Hormonal Indicators of Pubertal Onset & Their Relationship to Blood Lead Levels

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Previous research on the early onset of puberty has focused on specific subpopulations or clinical populations, and data on the patterns of pubertal onset, that is, in children as young as ages 6 to 8 years, in a nationally representative sample are lacking. Further, evidence suggests that exposure to environmental toxins, such as environmental lead (Pb) and endocrine disrupters, may adversely affect hormone levels and pubertal onset. However, data on how and whether environmental toxicants may be implicated in the decline or contribute to a delay in pubertal onset are scarce and have generally been confined to older children and adolescents. The target sample for these analyses is children, ages 6-11 years, examined as part of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-94). There are two objectives of these analyses of residual stored biologic specimens (serum) for children: (1) to estimate by assay of hormones (luteinizing hormone LH and inhibin B for boys and girls, testosterone for boys) the timing of the onset of pubertal development in a nationally representative sample of children, ages 6-11 years, and the patterns and concordance between hormonal indicators and pubertal onset based on physical maturation (Tanner sexual maturation scores) for children, ages 8-11 years; and (2) to determine if the recent findings linking blood lead (Pb) levels and delayed maturation based on Tanner scores (pubic hair) and age at menarche in girls can be confirmed by hormonal analysis and extended to younger ages and to determine for young boys if there are effects of blood Pb levels on timing of maturation. Whole blood Pb and, in addition, urinary cadmium (Cd) have already been analyzed for examined children in NHANES III. It is important to note that the 6-11 year old children in NHANES III were born in the years 1977-1988, before the Lead Contamination Control Act of 1988 virtually eliminated Pb in gasoline, so it is unlikely that later iterations of NHANES will be as useful in answering the question about the relationship between environmental Pb exposure and timing of puberty. Significant preliminary findings: For the sample of 774 boys, we found that inhibin B levels increased significantly with increasing age, genital and pubic hair stage (p<0.0001), with progressive increases from stages 1 to 2, and from 2 to 3 or greater. When compared across all ages for non-Hispanic White (NHW), non-Hispanic Black (NHB), and Mexican-American (MA) boys, levels of inhibin B were significantly higher overall in NHB (p<0.01). Among Tanner genital stage 1 boys, there was a significant effect of race/ethnicity (p=0.02) with NHB having the highest levels, but no significant effect of age. Conversely, among those with Tanner stage 2 or greater, there was no significant effect of race/ethnicity, but there was a significant effect of age (p=0.01). This is in contrast with testosterone, where concentrations increased significantly with both age and pubic hair stage, although not for genital stage, and there were no statistically significant racial/ethnic differences at any age. There was also considerable overlap in both inhibin B and testosterone between Tanner stages 1 and 2, and thus no cut-off level that clearly discriminates the onset of pubertal status because of the high inter-individual variation. These results represent hormone measurements in the first nationally-representative sample of pre-pubertal and pubertal U.S. boys. We observed significant racial/ethnic differences in inhibin B concentrations that parallel the earlier transition from Tanner genital stage 1 to 2 in NHANES III NHB boys, although the clinical significance of the generally higher levels in NHB boys at these ages is unclear. For girls, lead (PB) is a known reproductive toxicant thought to disrupt hormone production throughout sensitive developmental windows, such as puberrty. Lead exposure levels have decreased in recent decades, but concentrations even below toxic levels (defined now as 10 ug/dL) in young girls may still have adverse effects. We examined the association between blood Pb and inhibin B, in 667 6- to 11-year-old girls. Survey linear regression was used to estimate the association between continuous lead (log) and inhibin B levels and logistic regression for exposure categories (< 1, 1-4.9, =>5 ug/dL). Non-Hispanic black (NHB) girls had the highest (p<0.0001) lead concentrations (3.1 ug/dL), compared with Mexican-American (2.2 ug/dL) and non-Hispanic white girls (1.8 ug/dL). In linear models, Pb was significantly inversely associated with inhibin B, adjusting for race/ethnicity (beta = -0.17 log(pg/mL) per unit change in log(Pb), SE=0.08, p=0.03). We also found a significant interaction (p=0.04) between Pb and urinary cadmium in decreasing inhibin B. Thus, higher blood Pb levels were associated with decreased inhibin B and later achievement of the onset of puberty in young girls. These findings are consistent with prior research with NHANES III showing a later attainment of sexual maturation stages and age at menarche in older girls and suggest that the mechanism may be through systemic disruptions in the hypothalamic-pituitary-ovarian axis or more locally through a direct negative effect on ovarian development.