Puberty Study

Puberty may serve as a window of susceptibility that impacts adult morbidity and mortality, and peripubertal breast tissue may be especially susceptible to environmental exposures. The majority of bone mineral is deposited during teen years, and insulin resistance rises during puberty. Visceral fat is an important factor that increases risk of obesity complications, but little is known about early factors that impact deposition of visceral fat Environmental exposures may impact body composition, as well as pubertal outcomes. Age at menarche is associated with risk of breast cancer, but pubertal growth velocity may be the underlying biologic phenomenon that impacts greater risk of breast cancer in taller women and those with earlier menarche. The investigators will utilize a unique existing cohort of girls followed from ages 6 and 7 and who have had semiannual examinations over 3-5 years. Working closely with the other two BCERC epidemiology projects, and with the Cincinnati BCERC community outreach program, this study proposes to fill the gap towards understanding the relationships between timing of onset and pathway of puberty with menarche, interaction between endocrine disruptors and polymorphisms, and changes in body composition. The investigators will complete the maturation assessment in this established cohort of girls, to include age at menarche, tempo of maturation, age/value of peak height velocity, body composition and fat distribution, and bone mineral accrual during puberty, by pathway into puberty. The investigators plan to assess dimensions of the physical/social environments including exposures to endocrine disrupting toxicants (EDCs), and how these factors contribute to impact onset of puberty and menarche. The investigators will explore the relationships and interactions of EDCs and genetic polymorphisms, on benchmarks of pubertal maturation. The Cincinnati epidemiology and outreach programs will develop and disseminate materials for lay audiences about lifestyle choices and potential health risks of specific exposures in regard to breast cancer, and enhance protocols to report study findings to study families. This proposal should allow us to understand better how changes during puberty can inform future prevention strategies to decrease the prevalence of breast cancer.

The CYGNET Study (Cohort study of Young Girls’ Nutrition, Environment, and Transitions) is a prospective cohort study of 444 girls that is examining environmental, lifestyle, and genetic factors in the development of early puberty and other hallmarks of maturation. Participants were aged 6-8 years at the time of enrollment from June 2005 to August 2006, and the investigators are currently in their 5th annual (4th follow-up) exam cycle. The study rationale lies in the growing recognition that the pubertal transition may be an important window of susceptibility in establishing long-term risk of breast cancer. The potential exposures to chemicals that are hormonally active raise concerns that these exposures and other lifestyle and genetic factors may play important roles in modifying age-at-onset of puberty and other hallmarks of sexual maturation. This cohort study is thus focused on determining factors that are associated with various milestones in sexual maturation. A key focus has been on breast development, as assessed by Tanner stage at annual clinical exams. As they continue to follow study participants, other parameters that may be associated with breast cancer risk are of interest, including onset of menses, establishment of cycle regularity, tempo (the time from onset of puberty to onset of menses), peak height velocity, and attainment of adult height. Exposures of interest are assessed through clinical exam (e.g., anthropometry), interviews and questionnaires (e.g., personal care product use, physical activity, food intake, psychosocial factors), and collection and assay of biospecimens (urine, blood, saliva) for environmental and genetic factors. Interactions with study participants and the broader community are facilitated by close integration with community partners, who are also involved in all aspects of study protocol. Through the 4th annual exam cycle, the investigators collected data from 391 (88%) of the original cohort of 444 girls. After the 1st follow-up year, they have retained annually over 97% of the cohort. Assuming similar annual retention rates, they estimate that for the ninth exam cycle in 2013-2014 when girls are 14-16 years old, we will see approximately 339 girls. By then, we expect that all girls will have begun puberty, most will have experienced peak height velocity and onset of menarche, and a small number will have achieved their adult height. Using conservative assumptions, the investigators should have adequate power to detect associations for most major endpoints of about 1.57 comparing high and low quartiles of a continuous variable such as biomarker levels.

In this application, the investigators propose to continue their study of hormonally active environmental exposures and genetics in relation to pubertal development. Within the next 5 years, their cohort of Black and Latina girls will have virtually all reached menarche and attained their adult height. Through continued follow-up of these two ethnic groups who experience disparate breast cancer incidence rates, it will be possible to complete the original aims as well as study milestones such as peak height velocity that occur much earlier in minority girls and are intermediate to breast cancer. These milestones along with the trajectories through adolescence will be assessed annually with BCERP collaborators; endpoints include breast stages, menarche, peak height velocity, menstrual cyclicity, and attained height in the national cohort of 1231 girls. Environmental exposures are hypothesized to contribute to the timing and progression of these life stages. Association are proposed to differ among girls with polymorphisms coding for lower vs. higher enzyme activity for estrogen synthesis, growth and DNA regulation, xenobiotic metabolism, and obesity; for deficient dietary factors related to growth and DNA methylation; and for differing social stress. Of major interest are the so-called endocrine disrupters or EDs, particularly those with exposures that are high enough and potent enough, both individually and potentially in combination, that achieve a biologically relevant dose. Annual interviews and exams will quantify outcomes, exposures and covariates using methods that will continue to be standardized across three national sites. Extensive existing information on exposure source patterns as well as chemicals measured in biospecimens will describe a broad range of environmental exposures. Additional biospecimens, environmental biomarker measurements, and exposure information will be obtained to assess variability of these exposures over childhood and to identify specific sources of exposure. The impact of multiple exposures will be investigated. Based on preliminary information and the biology of EDs, modification of exposure effects by genetic and dietary factors related to growth and epigenetics will be studied. Accelerated failure time models will be used to estimate the association of risk factors with ages at the critical outcomes as well as with tempos, or intervals between these time points. Risk estimates will be adjusted for confounders from the extensive data collected annually on the cohort of 1231 girls. The Community Outreach and Translation efforts will link established black and Hispanic breast cancer advocates in East Harlem, NY with the study and will translate findings to our participating families, the wider community, and the national constituency.