Final Report: Environmental Exposures Related to Early Puberty

EPA Grant Number: R825816
Title: Environmental Exposures Related to Early Puberty
Investigators: Wolff, Mary S. , Berkowitz, Gertrud S. , Britton, Julie , Forman, Joel , Godbold, James , Hochman, Sarah , Kabat, Geoffrey , Kadlubar, Fred F. , Kase, Nathan , Larson, Signe , Leleiko, Neal , Serra, Nicole , Wetmur, James G.
Institution: Mount Sinai School of Medicine
EPA Project Officer: Hahn, Intaek
Project Period: January 16, 1998 through January 15, 2001
Project Amount: $380,482
RFA: Issues in Human Health Risk Assessment (1997) RFA Text |  Recipients Lists
Research Category: Economics and Decision Sciences , Health Effects , Human Health Risk Assessment , Health


The objective of this research project was to investigate the potential effect of cumulative, multiple environmental exposures on onset of puberty; in particular, early breast and hair development, which may be associated with hormonally active exposures. We investigated how racial/ethnic differences in pubertal onset may be explained by environmental exposures and by the susceptibility factors (genes) that govern their metabolism (e.g., the cytochrome P450 metabolizing enzymes). In this grant, we proposed to assess dietary and toxic exposures, early life events, and other susceptibility factors in relation to stage of puberty in a multiethnic group of 9-year-old girls.

Summary/Accomplishments (Outputs/Outcomes):

The study population was recruited from 1997-1998 from each of three ethnic groups (54 African-American, 66 Caucasian, 72 Hispanic). Both recent and usual dietary intake and potential confounders (height, weight, physical activity) were recorded. A blood sample was obtained and analyzed for organochlorines (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene or DDE; polychlorinated biphenyls or PCBs) and hormone-metabolizing genes. Spot urine samples were analyzed for isoflavones and other environmental agents were collected. We collected information on early life events such as birth weight and mother's weight at birth.

Results to date show strong positive associations of pubertal onset with body mass index (BMI) and African-American ethnicity. Differences are evident in physical activity among ethnic groups, and sedentary activity was positively associated with puberty, although not statistically significant. We have determined common polymorphisms (i.e., variants present in 10-50 percent of the population) in several genes that metabolize both hormones and environmental contaminants (CYP3A4, CYP3A5, CYP17, CYP1A2, CYP1B1). We found an association between CYP3A4 and breast pubertal onset, independent of race/ethnicity (OR 3.71, CI 1.44-9.58 per rapid CYP3A4 allele adjusted for race, age, height, BMI). The other gene variants were not associated with puberty. We now are completing the analysis of relationships among birthweight and pubertal onset, 9-year-old weight, metabolizing gene variants, and environmental exposures.

To explore the potential influence of diet on pubertal onset, we examined selected food items, nutrients, and phytoestrogen intake. The intake of calories and protein was significantly higher among African-American and Hispanic girls, while consumption of vegetables, lettuce, and apples was higher among Caucasians. Fiber and fruit intakes were lower in Hispanics than Caucasians. Dietary intakes were not different for Hispanics and African-Americans for most foods, although intake of green vegetables (but not all vegetables) was higher among African Americans than Hispanics. Total phytoestrogen consumption did not differ across racial/ethnic groups (flavonoids, lignans, and phytosterols, adjusted for calorie intake and BMI). However, some of the individual phytoestrogen dietary intakes differed by ethnicity (i.e., coumestrol, formononetin, and biochanin A intakes were higher among Hispanics compared to African Americans and Caucasians). There was no consistent, independent effect of phytoestrogens (e.g., lignans, isoflavones, flavonoids, and phytosterols) on pubertal onset, however, there was a significant inverse association of vitamin C with pubertal hair and a positive association of polyunsaturated fat intake with breast puberty (adjusted models). For phytoestrogens in urine, there were some differences in levels among ethnic groups. Genistein was lower, and quercetin metabolites were higher in urine among Caucasians (adjusted for creatinine). Preliminary analysis indicated no consistent relationships of urinary metabolites with pubertal onset, although there is a suggestive inverse association of one metabolite with pubertal onset.

To date, the major finding of this research was the strong association of a common genetic polymorphism in CYP3A4 with pubertal onset. This association is independent of ethnicity, yet there are wide differences in the distribution of the gene variants by ethnicity. CYP3A4 is the most abundant cytochrome P450 enzyme in liver. It metabolizes testosterone, estrogen, polycyclic aromatic hydrocarbons, and other substrates, including pharmaceuticals. Therefore, ethnic variability in the distribution of its activity has wide implications in terms of public health. On the other hand, preliminary data suggested that CYP3A4 is not associated with birthweight, whereas other P450 genotypes may be associated with birthweight. It is known that gene expression of different P450 enzymes differs over the period from in utero to adolescence, and this temporality may affect health outcomes, including body size. Such effects also may help define "windows of susceptibility" to endogenous and exogenous exposures. In addition, we have confirmed previous (i.e., PCB, DDE) or observed new (i.e., food intake) differences in environmental exposures among ethnic groups. We also have observed differences in dietary intake of both protective (i.e., vitamin C) and unhealthy (i.e., fat intake) dietary intakes among ethnic groups.

Some population subgroups have both adverse exposures and higher frequency of adverse genotypes, and may be at greater risk of associated adverse health effects. Our study was too small to examine gene-environment effects, but this will be a topic for future research. With knowledge of such risks, gene-environment risk groups can be investigated in heterogeneous populations where individual susceptibility and multiple exposures are measured. Through such research, it may be possible to reduce risk early in life to confer lifelong benefits to health. These health benefits include reducing cancer risk, and improving endocrine function and cardiovascular health.

Journal Articles on this Report : 2 Displayed | Download in RIS Format

Other project views: All 6 publications 2 publications in selected types All 2 journal articles
Type Citation Project Document Sources
Journal Article Kadlubar FF, Berkowitz GS, Delongchamp RR, Wang C, Green BL, Tang G, Lamba J, Schuetz E, Wolff MS. The CYP3A4*1B variant is related to the onset of puberty, a known risk factor for the development of breast cancer. Cancer Epidemiology Biomarkers and Prevention 2003;12(4):327-331. R825816 (Final)
R831711 (2005)
R831711 (2007)
  • Abstract from PubMed
  • Full-text: Cancer Epidemiology, Biomarkers and Prevention-Full Text HTML
  • Journal Article Wolff MS, Berkowitz GS, Brower S, Forman J, Godbold J, Kase N, Lapinski R, Larson S, Senie R, Tartter P. Hormonally active environmental exposures and their relationship to risk for reproductive cancer among women. Women and Cancer 1999;1:8-20. R825816 (Final)
    not available

    Supplemental Keywords:

    DDT, DDE, PCBs, chlordane, physical activity, environmental exposures, hormones, phytoestrogens, risk factors, prenatal., RFA, Health, Scientific Discipline, Genetics, Environmental Chemistry, Chemistry, endocrine disruptors, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Children's Health, genetic susceptability, Endocrine Disruptors - Human Health, health effects, interindividual variability, puberty, reproductive effects, risk assessment, adolescence, adolescents, breast cancer, childhood cancer, health risks, vulnerability, racial and ethnic differences, age-related differences, endocrine disrupting chemicals, exposure, gender, gene-environment interaction, children, environmental mutagens, fertility, human malformation, particle exposure models, human exposure, susceptibility, toxicity, cumulative environmental exposure, diet, environmental stressors, environmental toxicant, harmful environmental agents, race ethnicity, toxic environmental contaminants, biological markers, growth & development, reproductive health, toxicants, hispanics, isoflavones, age, cancer risk, developmental disorders, exposure assessment, genetic diversity, reproductive

    Relevant Websites: Exit

    Progress and Final Reports:

    Original Abstract
  • 1998
  • 1999 Progress Report