Childhood Infection and Pubertal Timing

 描述（由申请人提供）：初潮和乳房发育的早期年龄与乳腺癌风险增加有关。美国和全球的月经初潮平均年龄一直在下降，国家研究表明乳房发育年龄（由坦纳分期T2或更高定义）的下降幅度更大;更大比例的美国女孩在7-8岁时开始T2+。青春期发育早导致终生暴露于性类固醇（即雌激素和孕激素）的时间更长。性类固醇促进乳腺细胞增殖，从而增加对环境暴露的敏感性，从而可能引发致癌作用。儿童期体型较大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（例如，香港），有证据表明，青春期的时间也在下降，这表明其他因素也在起作用。 一个主要的生态变化是，公共卫生措施减少了儿童感染，从而减少了接触传染性病原体的机会，增强了对传染性病原体的抵抗力。新出现的证据虽然有限，但表明婴儿早期和儿童感染可能与青春期延迟有关。感染可能不允许身体以牺牲免疫系统为代价在青春期发育中消耗能量，下调类固醇激素的产生和/或受体;因此，导致青春期推迟和乳腺癌风险降低。虽然大多数文献集中在儿童肥胖，但迫切需要了解可能导致青春期时间的其他因素，如儿童感染。然而，世界上很少有队列可用于解决有关儿童感染和青春期时间的具体假设。使用LEGACY（R 01 CA 138822），这是一项前瞻性研究，包含有乳腺癌家族史的女孩（招募年龄为6- 13岁，N= 1，040），旨在研究儿童期暴露和青春期发育，我将阐述未充分研究的感染和青春期病因学途径。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有资格研究青春期与癌症之间的关系。（即乳房发育和初潮开始的年龄）和：1）流行感染的儿童血清学感染负担（EBV，CMV，HSV 1/2 32-68%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测量），在5个时间段（0-12个月，年龄（岁）1-5，6-10，11-13，14-18）。具体来说，通过有效地建立在女孩青春期的世界上最大的研究之一，并将我的新的研究问题与分子流行病学，以家庭为基础的研究，感染和健康，青春期发育和纵向建模的额外培训相结合，我也将能够检查与感染相关的分子变化，并与青春期时间相关，这是激素和免疫调节途径的一部分。这项研究将为儿童期感染暴露和青春期时间的作用提供必要的证据，依赖或独立于肥胖。

 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.