The causal role of endocrine disrupting chemicals in pubertal timing: a Mendelian randomization study.

Objectives: Endocrine disrupting chemicals (EDCs) interfere with hormonal homeostasis, and have been observationally linked to altered pubertal timing, defined by the age of menarche (AAM) in girls and the age at voice change (AVC) in boys. However, the causality of these associations remains unclear. We used Mendelian randomization (MR) to investigate if genetically altered serum EDC levels affect pubertal timing.

Methods: We performed univariate MR to assess the effects of 22 EDCs on AAM and AVC, using the largest GWAS for EDCs as well as European and multi-ethnic GWAS on AAM and AVC. Multivariate MR (MVMR) and two-step MR were conducted to examine mediating effects of body mass index (BMI).

Results: We found causal MR associations with AAM for three polychlorinated biphenyls (PCBs): PCB 74 (β_IVW: -0.015, 95 % CI [-0.028, -0.003], p=0.014), PCB 194 (β_IVW: -0.015, 95 % CI [-0.024, -0.007], p=3.27×10^-4), and PCB 206 (β_IVW: -0.024, 95 % CI [-0.041, -0.006], p=0.0068) and for dibutyl phthalate (DBP, β_IVW: 0.006, 95 % CI [0.001, 0.010], p=0.013). One MR association was found with AVC for bisphenol A (BPA, β_{Wald ratio}= -0.032, 95 % CI [-0.044, -0.019], p=2.62×10^-7). Mediation analyses by MVMR or Two-Step MR suggested BMI's mediating role in the associations of EDCs with AAM and AVC.

Conclusions: Our findings indicate that exposure to specific PCBs leads to earlier AAM whereas exposure to DBP delays AAM. Exposure to BPA leads to earlier AVC, with BMI potentially acting as a mediator.