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: 8467718
• 负责人: Heather B Patisaul
• 金额: $ 21.53万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467718
• 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.

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，其方式具有年龄和性别特异性。这些数据表明，BPA和其他内分泌干扰化合物（EDCs）的发育暴露可能导致儿童和成人中焦虑和情绪相关疾病的患病率不断上升。来自该实验室的初步数据显示，这些不良行为影响中的许多在保持富含大豆的饮食的Wistar大鼠中没有表现出来，这表明大豆异黄酮，如染料木黄酮（GEN）具有潜在的抵消作用。尚待确定的是（1）在BPA暴露的同时或之后，采用富含大豆的饮食是否可以减轻整个寿命期间的不良行为影响（2）单独的异黄酮（GEN）是否足以诱导抵消作用，以及（3）大豆本身（在不存在BPA的情况下）是否可以诱导行为变化。鉴于大豆婴儿配方奶粉日益流行，后者至关重要。因此，本文提出的实验将测试这样的假设，即即使在BPA暴露之后，食用益生菌也可能有助于“消除”BPA的有害行为影响。进一步假设BPA不是雌激素模拟物，而是通过表观遗传机制起作用。为了测试这些可能性，动物将在幼年和成年生活中进行行为评估，并将使用高通量方法来识别伴随效应的关键下丘脑区域（杏仁核、终纹床核和内侧视前区）内的神经和转录变化。拟议的研究有可能揭示神经行为通路中BPA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在多大程度上可以减轻BPA暴露对发育的社会性影响。具体目标2将探讨大豆摄入量对抗BPA影响的分子机制，通过评估下丘脑基因表达和DNA甲基化变化，这些变化与观察到的青少年和成年生活中的行为变化相关。

项目成果

Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain.

• DOI: 10.1016/j.jsbmb.2015.08.021
• 发表时间: 2016-06
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Rebuli ME;Patisaul HB
• 通讯作者: Patisaul HB

A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster).

神经内分泌毒理学的新模型：亲社会物种草原田鼠（田鼠）接触 BPA 的神经行为影响。

• DOI: 10.1210/en.2014-1379
• 发表时间: 2014
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Sullivan,AlanaW;Beach,ElsworthC;Stetzik,LucasA;Perry,Amy;D'Addezio,AlyssaS;Cushing,BruceS;Patisaul,HeatherB
• 通讯作者: Patisaul,HeatherB

Soy but not bisphenol A (BPA) induces hallmarks of polycystic ovary syndrome (PCOS) and related metabolic co-morbidities in rats.

• DOI: 10.1016/j.reprotox.2014.09.003
• 发表时间: 2014-11
• 期刊: Reproductive toxicology (Elmsford, N.Y.)
• 作者: Patisaul HB;Mabrey N;Adewale HB;Sullivan AW
• 通讯作者: Sullivan AW

Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours.

• DOI: 10.1017/s0029665116000677
• 发表时间: 2017-05
• 期刊: The Proceedings of the Nutrition Society
• 作者: Patisaul HB