Interaction of fetal growth and bisphenol A in obesity

胎儿生长与双酚 A 在肥胖中的相互作用

基本信息

批准号：
8266857
负责人：
SUSAN C NAGEL
金额：
$ 49.22万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-25 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266857
关键词：
Abdomen Acceleration Adipocytes Adult Animals Barker Hypothesis Biological Models Birth Blood flow Body Weight Cell physiology Childhood Consumption Crowding DNA Methylation Data Deposition Development Diet Dose Eating Endocrine Disruptors Epidemiology Epigenetic Process Estrogens Etiology Exercise Exposure to Fatty acid glycerol esters Feeds Female Fetal Growth Fetal Growth Retardation Fetus Food Packaging Gene Expression Gene Expression Profile Genes Genotype Glucose Intolerance Growth Horns Human Hypertrophy Insulin Intervention Lead Life Location Metabolic Metabolic Diseases Methylation Modeling Molecular Profiling Mothers Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Oral Administration Overweight Perinatal Perinatal Exposure Phenotype Plastics Population Rattus Regulation Relative (related person)Reporting Sex Characteristics Siblings Testing Uterus Weaning Weight abdominal fat adipocyte differentiation base bisphenol A blood glucose regulation critical period environmental chemical experience feeding fetal food consumption food restriction genetic strain high risk lipid biosynthesis male mouse model next generation novel nutrition offspring postnatal pregnant prenatal rapid growth response sex

项目摘要

DESCRIPTION (provided by applicant): There continues to be controversy concerning the "obesogen" hypothesis, which proposes that exposure to certain environmental chemicals during critical periods in development is contributing to the dramatic increase in obesity that has occurred over the last two decades. We have developed a novel mouse model that results in siblings produced by hemiovariectomized mothers that range from intrauterine growth restricted (IUGR) to macrosomic based on location in one crowded uterine horn. The IUGR mice experience a dramatic 90% increase in body weight, while macrosomic males only experience a 30% increase in body weight, during the first week after weaning, after which IUGR and macrosomic males remain significantly heavier than males with a median body weight at birth. Adult IUGR mice show marked similarities to IUGR humans in terms of glucose intolerance, elevated insulin as well as an increase in total abdominal fat weight, but have markedly fewer gonadal fat pad adipocytes and markedly different gene expression profiles relative to equally obese macrosomic mice. Perinatal exposure to very low doses of BPA results in a significant increase in body weight in adulthood but a decrease in adult gonadal fat pad adipocyte and glucose intolerance, similar to untreated IUGR males, but very different from untreated macrosomic males. We propose to use our novel model in two strains of mice with different sensitivities to estrogen to examine the interaction between genotype, rate of fetal growth, postnatal nutrition (by using high and low energy feeds), and BPA exposure at human relevant doses during the critical period of adipocyte differentiation in causing different trajectories to adult obesity. We will examine effects of different doses of BPA during development in C57 and CD-1 males and females on growth, fat deposition, insulin and glucose homeostasis, adipocyte number and size, gene expression by qPCR and Next Generation sequencing and DNA methylation in adulthood and on PND 21-28. Our overarching hypothesis is that mouse fetuses with IUGR, macrosomia and normal fetal growth will show differences in the methylation pattern and expression of genes involved in the differentiation, proliferation and regulation of lipogenesis in abdominal adipocytes. In addition, a low maternal oral dose of BPA is predicted to exacerbate obesity in IUGR offspring due to acceleration of postnatal growth. We predict the effects of BPA will be related to differential DNA methylation as well as differential expression of estrogen-responsive genes in adipocytes, and that BPA will lead to a decrease in the number of adipocytes that are functionally altered and prone to hypertrophy. Perinatal exposure to BPA is predicted to interact synergistically with IUGR via additional epigenetic changes in adipocytes that alter the expression of estrogen-responsive genes and further accelerate postnatal growth. PUBLIC HEALTH RELEVANCE: There continues to be controversy concerning the "obesogen" hypothesis, which proposes that exposure to certain environmental chemicals during critical periods in development, is contributing to the dramatic increase in obesity that has occurred over the last two decades. We will examine the effects of a putative obesogen used in plastic food packaging, bisphenol A, on the development of fat cell function using a novel model system to study the interaction of bisphenol A with growth during fetal life in the etiology of adut obesity.

描述（由申请人提供）：关于“致肥胖”假说仍然存在争议，该假说提出，在发育的关键时期接触某些环境化学物质会导致肥胖的急剧增加。发生在过去二十年里。我们开发了一种新型小鼠模型，该模型可以使单侧卵巢切除的母亲产生兄弟姐妹，根据拥挤的子宫角的位置，这些兄弟姐妹的范围从宫内生长受限（IUGR）到巨大体。在断奶后第一周，IUGR 小鼠的体重急剧增加了 90%，而巨大体雄性小鼠的体重仅增加了 30%，此后 IUGR 和巨大体雄性小鼠的体重仍显着重于中位体重为出生。成年 IUGR 小鼠在葡萄糖不耐症、胰岛素升高以及腹部脂肪总重量增加方面与 IUGR 人类显着相似，但与同样肥胖的巨大小鼠相比，其性腺脂肪垫脂肪细胞明显较少，基因表达谱明显不同。围产期接触极低剂量的 BPA 会导致成年期体重显着增加，但成年性腺脂肪垫脂肪细胞和葡萄糖耐受不良减少，与未经治疗的 IUGR 男性相似，但与未经治疗的巨大体男性有很大不同。我们建议在对雌激素具有不同敏感性的两种小鼠品系中使用我们的新模型，以检查基因型、胎儿生长速度、产后营养（通过使用高能量和低能量饲料）以及在人类相关剂量下的 BPA 暴露之间的相互作用。脂肪细胞分化导致成人肥胖不同轨迹的关键时期。我们将研究不同剂量的 BPA 在 C57 和 CD-1 雄性发育过程中的影响女性成年期和 PND 21-28 的生长、脂肪沉积、胰岛素和葡萄糖稳态、脂肪细胞数量和大小、qPCR 和下一代测序的基因表达以及 DNA 甲基化。我们的总体假设是，患有 IUGR、巨大儿和正常胎儿生长的小鼠胎儿将在甲基化模式和参与分化、增殖和脂肪生成调节的基因表达上表现出差异。腹部脂肪细胞。此外，预计母体口服低剂量的 BPA 会因产后生长加速而加剧 IUGR 后代的肥胖。我们预测 BPA 的影响与 DNA 甲基化差异以及脂肪细胞中雌激素反应基因的差异表达有关，并且 BPA 将导致功能改变和易于肥大的脂肪细胞数量减少。预计围产期接触 BPA 会通过脂肪细胞中额外的表观遗传变化与 IUGR 产生协同相互作用，从而改变雌激素反应基因的表达并进一步加速产后生长。公共健康相关性：关于“致肥胖”假说仍然存在争议，该假说认为，在发育的关键时期接触某些环境化学物质，会导致过去二十年来肥胖症的急剧增加。我们将使用一种新的模型系统来研究塑料食品包装中使用的假定肥胖源双酚 A 对脂肪细胞功能发育的影响，以研究双酚 A 与胎儿生长期间成人肥胖病因的相互作用。