Childhood Infection and Pubertal Timing

 描述(由申请人提供)：初潮年龄较早和乳房发育与乳腺癌风险增加有关。在美国和全球，初潮的平均年龄一直在下降，全国性的研究表明，乳房发育年龄的下降幅度更大(定义为Tanner阶段T2或更高)；更大比例的美国女孩从7-8岁开始T2+。青春期发育早期会导致终生接触性激素(即雌激素和孕激素)的时间更长。性激素促进乳腺细胞增殖，从而增加对环境暴露的易感性，从而可能引发癌症。童年时期较大的体型是青春期发育下降的一个主要原因。然而，即使在儿童肥胖率低得多的文化中(如香港)，也有证据表明青春期时机也在下降，这表明其他因素在起作用。 一项重大的生态变化是公共卫生措施导致的儿童感染减少，从而减少了接触，增加了对传染病病原体的抵抗力。新出现的证据虽然有限，但表明早期婴儿期和儿童期感染可能与青春期延迟有关。感染可能不会让身体在青春期发育过程中消耗能量，损害免疫系统，下调类固醇激素的产生和/或受体；因此，导致青春期时间较晚，乳腺癌风险降低。虽然大多数文献关注的是儿童肥胖症，但迫切需要了解其他可能导致青春期时机选择的因素，如儿童感染。然而，世界上几乎没有队列可以用来解决关于儿童感染和青春期时机的具体假设。利用LEGISE(R01CA138822)，这是一项前瞻性研究，丰富了有乳腺癌家族史(招募年龄为6-13岁，N=1,040岁)的女孩，旨在研究儿童时期的暴露和青春期发育，我将解决感染和青春期的未被充分研究的病因途径。我在传染病流行病学、行为肿瘤学和癌症流行病学方面的训练，使我唯一有资格研究青春期(即乳房发育开始年龄和月经初潮)和：1)儿童流行感染的血清学感染负担(EBV、CMV、HSV1/2 32-68%的全国血清阳性率)和2)儿童感染负担(根据母亲报告的感染暴露和医疗记录衡量)，跨越5个时间段(0-12个月，年龄(岁)1-5，6-10，11-13，14-18)。具体地说，通过有效地建立在世界上关于女孩青春期的最大研究之一的基础上，并将我的新研究问题与分子流行病学、基于家庭的研究、感染与健康、青春期发育和纵向建模方面的额外培训相结合，我还将能够检查与感染相关的分子变化，以及与青春期时机相关的分子变化，这是荷尔蒙和免疫调节途径的一部分。这项研究将为暴露于儿童感染和青春期时机的作用提供必要的证据，无论是依赖还是独立于肥胖。

 DESCRIPTION (provided by applicant): Earlier age at menarche and breast development is associated with an increased risk of breast cancer. The average age at menarche has been declining in the U.S. and globally, and national studies show even more dramatic declines in the age of breast development (as defined by Tanner stage T2 or higher); a greater proportion of U.S. girls are beginning T2+ at ages 7-8. Early pubertal development results in longer lifelong exposure to sex steroids (i.e. estrogen and progesterone). Sex-steroids promote mammary cell proliferation, which increases susceptibility to environmental exposures that could initiate carcinogenesis. Larger childhood body size is one major explanation for the declines in pubertal development. However, even in cultures with much lower childhood obesity (e.g., Hong Kong), there is evidence that pubertal timing is also declining suggesting that other factors are at play. One major ecological change has been the decline in childhood infections from public health measures that have resulted in reduced exposure and increased resistance to infectious agents. Emerging lines of evidence, though limited, suggests that early infancy and childhood infections may be associated with delayed pubertal timing. Infection may not allow the body to spend energy in pubertal development at the expense of the immune system, down-regulating steroid hormone production and/or receptors; therefore, resulting in later pubertal timing and a decrease in breast cancer risk. While the majority of literature focuses on childhood obesity, there is an urgent need to understand other factors that may contribute to pubertal timing, such as childhood infections. There are few cohorts in the world however that are available to address specific hypotheses about childhood infections and pubertal timing. Using LEGACY (R01CA138822), a prospective study enriched with girls with a breast cancer family history (recruited ages 6- 13 years, N=1,040) designed to study childhood exposures and pubertal development, I will address the understudied etiological pathway of infection and puberty. My training in infectious disease epidemiology, behavioral oncology, and cancer epidemiology make me uniquely qualified to examine the association between puberty (i.e. age of onset of breast development and menarche) and: 1) childhood serologic infection burden of prevalent infections (EBV, CMV, HSV1/2 32-68% national seroprevalence) and 2) childhood infection burden (as measured by mother reported infectious exposures and medical records) across 5 time periods (0-12 months, age (years) 1-5 , 6-10, 11-13, 14-18). Specifically, by building efficiently on one of the largest studies in the world of girls' puberty and coupling my novel research questions with additional training in molecular epidemiology, family-based studies, infection and health, pubertal development, and longitudinal modeling, I will be able to also examine molecular changes related to infections and relevant to pubertal timing that are a part of the hormonal and immunoregulatory pathways. This study will provide essential evidence for the role of exposures to childhood infection and pubertal timing, dependent or independent of adiposity.