Effects of In Utero and Transgenerational Exposure of Avy Mice to Bisphenol A

家禽小鼠在子宫内和跨代暴露于双酚 A 的影响

• 批准号: 7936934
• 负责人: Cheryl Susan Rosenfeld
• 金额: $ 53.51万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936934
• 关键词: Address; Adult; Adverse effects; Affect; Age; Androgen Receptor; Animal Model; Anxiety; Appearance; Area; Aryl Hydrocarbon Receptor; Behavior; Behavior assessment; Behavioral; Blood; Body Weight; Breeding; Chemical Industry; Chemicals; Child; Color; Corticosterone; Data; Dental Materials; Development; Diabetes Mellitus; Diet; Diethylstilbestrol; Disease; Dose; Endocrine; Endocrine Disruptors; Environment; Environmental Exposure; Epigenetic Process; Estrogen Receptors; Estrogens; Exposure to; Fatty Acids; Female; Fetus; Generations; Genes; Genistein; Genomics; Glucose; Hormonal; Hormones; Human; IGF1 gene; Individual; Insulin; Intracisternal A-Particle Elements; Learning; Leptin; Malignant Neoplasms; Measures; Medical; Memory; Metabolic; Methylation; Mus; Nonesterified Fatty Acids; Obesity; Outcome; Paper; Pathway interactions; Pattern; Perinatal Exposure; Phenotype; Plastics; Pregnancy; Pregnant Women; Procedures; Production; Publishing; Reporting; Rodent; Serum; Siblings; Site; Social Welfare; Source; Testing; Testosterone; Therapeutic Intervention; Thyroid Hormone Receptor; Water; Weaning; Weight; Weight Gain; Woman; bisphenol A; diabetic; environmental change; estrogen-related receptor; exposed human population; feeding; grandchild; in utero; insight; landfill; male; mouse model; offspring; pregnant; prevent; promoter; public health relevance; pup; receptor; response; sex; toxicant; vinclozolin

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-ES-104, Identification of alterations in epigenetic marks related to environmental exposures. In Avy mice that have an intracisternal A particle (IAP) in their agouti gene, exposure to a maternal diet-enriched in genistein or methyl- donors results in methylation of the IAP site and a graded shift from yellow coat color to pseudoagouti offspring. However, bisphenol A (BPA) exposure of pregnant black females that are carrying Avy fetuses results in more yellow coat color offspring. Yellow coat color offspring with a de-methylated promoter develop diabetes, obesity, and, in certain strains, cancer, but their darker siblings with a brown coat color remain healthy. These mice are a classic animal model to study epigenetics, as they are exquisitely sensitive to environmental changes. While one previous study has documented the overt coat color changes that occur in these mice in response to in utero exposure to BPA, which is an environmental estrogenic contaminant found in most plastic compounds, no study has examined the subtle phenotypic alterations, including in behavior and serum metabolite and hormone concentrations, and pathological changes that might also occur in the various coat color Avy mice. Moreover, in utero exposure of a single generation (F1) to BPA could result transgenerational effects into their great grand-offspring (F3), whose only exposure is through their predecessors. While the transgenerational effects of other compounds, including vinclozolin and diethylstilbestrol (DES) have been examined in rodents and humans (in the case of DES), not a single study to date has examined the transgenerational effects of BPA. Yet, such studies are highly relevant to humans, where we cannot easily assess the effects that exposure of one generation to endocrine disruptors, such as BPA, has on proceeding generations. However, with their 18 to 21-day gestation period and early sexual maturity (6 to 8wks of age), such transgenerational studies can readily be accomplished in mice. Herein, we will determine whether BPA can exert transgenerational effects by breeding black (a/a) females to viable yellow (Avy/a) males. Two weeks prior to breeding and throughout gestation, these females will be exposed to one of three doses of BPA (501/4g/kg/day, 5mg/kg/day, or 50mg/kg/day) through their diet. Control a/a females will be maintained on the AIN-93G diet. Pre- and post-weaning behavioral assessments will be performed on the pups to determine whether BPA affects their anxiety levels, learning and memory responses, and other developmental parameters. Femoral blood will be drawn weekly to measure the serum concentrations of metabolic and sex-regulating hormones, free fatty acids, and glucose, and their weight and overall appearance tracked. At 10 wks of age, the resultingY0 Avy males and females will be bred to control a/a females and a/a males, respectively, to determine whether any transgenerational effects can be passed through the male and female germlines. Additionally, their black coat color (a/a) (F1) siblings will be bred to determine if BPA underpins transgenerational effects independent of the Avy locus. The same experimental procedures will be repeated on the F2 and eventually the F3 generation, whose only exposure to BPA will be through their predecessors. These studies will permit us to examine the subtle changes in behavior, body weight, blood metabolites and hormone concentrations, and pathological changes that might ensue in viable yellow mice exposed in utero to BPA. Additionally, this study will examine the putative transgenerational effects that BPA can exert in a/a and Avy/a mice, the latter being a classic epigenetic animal model These studies have considerable relevance to humans, as they might serve as forewarning that our current exposure to "endocrine disruptors", such as BPA, has already compromised the welfare of our descendents. Should negative outcomes be detected in these transgenerational rodent studies, it might buttress public and congressional support to begin to curb BPA in the environmental and consumer goods to prevent such adverse effects in our descendents. Additionally, these data might provide insight into the impending medical conditions that our current exposure to BPA has imposed on our offspring, grand-offspring and even potentially great grand- offspring so that we are better prepared to therapeutically intervene in these generations. PUBLIC HEALTH RELEVANCE: Bisphenol A is one of the most commonly produced chemicals, as it used to make a variety of items, including plastics for baby bottles and re-usable water bottles, metallic cans, dental material, and in the production of cardboard and paper items. While numerous other studies have examined the effects that bisphenol A can exert on the individual, no previous study has ascertained the effects that it might have on the descendents of those subjected to this compounds. We will examine the behavioral, hormonal, and overall abnormal changes that might occur in in utero bisphenol A exposed mice and the ramifications that this early exposure has on their offspring through great grand-offspring to determine if bisphenol A exerts any potential transgenerational effects.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (08) 基因组学和特定挑战主题，08-ES-104，与环境暴露相关的表观遗传标记变化的识别。在刺豚鼠基因中含有脑池内 A 颗粒 (IAP) 的 Avy 小鼠中，暴露于富含金雀异黄素或甲基供体的母体饮食会导致 IAP 位点甲基化，并导致毛色从黄色逐渐转变为伪刺豚鼠后代。然而，怀有 A​​vy 胎儿的怀孕黑人雌性接触双酚 A (BPA) 会导致后代毛色呈更多黄色。带有去甲基化启动子的黄色毛色后代会患上糖尿病、肥胖症，在某些品系中还会患癌症，但它们的棕色毛色的深色兄弟姐妹仍然保持健康。这些小鼠是研究表观遗传学的经典动物模型，因为它们对环境变化非常敏感。虽然之前的一项研究已经记录了这些小鼠在子宫内接触 BPA（大多数塑料化合物中发现的一种环境雌激素污染物）时发生的明显毛色变化，但没有研究检查细微的表型变化，包括行为、血清代谢物和激素浓度，以及各种毛色 Avy 小鼠中也可能发生的病理变化。此外，单代 (F1) 在子宫内接触 BPA 可能会对其曾孙 (F3) 产生跨代影响，而其唯一的接触途径是通过其前辈。虽然乙烯菌核利和己烯雌酚 (DES) 等其他化合物的跨代影响已在啮齿类动物和人类（以 DES 为例）中进行了研究，但迄今为止还没有一项研究考察了 BPA 的跨代影响。然而，此类研究与人类高度相关，我们无法轻易评估一代人暴露于 BPA 等内分泌干扰物对后代的影响。然而，由于它们的妊娠期为 18 至 21 天，且性成熟较早（6 至 8 周龄），此类跨代研究可以很容易地在小鼠身上完成。在此，我们将确定 BPA 是否可以通过将黑色 (a/a) 雌性繁殖为可存活的黄色 (Avy/a) 雄性来发挥跨代效应。在繁殖前两周和整个妊娠期间，这些雌性将通过饮食接触三种剂量的 BPA（501/4g/kg/天、5mg/kg/天或 50mg/kg/天）之一。对照 a/a 雌性将维持 AIN-93G 饮食。将对幼犬进行断奶前和断奶后行为评估，以确定 BPA 是否影响它们的焦虑水平、学习和记忆反应以及其他发育参数。每周抽取股血以测量代谢和性调节激素、游离脂肪酸和葡萄糖的血清浓度，并跟踪其体重和整体外观。 10周龄时，将培育所得的Y0 Avy雄性和雌性，分别对照a/a雌性和a/a雄性，以确定是否有任何跨代效应可以通过雄性和雌性种系传递。此外，还将培育它们的黑色毛色 (a/a) (F1) 兄弟姐妹，以确定 BPA 是否支持独立于 Avy 基因座的跨代效应。同样的实验程序将在 F2 和最终的 F3 一代上重复，他们唯一接触 BPA 的途径是通过他们的前辈。这些研究将使我们能够检查行为、体重、血液代谢物和激素浓度的微妙变化，以及子宫内暴露于 BPA 的存活黄色小鼠可能发生的病理变化。此外，这项研究还将检验 BPA 在 a/a 和 Avy/a 小鼠中可能产生的假定跨代效应，后者是经典的表观遗传动物模型。这些研究与人类具有相当大的相关性，因为它们可能作为预警，表明我们目前接触的“内分泌干扰物”（例如 BPA）已经损害了我们后代的福利。如果这些跨代啮齿动物研究中发现负面结果，可能会支持公众和国会支持开始遏制环境和消费品中的 BPA，以防止对我们的后代产生此类不利影响。此外，这些数据可能有助于了解我们目前接触的 BPA 给我们的后代、孙子甚至潜在的曾孙子带来的即将发生的医疗状况，以便我们更好地准备对这些世代进行治疗干预。 公共健康相关性：双酚 A 是最常生产的化学品之一，因为它用于制造各种物品，包括用于婴儿奶瓶和可重复使用的水瓶的塑料、金属罐、牙科材料以及纸板和纸制品的生产。虽然许多其他研究已经检验了双酚 A 对个体的影响，但之前没有研究确定它可能对受到这种化合物影响的后代产生的影响。我们将检查子宫内双酚 A 暴露小鼠可能发生的行为、荷尔蒙和整体异常​​变化，以及这种早期暴露对它们的后代（通过曾孙）的影响，以确定双酚 A 是否会产生任何潜在的跨代影响。