee Panjabud, Kasidit Kasitipradit, Pattanachat Lertpeerapan, Kwanjira Songsritaya, Wasana Yuwattana, Thanawin Jantheang, Depicha Jindatip, Valerie W Hu, Takako Kikkawa, Noriko Osumi, Tewarit Sarachana
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Abstract

Background: Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring's hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated.

Methods: We obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique.

Results: Genes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males.

Conclusion: This is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring's prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation.

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产前双酚 A 暴露对后代前额叶皮层中与皮层发育、社交行为和自闭症相关基因的性别特异性影响。
背景:最近的研究表明,产前暴露于双酚A会改变后代海马中自闭症相关基因的转录组图谱,破坏海马神经元的生成,导致男性特有的学习障碍。然而,产前暴露于双酚 A 对发育中的前额叶皮层(另一个与自闭症谱系障碍(ASD)高度相关的脑区)的影响的性别差异尚未得到研究:我们从RNA测序分析中获得了产前暴露于双酚A或对照组的雌雄幼鼠前额叶皮层的转录组数据,并对其进行了重新分析。通过 qRT-PCR 分析,筛选出与大脑皮层发育和社会行为相关的 BPA 反应基因进行确认。检测了产前暴露于双酚 A 或对照组的幼鼠前额叶皮层原代细胞的神经发生。使用两试验和三腔试验评估了幼鼠的社会行为。通过宫内电穿孔技术,使用 siRNA 介导的基因敲除技术,研究了选定的双酚 A 反应基因(即 Sema5a)下调对体内大脑皮层发育的雄性特异性影响:结果:因产前暴露于双酚 A 而被破坏的基因与 ASD 有关,并表现出性别特异性失调。参与神经元发生和社会行为的 Sema5a 和 Slc9a9 仅在男性中被下调,而同样与神经元发生和社会行为有关的 Anxa2 和 Junb 仅在女性中被抑制。雄性的神经发生增加,并与Sema5a和Slc9a9的表达水平呈强烈的反相关,而雌性的神经发生减少,并与Anexa2和Junb的表达水平相关。siRNA 介导的男性 Sema5a 基因敲除也会影响子宫内的大脑皮层发育。与 Anxa2 和 Junb 的下调相一致的是,只在雌性后代中观察到社交新奇性缺陷,而在雄性后代中没有观察到:这是首次研究表明,产前暴露于双酚 A 会导致 ASD 相关基因和功能的表达失调,包括大脑皮层神经元的发生和发育以及社会行为。我们的研究结果表明,除了海马体外,双酚A还可能通过后代前额叶皮层的性别特异性分子机制产生不良影响,进而导致ASD相关神经病理学和临床表现的性别差异,这值得进一步研究。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
期刊最新文献
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