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

Abstract

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.

A Comparison of the Nephrotoxicity of Low Doses of Cadmium and Lead

“…The mean E Cd /C cr in men was almost identical to that of women (Table 1). It is increasingly recognized that creatinine adjustment is problematic, and urine specific gravity has been used to correct for dilution effects [9,44,45,[50][51][52]. Herein, we have demonstrated the utility of normalizing excretion rate of metals to creatinine clearance that only required simultaneous urine and blood sampling together with the equations, given in Section 2.3 [33,35].…”

Potential Sex Differences Relative to Autism Spectrum Disorder and Metals

“…Metals such as lead interact heavily with calcium in the body [77], and a recent study looking at metal interactions via calcium pathways showed broader differences in body stores of metals in children during puberty [78]. Several metals, including lead, cadmium, arsenic, thallium, and copper, can also affect levels of free testosterone and estradiol [79–81], Differential levels of sex hormones also result in sex-specific variation in development of the brain. Studies have reported sex differences in prenatal testosterone levels and later development of behavioral disorders [82].…”

“…Cadmium has also been shown to interact with sex hormones and cause an increase in testosterone production in women [81]. Another study showed that several metals, including cadmium, arsenic, thallium, and copper, have an impact on sexual maturation and hormone levels [79]. Additionally, lead is well known to affect hormone levels of free testosterone and estradiol [79, 80].…”

“…Another study showed that several metals, including cadmium, arsenic, thallium, and copper, have an impact on sexual maturation and hormone levels [79]. Additionally, lead is well known to affect hormone levels of free testosterone and estradiol [79, 80]. This further complicates the interaction of hormones with metals, as accumulation and biomarkers for certain metals can be affected by disruptions in storage and metabolism of other metals.…”

The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds

“…Within the framework of GOLIATH, we will explore epidemiologic associations in the "Flemish Environment and Health Studies" that have been running since 2002 (FLEHS, http://www.milieuen-gezondheid.be/) [95][96][97][98][99][100][101][102] and in the "Prevention and Incidence of Asthma and Mite Allergy" cohort study (PIAMA, https://piama.iras.uu.nl/english/) that has been running since 1996 [103,104]. Both cohort studies contain a detailed characterization of lifestyle and environmental exposures as well as information on metabolically relevant molecular and physical outcome parameters at multiple ages in childhood and adolescence.…”