Meconium Concentrations of Pesticides and Risk of Hypospadias: A Case-Control Study in Brittany, France

Background: Hypospadias is a male genital tract defect for which an increase in prevalence has been documented over the last few decades. A role for environmental risk factors is suspected, including prenatal exposure to pesticides. Objectives: To study the risk of hypospadias in association with multiple pesticide measurements in meconium samples. Methods: The Brittany Registry of Congenital Anomalies (France) conducted a casecontrol study between 2012 and 2018. Cases were hypospadias, ascertained by a pediatrician and a pediatric surgeon, excluding genetic conditions, following European Surveillance of Congenital Anomalies guidelines (N = 69). Controls (N = 135) were two male infants without congenital anomaly born after each case in the same maternity unit. Mothers in the maternity units completed a self-administered questionnaire, we collected medical data from hospital records, and medical staff collected meconium samples. We performed chemical analysis of 38 pesticides (parent compound and/or metabolite) by UHPLC/MS/MS following strict quality assurance/quality control criteria and blind to casecontrol status. We carried out logistic regression accounting for frequency-matching variables and major risk factors. Results: Among the 38 pesticides measured, 16 (42%) were never detected in the meconium samples, 18 (47%) were in <5% of samples, and 4 (11%) in >= 5% of the samples. We observed an association between the detection of fenitrothion in meconium and the risk of hypospadias (OR = 2.6 [1.06.3] with n(cases) = 13, n(controls) = 21), but not the other pesticides. Conclusions: Our small study provides a robust assessment of fetal exposure. Fenitrothions established antiandrogenic activities provide biologic plausibility for our observations. Further studies are needed to confirm this hypothesis.