Metals, hormones and sexual maturation in Flemish adolescents in three cross-sectional studies (2002-2015).

Sex hormone levels and timing of sexual maturation are considered important markers for health status of adolescents in puberty, and previous research suggests they might be influenced by metal exposure. In three campaigns of the Flemish Environment and Health Study (FLEHS I 2002-2006; FLEHS II 2007-2011 and FLEHS III 2012-2015), data were collected on internal exposure to metals (Cd, Cu, Pb, Cr, Mn, Tl, Ni, Sb, Hg, As and As species) and sexual maturation in 2671 14-15years old adolescents. All metals were measured in blood and/or urine, except total- and methylmercury which were measured in hair samples. Sex hormone levels were measured in blood serum of adolescent males of the cohorts of FLEHS I and FLESH II. The use of a uniform methodology in successive campaigns allows to confirm associations between exposure and health in different cohorts and over time. Furthermore, mathematical and statistical density correction methods using creatinine or specific gravity were tested for urinary markers. Significant associations between sex hormones and maturity markers were observed in the FLEHS I and II campaigns, when both were assessed together. Regardless of the applied correction method, creatinine correction systematically introduced bias due to associations of creatinine with sex hormones and maturation markers, especially in adolescent males, while this is not the case for specific gravity. A series of exposure-response associations were found, but several involving Cd, Pb, As, Tl and Cu persisted in different FLEHS campaigns. The effects of Pb and Cu on luteinizing hormone, (free) testosterone, (free) oestradiol and maturation support a xenoestrogenic agonistic action on the feedback of oestradiol to the hypothalamus-pituitary-gonadal axis. Our results suggest that specific care should be taken when selecting urine density correction for investigating associations with hormonal and maturation markers in adolescent males. Furthermore, the possibility of xenoestrogenic effects of certain metals in environmentally exposed adolescents warrants further investigation.