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 (βIVW: −0.015, 95 % CI [−0.028, −0.003], p=0.014), PCB 194 (βIVW: −0.015, 95 % CI [−0.024, −0.007], p=3.27×10−4), and PCB 206 (βIVW: −0.024, 95 % CI [−0.041, −0.006], p=0.0068) and for dibutyl phthalate (DBP, βIVW: 0.006, 95 % CI [0.001, 0.010], p=0.013). One MR association was found with AVC for bisphenol A (BPA, βWald 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.