Associations of prenatal exposure to multiple metals with testicular volume and anogenital distance in infant boys: A longitudinal cohort study
Lulu HuangSifang HuangXiaoyu LuoLongman LiXiang ChenGaohui ZanYanli TanChaoqun LiuQingzhi HouXiaoting GeChunfei ChenHong XinYan TianAimin YangPan ChenMujun LiZengnan MoXiaobo Yang
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Abstract:
Human are widely exposed to multiple metals, some of which have suspected reproductive toxicity, but no human studies have investigated the developmental effects of prenatal metal exposure. We aimed to evaluate the associations between prenatal multiple metal exposure and reproductive development in boys at 2–3 years using multi-pollutant approach. This prospective study used data of 564 mother–child pairs recruited from the Guangxi Birth Cohort Study. Twenty serum metal concentrations were measured. Least absolute shrinkage and selection operator (LASSO) penalized regression was used to identify independent associations between prenatal multiple metal exposure and testicular volume (TV), and anogenital distance (AGD). Adjusted estimates were then obtained using multiple linear regression analysis, and the regression tree method was used to explore the interactions. Boys in the highest quartile of prenatal lead exposure had a 0.064 mL (95% CI: −0.124, −0.004) smaller ln-transformed TV, 0.060 cm (95% CI: −0.110, −0.011) shorter ln-transformed anopenile distance (AGDap), and 0.115 cm (95% CI: −0.190, −0.039) shorter ln-transformed anoscrotal distance (AGDas) than boys in the lowest quartile (all Ptrend < 0.05). Chromium was inversely with ln-transformed AGDap (β = −0.078, 95% CI: −0.127, −0.030) and ln-transformed AGDas (β = −0.113, 95% CI: −0.188, −0.038), while stibium was positivity associated with ln-transformed AGDap (β = 0.091, 95% CI: 0.046, 0.136) and strontium was positivity associated with ln-transformed AGDas (β = 0.120, 95% CI: 0.051, 0.189) (all Ptrend < 0.05). And the critical window of vulnerability may be the late pregnancy (the second and third trimester). Moreover, we detected interaction effects between lead, chromium and stibium on AGDap; lead, chromium and strontium on AGDas. The results suggest that prenatal exposure to lead, chromium, stibium and strontium may affect TV and/or AGD in infant boys. Potential mechanisms for the complex metal interactive effects during vulnerable periods are worthy of further investigation.Keywords:
Quartile
Anogenital distance
Vaginal candidiasis is frequent among pregnant women and it is treated with anti-fungal medication (conazoles). Conazoles have anti-androgenic properties and prenatal exposure in rodents is associated with a shorter (less masculine) anogenital distance (AGD) in male offspring. To our knowledge this has never been studied in humans. In the Odense Child Cohort pregnant women residing in Odense municipality, Denmark, were recruited at gestational age 8–16 weeks between 2010 and 2012. Of the eligible 2421 mother-child pairs, 812 mother-son pairs were included. Questionnaire data on medicine use were collected in first and third trimester and physical examination at age 3 month was performed. Ano-scrotal distance; measured from the centre of anus to the posterior base of scrotum (AGDas). Ano-cephalad distance; measured from the centre of anus to the cephalad insertion of the penis (AGDap) and penile width; measured at the base of the penis. Eighty seven women had used antifungal medicine during pregnancy. Maternal use of oral fluconazole (n = 4) was associated with a 6.4 mm shorter AGDas (95% CI: -11.9;-0.9) in the male offspring. Use of antifungal vaginal tablets (n = 21), was associated with a non-significantly shorter AGDas (−1.9 mm; 95% CI: -4.3; 0.5) whereas exposure to vaginal cream (n = 23) was not associated to AGDas. Use of antifungal medicine in the window of genital development between 8 and 14 weeks of gestation was associated with a larger reduction in AGDas than exposure outside this window. Antifungal medicine intake was not associated with AGDap and penil width. Our preliminary findings prompted us to hypothesize that maternal use of conazole antifungal medication during pregnancy may affect the masculinization of male offspring. If confirmed, pregnant women should be advised to use antifungal medicine with caution.
Anogenital distance
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