Impact of peripubertal exposure to xenohormones on fat distribution and cytokines

描述(申请人提供)：青春期是一个动态的时期，其中包括生理和生化变化，并可能成为成人发病率和死亡率的易感窗口。例如，女性的大部分骨矿含量是在青少年时期沉积的，骨矿密度较高与乳腺癌之间的关系已经确立。青春期也是身体成分发生戏剧性变化的时期，胰岛素抵抗增加。内脏脂肪的沉积被认为会增加肥胖代谢并发症的风险，但对童年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)会影响身体成分和青春期的时间。对成年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，而脂联素与乳腺癌的发生呈负相关。我们建议利用现有的一个独特的不同种族和民族的女孩队列，她们从6岁到7岁开始进行纵向跟踪。这些女孩在2-4年期间接受了一系列检查，包括身高、体重和青春期成熟的评估，以及基线时获得的尿液生物标记物。我们的目标是：评估种族在青春期成熟过程中脂肪积累与青春期时间、邻苯二甲酸盐和植物雌激素暴露之间的关系；以及评估内分泌干扰物早期暴露、青春期成熟时间、胰岛素抵抗的发生以及瘦素和脂联素变化之间的纵向关系。这项建议将把先前纵向研究中的人体测量和成熟度数据与早期的生物标志物数据结合起来，用于目前的评估：身体成分、区域脂肪分布和骨密度；空腹胰岛素、血糖和脂谱；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血糖水平已经在基线水平获得，我们建议增加从那时起存储的血清的分析，以分析瘦素和脂联素水平。这将使我们更好地了解青春期时间、暴露于内分泌干扰物、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的干预措施提供信息。 公共卫生相关性：本议定书中的女孩队列从6岁和7岁开始进行纵向跟踪，进行体检并测量环境和饮食暴露。这项提案中的其他研究将使研究人员能够观察青春期期间身体成分、骨骼含量和生化过程的变化，青春期是生长和发育的关键时期。

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.