In this prospective cohort study of Russian boys, we observed significantly later pubertal onset for boys with BLLs ≥5 µg/dL as compared to those with BLLs< 5 µg/dL; this finding was consistent across measures of pubertal onset based on testicular volume as well as genital and pubic hair staging, and persisted after adjustment for potential confounders. These findings are consistent with previous cross-sectional studies in US girls,20–21
which found delayed pubertal onset for girls with higher lead levels, and with our initial cross-sectional data on Russian boys.26
BLLs in the US have declined over time; however, 6% of US children under age 6 still had BLLs of 5–10 µg/dL in 1999–2004, and rates in some subgroups remain even higher (17% above 5 µg/dL among non-Hispanic blacks).36
BLLs in other countries may be similar or higher, particularly where leaded gasoline is still used.
Changes in genital staging and testicular volume are generally thought to occur in parallel, but few epidemiologic studies have simultaneously assessed both measures of pubertal maturation. We observed a median age at pubertal onset of 10.5 years based on TV>3ml, but a full year earlier for onset defined by genital staging. Despite these shifts across different pubertal onset measures, BLLs ≥5 µg/dL were consistently associated with a 6–8 month delay in pubertal onset relative to those with BLLs <5 µg/dL. This consistency is reassuring and has practical implications, given the relative ease in assessing pubertal staging in clinical settings and the lack of TV measurements in most epidemiologic studies.
It is unclear whether delays in pubertal onset occur at the level of the hypothalamic-pituitary gonadal axis by altering the activation of the GnRH pulse generator, or by altering other hormonal pathways that intersect with the reproductive hormones. Animal models suggest that lead exposure decreases concentrations of growth hormone, insulin-like growth factor 1 (IGF-1), testosterone and other hormones responsible for growth and pubertal development.16–19
The implications of altered pubertal timing have received more attention for early maturation, which has been associated with increased incidence of antisocial behaviors, substance use, and depression.37,38
However, late maturation in boys has also been associated with risk for psychosocial problems including lower self-esteem, depressive symptoms and eating disorders.39
It should be emphasized that the delays in pubertal onset we observed did not represent clinical delays for individual boys, but rather a shift in the mean age at pubertal onset for those with higher lead levels as compared to lower levels. However, given the large numbers of children with BLLs≥5 µg/dL in the US and worldwide, such a population shift has important implications from a public health perspective.41
BLLs above 10 µg/dL have been long recognized as having a strong association with neurocognitive and motor deficits in young children, leading to identification of this level as indicative of lead poisoning by the US Centers for Disease Control and Prevention.42
Yet BLLs well below 10 µg/dL are increasingly identified as being associated with mild neurologic impairment and diminished growth.43
Our results indicate that timing of pubertal onset can also be affected at BLLs in the 5–10 µg/dL range; these findings add to concern regarding BLLs in this lower range and support review of current policies.
We report an association of high BLLs with later pubertal onset even after adjusting for BMI and height at study entry. These anthropometric measures, however, may be on the causal pathway between lead exposure and pubertal onset. Measured BLLs may reflect chronic lead exposure or exposures during earlier periods, which in turn may result in diminished growth by age 8 to 9 years. In addition, it is known that bone mass increases during pubertal growth40
which leads to an increased distribution volume for lead and thus lower BLLs. Thus, including these growth measures at study entry in our models may have resulted in over-adjustment and attenuation of estimated effects.
Our study’s strengths include its size, prospective design, and consistent assessment of pubertal status by a single trained physician. Longitudinal pubertal onset assessments over this age range provided greater power and precision for estimating exposure effects than our previous cross-sectional analysis. It is also one of the few large-scale epidemiologic studies to include both physician-assessed pubertal staging and measured testicular volume. Limitations of our study include the lack of pre-natal and early childhood lead measurements, and the possibility of residual confounding by socioeconomic status.
In conclusion, this is the first prospective epidemiologic study to demonstrate a relationship between lead and later pubertal onset in boys. These associations occurred at levels which remain relevant for US, Russian, and other populations, raising concerns regarding the potential consequences for population-wide alterations in male pubertal timing.