Interaction of BPA and soy isoflavones on sociosexual behavior

BPA 和大豆异黄酮对社会性行为的相互作用

• 批准号: 8259566
• 负责人: Heather B Patisaul
• 金额: $ 22万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-08 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259566
• 关键词: Adolescence; Adolescent; Adoption; Adult; Adverse effects; Age; Amygdaloid structure; Animals; Anti-Anxiety Agents; Anxiety; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Behavioral Mechanisms; Brain; Brain region; Candidate Disease Gene; Chemicals; Child; Consumption; DNA Methylation; Data; Development; Diet; Disease; Dopamine Receptor; Elements; Endocrine Disruptors; Epidemiology; Epigenetic Process; Estrogens; Exposure to; Future; Gene Expression; Generalized Anxiety Disorder; Genes; Genistein; Glucocorticoid Receptor; Goals; Human; Hyperactive behavior; Hypothalamic structure; Incidence; Individual; Infant formula; Intake; Isoflavones; Laboratories; Lead; Life; Link; Longevity; Medial; Mediating; Mental disorders; Methylation; Molecular; Molecular Profiling; Moods; Motor Activity; Mouse Strains; Mus; Neurosecretory Systems; Pathway interactions; Pattern; Perinatal; Perinatal Exposure; Phenotype; Pregnancy; Preoptic Areas; Prevalence; Primates; Property; Puberty; Publishing; Rattus; Research; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Sex Behavior; Structure of terminal stria nuclei of preoptic region; Testing; Weaning; Wistar Rats; Work; bisphenol A; bisulfite; critical developmental period; density; girls; mRNA Expression; neurobehavioral; nonhuman primate; novel; prenatal; pup; relating to nervous system; research study; sex; soy; soy protein isolate; steroid hormone receptor

DESCRIPTION (provided by applicant): Prior work from this lab and others has revealed that perinatal exposure to bisphenol A (BPA) alters sociosexual and mood-related behaviors in rodents, primates, and humans in ways which are age and sex specific. These data suggest that developmental exposure to BPA and other endocrine disrupting compounds (EDCs) might be contributing to the growing prevalence of anxiety- and mood-related disorders in children and adults. Preliminary data from this laboratory reveal that many of these adverse behavioral effects do not manifest in Wistar rats maintained on a soy-rich diet, suggesting that soy isoflavones, such as genistein (GEN) have potentially counteracting effects. What remains to be determined, and will be the focus of the proposed work, is (1) if adoption of a soy-rich diet, either simultaneously or after BPA exposure can mitigate the adverse behavioral effects across the lifespan (2) if the individual isoflavone genistein (GEN) alone is sufficient to induce the counteracting effects and (3) if soy itself (in the absence of BPA) can induce behavioral changes. The latter is critical given the growing prevalence of soy infant formula. Thus, the experiments proposed herein will test the hypothesis that isoflavone consumption, even after BPA exposure has occurred, may help "undo" the deleterious behavioral effects of BPA. It is further hypothesized that BPA is not acting as an estrogen mimic, but rather, via an epigenetic mechanism. To test these possibilities animals will undergo behavioral assessment in juvenile and adult life and a high throughput approach will be used to identify both neural and transcriptional changes within key hypothalamic regions (amygdala, bed nucleus of the stria terminalis and medial preoptic area) accompanying the effects. The proposed studies have the potential to uncover novel mechanisms of BPA action within neurobehavioral pathways, including those not directly mediated by ERs, and how they might be mitigated by soy isoflavones such as GEN. Specific Aim 1 seeks to determine the degree to which consumption of a soy-rich diet or GEN can mitigate the sociosexual effects of developmental BPA exposure. Specific Aim 2 will explore the molecular mechanisms by which soy intake counters BPA effects by assessing the hypothalamic gene expression and DNA methylation changes that correlate with observed behavioral changes in juvenile and adult life. PUBLIC HEALTH RELEVANCE: Epidemiological data suggest that the incidence of adolescent mental health disorders is increasing and it has been hypothesis that exposure to neuroendocrine disrupting chemicals may be a contributing factor. The goal of this research is explore the hypothesis that perinatal exposure to BPA alters sociosexual behaviors by interfering with development and function of the neuroendocrine pathways which regulate them. We will also test the hypothesis that consumption of an isoflavone-rich soy diet may mitigate these effects via an epigenetic mechanism.

描述（由申请人提供）：本实验室和其他实验室的先前工作表明，围产期暴露于双酚A （BPA）会以特定年龄和性别的方式改变啮齿动物、灵长类动物和人类的社会性行为和情绪相关行为。这些数据表明，在发育过程中暴露于BPA和其他内分泌干扰化合物（EDCs）可能会导致儿童和成人中焦虑和情绪相关疾病的日益流行。该实验室的初步数据显示，在食用富含大豆的饮食的Wistar大鼠中，许多这些不良行为影响并未表现出来，这表明大豆异黄酮，如染料木素（GEN）具有潜在的抵消作用。目前尚待确定的是(1)是否采用富含大豆的饮食，无论是同时还是在BPA暴露之后，都可以减轻整个生命周期中的不良行为影响(2)是否单独的异黄酮染料木素（GEN）足以诱导抵消效应(3)大豆本身（在没有BPA的情况下）是否可以诱导行为改变。鉴于大豆婴儿配方奶粉的日益普及，后者至关重要。因此，本文提出的实验将检验这样一种假设，即即使在BPA暴露之后，异黄酮的摄入也可能有助于“消除”BPA的有害行为影响。进一步的假设是BPA不是雌激素的模拟物，而是通过一种表观遗传机制。为了验证这些可能性，研究人员将对动物进行幼年期和成年期的行为评估，并采用高通量方法识别下丘脑关键区域（杏仁核、终纹床核和内侧视前区）的神经和转录变化。拟议的研究有可能揭示神经行为途径中双酚a作用的新机制，包括那些不直接由er介导的机制，以及它们如何被大豆异黄酮（如GEN）减轻。具体目标1旨在确定食用富含大豆的饮食或GEN可以在多大程度上减轻发育期双酚a暴露的社会性影响。Specific Aim 2将通过评估下丘脑基因表达和DNA甲基化变化与观察到的青少年和成人生活中的行为变化相关，探索大豆摄入对抗BPA影响的分子机制。