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: 8073731
• 负责人: Cheryl Susan Rosenfeld
• 金额: $ 0.79万
• 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/8073731
• 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.

描述（由申请人提供）：本申请涉及广泛的挑战领域（08）基因组学和特定的挑战主题，08-ES-104，鉴定与环境暴露相关的表观遗传标记的改变。在具有脑池内A颗粒（IAP）在其聚集蛋白基因中的Avy小鼠中，暴露于富含染料木黄酮或甲基供体的母体饮食导致IAP位点的甲基化和从黄色毛色到假聚集蛋白后代的分级转变。然而，双酚A（BPA）暴露怀孕的黑人女性携带阿维胎儿的结果在更多的黄色毛色后代。带有去甲基化启动子的黄色毛色后代会患糖尿病、肥胖症，在某些品系中还会患癌症，但它们的深色毛色兄弟姐妹却保持健康。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。虽然以前的一项研究已经记录了这些小鼠在子宫内暴露于BPA时发生的明显毛色变化，BPA是一种在大多数塑料化合物中发现的环境雌激素污染物，但没有研究检查过微妙的表型改变，包括行为和血清代谢物和激素浓度，以及可能发生在各种毛色Avy小鼠中的病理变化。此外，在子宫内暴露于BPA的一代（F1）可能会对他们的曾孙（F3）产生跨代影响，他们唯一的暴露是通过他们的前辈。虽然已在啮齿动物和人类（在DES的情况下）中检查了其他化合物（包括乙烯氯唑啉和己烯雌酚（DES））的跨代效应，但迄今为止还没有一项研究检查了BPA的跨代效应。然而，这些研究与人类高度相关，我们无法轻易评估一代人暴露于内分泌干扰物（如BPA）对后代的影响。然而，由于它们的妊娠期为18至21天，性成熟较早（6至8周龄），这种跨代研究可以很容易地在小鼠中完成。在此，我们将确定BPA是否可以发挥跨代的影响，繁殖黑色（a/a）女性可行的黄色（Avy/a）男性。在繁殖前两周和整个妊娠期间，这些雌性动物将通过饮食暴露于三种剂量的BPA（501/4g/kg/天、5 mg/kg/天或50 mg/kg/天）之一。对照a/a雌性动物将维持AIN-93 G饲料。将对幼犬进行断奶前和断奶后的行为评估，以确定BPA是否影响其焦虑水平、学习和记忆反应以及其他发育参数。每周抽取股静脉血，测量代谢和性别调节激素、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。在10周龄时，将繁殖得到的Y 0 Avy雄性和雌性，以分别对照a/a雌性和a/a雄性，以确定任何跨代效应是否可以通过雄性和雌性生殖系传递。此外，他们的黑色毛色（a/a）（F1）的兄弟姐妹将进行繁殖，以确定BPA是否独立于Avy基因座的跨代效应。同样的实验程序将在F2代和最终的F3代上重复，他们唯一接触BPA的是他们的前辈。这些研究将使我们能够检查行为，体重，血液代谢产物和激素浓度的微妙变化，以及在子宫内暴露于BPA的可存活黄色小鼠可能发生的病理变化。此外，这项研究将检查BPA可以在a/a和Avy/a小鼠中发挥的假定跨代效应，后者是经典的表观遗传动物模型。这些研究与人类有相当大的相关性，因为它们可能作为预警，我们目前暴露于“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发现负面结果，它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，以防止我们的后代受到这种不利影响。此外，这些数据可能会让我们深入了解我们目前暴露于BPA对我们的后代，孙子，甚至是潜在的伟大的孙子造成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。

项目成果

Environmental Health Factors and Sexually Dimorphic Differences in Behavioral Disruptions.

• DOI: 10.1007/s40572-014-0027-7
• 发表时间: 2014-12
• 期刊: Current environmental health reports
• 影响因子: 7.9

Sexually selected traits: a fundamental framework for studies on behavioral epigenetics.

• DOI: 10.1093/ilar.53.3-4.253
• 发表时间: 2012
• 期刊: ILAR journal
• 影响因子: 2.5
• 作者: Jašarević E;Geary DC;Rosenfeld CS
• 通讯作者: Rosenfeld CS

Sex and dose-dependent effects of developmental exposure to bisphenol A on anxiety and spatial learning in deer mice (Peromyscus maniculatus bairdii) offspring.

• DOI: 10.1016/j.yhbeh.2012.09.009
• 发表时间: 2013-01
• 期刊: HORMONES AND BEHAVIOR
• 影响因子: 3.5
• 作者: Jasarevic, Eldin;Williams, Scott A.;Vandas, Gregory M.;Ellersieck, Mark R.;Liao, Chunyang;Kannan, Kurunthachalam;Roberts, R. Michael;Geary, David C.;Rosenfeld, Cheryl S.
• 通讯作者: Rosenfeld, Cheryl S.

Comparison of serum bisphenol A concentrations in mice exposed to bisphenol A through the diet versus oral bolus exposure.

• DOI: 10.1289/ehp.1003385
• 发表时间: 2011-09
• 期刊: Environmental health perspectives
• 影响因子: 10.4
• 作者: Sieli PT;Jašarevic E;Warzak DA;Mao J;Ellersieck MR;Liao C;Kannan K;Collet SH;Toutain PL;Vom Saal FS;Rosenfeld CS
• 通讯作者: Rosenfeld CS

Current concepts in neuroendocrine disruption.

神经内分泌干扰的当前概念。

• DOI: 10.1016/j.ygcen.2014.02.005
• 发表时间: 2014-07-01
• 期刊: General and comparative endocrinology
• 影响因子: 2.7
• 作者: León-Olea M;Martyniuk CJ;Orlando EF;Ottinger MA;Rosenfeld C;Wolstenholme J;Trudeau VL
• 通讯作者: Trudeau VL