In utero and peripubertal metals exposure in relation to reproductive hormones and sexual maturation and progression among girls in Mexico City

Abstract

There is increasing evidence that several metals are endocrine disrupting chemicals (EDCs). In utero development and adolescence are critical windows of susceptibility to EDC exposure. With the exception of a few heavy metals, few human studies have evaluated the impact of metal exposure on pubertal development. Our aim was to investigate measures of in utero and peripubertal metal exposure in relation to reproductive hormone levels and sexual maturation and progression among girls from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohorts. We measured urinary concentrations of aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), cobalt (Co), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), nickel (Ni), antimony (Sb), selenium (Se), and zinc (Zn) in samples collected from women during their third trimester of pregnancy and from their female children at 8-13 years (n = 132). We measured serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG) at age 8-13, and assessed Tanner stages for sexual maturation (breast, pubic hair development, and menarche status), at two time points (8-13, 14-18 years). We used linear regression to independently examine in utero and peripubertal metal concentrations as predictors of peripubertal hormones. In a longitudinal analysis using generalized estimation equations, we evaluated Tanner stage and menarche progression in relation to individual in utero and peripubertal metal concentrations. We found that higher in utero Zn was associated with increased inhibin B. Several metals at 8-13 years were associated with higher DHEA-S and estradiol, while Ni was positively but Cu was negatively associated with testosterone. In utero Ni, Al, and Cd were associated with slower progression of breast development after adjustment for child age and BMI z-score. For example, an IQR increase in in utero Al exposure was associated with 0.82 times lower odds of progressing to a higher Tanner stage for breast development per year (95% CI: 0.68, 0.99). Peripubertal concentrations of Ba and Al were also associated with being at a higher pubic hair Tanner stage and menarche at 8-13, but lower odds of progressing to the next stage at 14-18 years. We used Bayesian kernel machine regression (BKMR) to model the joint effect of multiple metals while accounting for correlated exposures, as well as potential non-linear relationships between metals and outcomes of interest, which yielded results similar to individual analyses. These findings suggest that female reproductive development may be vulnerable to the effects of metal exposure, and using both Tanner stages and hormone levels may provide clues about underlying mechanisms in two sensitive periods of development.

Keywords: Hormone; In utero exposure; Metal; Pregnancy; Puberty.

Figure 1.

Recruitment, sample collection and examination timeline for the ELEMENT study, a prospective birth cohort in Mexico City, Mexico.

Figure 2.

Percent difference in peripubertal hormone levels associated with an interquartile range (IQR) increase in in utero and peripubertal metal concentration among ELEMENT girls^a. ^a Linear regression models were adjusted for child age, BMI z-score and specific gravity * Significant associations detected (p value<0.05)

Figure 3.

Odds Ratios and 95% Confidence Intervals for the Ordinal Generalized Linear Regression of in utero Metal Exposure and Tanner Stage^{a a} GEE models were adjusted for child age and BMI z-score (baseline and change) * Significant associations detected (p value<0.05)

Figure 4.

Odds Ratios and 95% Confidence Intervals for the Ordinal Generalized Linear Regression of peripubertal Metal Exposure and Tanner Stage^{a a} GEE models are adjusted for child age and BMI z-score (baseline and change) * Significant associations detected (p value<0.05)