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: 7816457
• 负责人: Cheryl Susan Rosenfeld
• 金额: $ 44.73万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7816457
• 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，识别与环境暴露相关的表观遗传标记的改变。在Avy小鼠的脑室内A粒子(IAP)基因中，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，并逐渐从黄色毛色转变为假毛鼠后代。然而，双酚A(BPA)暴露在怀孕的黑人女性身上会导致更多的黄色后代。带有去甲基化启动子的黄色后代会患上糖尿病、肥胖症，在某些品系中还会患上癌症，但它们拥有棕色毛色的深色兄弟姐妹仍然健康。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暴露于BPA(一种在大多数塑料化合物中发现的一种环境雌激素污染物)时发生的明显的毛色变化，但还没有研究检查细微的表型变化，包括行为和血清代谢物和激素浓度，以及各种毛色的Avy小鼠也可能发生的病理变化。此外，单代(F1)在宫内暴露于双酚A可能会对其伟大的孙辈(F3)产生跨代影响，后者唯一的暴露是通过他们的前辈。虽然包括长春新灵和己烯雌酚(DES)在内的其他化合物的跨代效应已经在啮齿动物和人类中进行了研究(就DES而言)，但到目前为止还没有一项研究研究BPA的跨代效应。然而，这类研究与人类高度相关，我们不能轻易评估一代人接触双酚A等内分泌干扰物对后续几代人的影响。然而，由于它们的妊娠期为18至21天，性成熟较早(6至8周)，这样的跨代研究很容易在小鼠身上完成。在这里，我们将确定BPA是否可以通过将黑色(a/a)雌性繁殖到可存活的黄色(avy/a)雄性来发挥跨代效应。在繁殖前两周和整个怀孕期间，这些雌性将通过饮食接触三种剂量的双酚A之一(501/4g/kg/天、5 mg/kg/天或50 mg/kg/天)。对照A/A雌性将维持在AIN-93G饮食中。断奶前和断奶后的行为评估将对幼崽进行，以确定双酚A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。每周将抽取股动脉血，以测量血清中代谢和性别调节激素、游离脂肪酸和葡萄糖的浓度，并跟踪它们的体重和整体外观。在10周龄时，将分别培育出控制a/a雌性和a/a雄性的Y0公羊和雌性公羊，以确定是否有任何跨代效应可以通过雄性和雌性生殖系传递。此外，它们的黑色皮毛颜色(a/a)(F1)同胞将被培育出来，以确定BPA是否独立于Avy基因座而支持跨代效应。同样的实验程序将在F2代和最终的F3代身上重复，他们对双酚A的唯一接触将是通过他们的前辈。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细微变化，以及在子宫内暴露于双酚A的存活小鼠可能发生的病理变化。此外，这项研究将考察BPA对a/a和avy/a小鼠可能产生的跨代影响，后者是一个经典的表观遗传动物模型，这些研究与人类有相当大的相关性，因为它们可能是预先警告，我们目前接触的“内分泌干扰物”，如BPA，已经损害了我们后代的福利。如果在这些跨代啮齿动物研究中检测到负面结果，可能会加强公众和国会的支持，开始限制环境和消费品中的BPA，以防止对我们后代的这种不利影响。此外，这些数据可能为我们目前暴露于双酚A对我们的后代、孙辈甚至可能是伟大的孙辈施加的迫在眉睫的医疗状况提供洞察，以便我们更好地准备对这些世代进行治疗干预。 与公共健康相关：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，包括婴儿奶瓶和可重复使用水瓶的塑料、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研究了双酚A对个体的影响，但之前还没有研究确定它可能对那些受到这种化合物影响的人的后代产生的影响。我们将检查子宫内双酚A暴露小鼠可能发生的行为、激素和整体异常变化，以及这种早期暴露对其后代通过伟大的孙代产生的影响，以确定双酚A是否具有任何潜在的跨代影响。