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

• 批准号: 8619628
• 负责人: SUSAN C NAGEL
• 金额: $ 47.17万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 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/8619628
• 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 sequencing; novel; nutrition; obesogen; offspring; postnatal; pregnant; prenatal; rapid growth; response; sex

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.

描述（由申请人提供）：关于“肥胖原”假说仍然存在争议，该假说提出，在发育的关键时期暴露于某些环境化学物质是导致肥胖症急剧增加的原因， 发生在过去的二十年里。我们已经开发了一种新的小鼠模型，其结果是由半卵巢切除的母亲产生的兄弟姐妹，其范围从子宫内生长受限（IUGR）到基于在一个拥挤的子宫角中的位置的巨大体。在断奶后的第一周内，IUGR小鼠的体重显著增加90%，而巨大体雄性小鼠的体重仅增加30%，此后IUGR和巨大体雄性小鼠的体重仍显著高于出生时体重中位数的雄性小鼠。成年IUGR小鼠在葡萄糖耐受不良、胰岛素升高以及腹部总脂肪重量增加方面与IUGR人类表现出显著的相似性，但相对于同样肥胖的巨体小鼠，其性腺脂肪垫脂肪细胞明显较少，基因表达谱明显不同。围产期暴露于非常低剂量的BPA导致成年体重显著增加，但成年性腺脂肪垫脂肪细胞和葡萄糖耐受不良减少，类似于未经治疗的IUGR男性，但与未经治疗的巨大体男性非常不同。我们建议在两种对雌激素具有不同敏感性的小鼠品系中使用我们的新模型，以检查基因型，胎儿生长速率，出生后营养（通过使用高能量和低能量饲料）和BPA暴露之间的相互作用，在脂肪细胞分化的关键时期，人体相关剂量，导致成人肥胖的不同轨迹。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， 雌性在成年期和PND 21-28时对生长、脂肪沉积、胰岛素和葡萄糖稳态、脂肪细胞数量和大小、通过qPCR和下一代测序的基因表达和DNA甲基化的影响。我们的总体假设是，IUGR、巨大儿和正常胎儿生长的小鼠胎儿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方面存在差异， 腹部脂肪细胞此外，由于出生后生长的加速，预计母亲口服低剂量的BPA会加剧IUGR后代的肥胖。我们预测BPA的影响将与脂肪细胞中的差异DNA甲基化以及雌激素反应基因的差异表达有关，并且BPA将导致功能改变并易于肥大的脂肪细胞数量减少。预计围产期暴露于BPA与IUGR通过脂肪细胞的额外表观遗传变化协同作用，改变雌激素反应基因的表达，进一步加速出生后生长。