Impact of peripubertal exposure to xenohormones on fat distribution and cytokines

描述（由申请人提供）：青春期是一个包括生理生化变化的动态时期，可能是成人发病率和死亡率的易感性窗口。例如，女性的大部分骨矿物质含量在青少年时期沉积，并且建立了较高的骨矿物质密度与乳腺癌之间的关系。青春期也是身体成分发生巨大变化的时期，胰岛素抵抗会增加。人们认为，内脏脂肪的沉积会增加肥胖代谢并发症的风险，但对儿童时期影响内脏脂肪沉积的因素知之甚少。某些环境暴露（例如，内分泌干扰物）会影响身体成分以及青春期的时间。对成人的研究描述了乳腺癌、肥胖、胰岛素抵抗和脂肪因子之间的关系。瘦素和促炎细胞因子诱导芳香酶活性和雌激素的产生，并导致胰岛素抵抗，而脂联素与乳腺癌呈反比关系。我们建议利用一个独特的现有的种族和民族多样化的女孩队列，这些女孩从6岁到7岁一直被纵向跟踪。这些女孩在2-4年内进行了一系列检查，包括身高、体重、青春期成熟度评估，以及基线时获得的尿液生物标志物。我们的目的是：评估在青春期成熟过程中脂肪的积累与种族和青春期时间之间的关系，以及接触邻苯二甲酸酯和植物雌激素；并评估早期接触内分泌干扰物、青春期成熟时间、胰岛素抵抗的发展以及瘦素和脂联素变化之间的纵向关系。该提案将结合先前纵向研究的人体测量和成熟数据以及早期的生物标志物数据，到目前的评估：身体成分，区域脂肪分布和骨密度；空腹胰岛素、血糖和血脂；脂肪因子瘦素和脂联素；以及炎症标志物IL-6。此外，一个亚组的胰岛素和葡萄糖水平在基线时获得，我们建议增加对当时储存的血清的分析，以分析瘦素和脂联素水平。这将使我们更好地理解青春期时间、内分泌干扰物暴露、青春期身体成分变化以及胰岛素抵抗与肥胖和代谢综合征的潜在机制之间的关系。这项研究可能有助于为预防乳腺癌和肥胖的代谢后果提供干预措施。

DESCRIPTION (provided by applicant): Puberty is a dynamic period which includes physiologic and biochemical changes, and may serve as a window of susceptibility for adult morbidity and mortality. For example, the majority of bone mineral content in females is deposited during the teen years, and the relationship between greater bone mineral density and breast cancer is established. Puberty is also a time of dramatic changes in body composition, with a rise in insulin resistance. The deposition of visceral fat is believed to increase the risk of metabolic complications of obesity, but little is known about factors in childhood that impact deposition of visceral fat. Certain environmental exposures (e.g., endocrine disruptors) impact body composition as well as timing of puberty. Studies in adults describe the relationship between breast cancer, obesity, insulin resistance, and adipokines. Leptin and pro-inflammatory cytokines induce aromatase activity and production of estrogen, as well as lead to insulin resistance, whereas adiponectin has an inverse relationship with breast cancer. We propose to utilize a unique existing cohort of racially and ethnically diverse girls who have been followed longitudinally from ages 6 and 7. These girls have had serial examinations over 2-4 years, including height, weight, and assessment of pubertal maturation, as well as urine biomarkers obtained at baseline. Our aims are: to evaluate the relationship between the accumulation of fat during pubertal maturation by race and timing of puberty, and exposure to phthalates and phytoestrogens; and evaluate the longitudinal relationship between the early exposures to endocrine disruptors, timing of pubertal maturation, development of insulin resistance, and changes in leptin and adiponectin. This proposal will incorporate anthropometric and maturation data from the previous longitudinal study with earlier biomarker data, to current assessments of: body composition, regional fat distribution, and bone density; fasting insulin, glucose, and lipid profile; the adipokines leptin and adiponectin; and an inflammatory marker, IL-6. Additionally, one subgroup has had insulin and glucose levels obtained at baseline, and we propose to add analyses of stored sera from that time for analysis of leptin and adiponectin levels. This will allow us to better understand the relationships between timing of puberty, exposures to endocrine disruptors, pubertal body composition changes, and underlying mechanisms of insulin resistance with obesity and the metabolic syndrome. This study may help to inform interventions for prevention of breast cancer and the metabolic consequences of obesity. PUBLIC HEALTH RELEVANCE: The cohort of girls in this protocol have been followed longitudinally from ages 6 and 7 with physical examinations and measurement of environmental and dietary exposures. The additional studies in this proposal will allow the investigators to observe changes in body composition, bone content, and biochemical processes during puberty, a crucial period of growth and development.