Zuo Melody, Gamache Isabel, Fagbemi Kaossarath, Day Felix R, Ong Ken K, Manousaki Despoina
Research Center of the Sainte-Justine University Hospital, Université de Montréal, Montreal, QC, Canada.
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
J Pediatr Endocrinol Metab. 2025 May 22. doi: 10.1515/jpem-2025-0146.
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.
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).
We found causal MR associations with AAM for three polychlorinated biphenyls (PCBs): PCB 74 (β: -0.015, 95 % CI [-0.028, -0.003], p=0.014), PCB 194 (β: -0.015, 95 % CI [-0.024, -0.007], p=3.27×10), and PCB 206 (β: -0.024, 95 % CI [-0.041, -0.006], p=0.0068) and for dibutyl phthalate (DBP, β: 0.006, 95 % CI [0.001, 0.010], p=0.013). One MR association was found with AVC for bisphenol A (BPA, β= -0.032, 95 % CI [-0.044, -0.019], p=2.62×10). Mediation analyses by MVMR or Two-Step MR suggested BMI's mediating role in the associations of EDCs with AAM and AVC.
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.
内分泌干扰化学物（EDCs）会干扰激素稳态，且观察发现其与青春期发育时间改变有关，青春期发育时间改变在女孩中由初潮年龄（AAM）定义，在男孩中由变声年龄（AVC）定义。然而，这些关联的因果关系仍不明确。我们采用孟德尔随机化（MR）方法来研究基因改变的血清EDC水平是否会影响青春期发育时间。
我们进行了单变量MR，以评估22种EDCs对AAM和AVC的影响，使用了关于EDCs的最大全基因组关联研究（GWAS）以及关于AAM和AVC的欧洲和多民族GWAS。进行了多变量MR（MVMR）和两步MR以检验体重指数（BMI）的中介作用。
我们发现三种多氯联苯（PCBs），即PCB 74（β：-0.015，95%置信区间[-0.028，-0.003]，p = 0.014）、PCB 194（β：-0.015，95%置信区间[-0.024，-0.007]，p = 3.27×10）和PCB 206（β：-0.024，95%置信区间[-0.041，-0.006]，p = 0.0068）以及邻苯二甲酸二丁酯（DBP，β：0.006，95%置信区间[0.001，0.010]，p = 0.013）与AAM存在因果MR关联。发现双酚A（BPA，β = -0.032，95%置信区间[-0.044，-0.019]，p = 2.62×10）与AVC存在一种MR关联。MVMR或两步MR的中介分析表明BMI在EDCs与AAM和AVC的关联中起中介作用。
我们的研究结果表明，接触特定的多氯联苯会导致AAM提前，而接触邻苯二甲酸二丁酯会使AAM延迟。接触双酚A会导致AVC提前，体重指数可能起到中介作用。
