Interaction of fetal growth and bisphenol A in obesity

描述(申请人提供)：“肥胖原”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是导致肥胖症急剧增加的原因之一。 发生在过去的二十年里。我们开发了一种新的小鼠模型，可以产生半侧卵巢切除的母亲所生的兄弟姐妹，从宫内生长受限(IUGR)到基于一个拥挤的子宫角的位置的巨型。在断奶后的第一周内，IUGR小鼠的体重急剧增加了90%，而长体雄性小鼠的体重只增加了30%，在此之后，IUGR和长体雄性小鼠的体重仍然显著高于出生时体重中值的雄性小鼠。成年IUGR小鼠在葡萄糖耐量、胰岛素升高以及腹部总脂肪重量增加方面与IUGR人类有显著相似之处，但性腺脂肪垫脂肪细胞明显少于同样肥胖的巨型小鼠，并且基因表达谱明显不同。围产期暴露于极低剂量的BPA会导致成年后体重显著增加，但成人性腺脂肪垫脂肪细胞和葡萄糖耐量减少，与未治疗的IUGR男性相似，但与未治疗的巨型男性非常不同。我们建议使用我们的新模型在两种对雌激素不同敏感的小鼠身上，研究在脂肪细胞分化的关键时期，基因、胎儿生长速度、出生后营养(通过使用高能量和低能量饲料)和BPA暴露之间的交互作用，从而导致成年肥胖的不同轨迹。我们将研究不同剂量的双酚A在发育过程中对C57和CD-1男性和 女性在成年期和PND 21-28的生长、脂肪沉积、胰岛素和葡萄糖的动态平衡、脂肪细胞的数量和大小、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，IUGR、巨大儿和正常胎儿生长发育的小鼠胚胎将显示出不同的甲基化模式和参与分化、增殖和调节脂肪生成的基因表达。 腹部脂肪细胞。此外，孕妇口服低剂量双酚A预计会加剧IUGR后代的肥胖，因为出生后生长加速。我们预测BPA的作用将与脂肪细胞中不同的DNA甲基化以及雌激素反应基因的差异表达有关，BPA将导致功能改变和容易肥大的脂肪细胞数量减少。据预测，围产期暴露于BPA将通过脂肪细胞的额外表观遗传学变化与IUGR协同作用，这些变化改变了雌激素反应基因的表达，并进一步加速了出生后的生长。

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.