Prenatal neonicotinoid insecticide exposure, maternal steroid hormone levels, and precocious puberty in girls: A nested case-control study.

Neonicotinoid insecticides (NNIs) are globally prevalent environmental contaminants with suspected endocrine-disrupting properties, yet their effects on maternal steroid hormone homeostasis and the subsequent risks of precocious puberty (PP) in offspring remain poorly understood. In this prospective nested case-control study embedded in a birth cohort in Wuhan, China (2012-2014; follow-up to 2023), we included 202 PP cases (115 incomplete [ICPP], 87 central [CPP]) and 606 matched controls. Third-trimester maternal urine samples were analyzed for 19 NNI biomarkers (8 detected in ≥74.1% of the samples) and 12 steroid hormones. Higher maternal urinary imidacloprid (IMI) and metabolites were significantly associated with increased odds of ICPP, but not CPP. Mixture analyses using generalized weighted quantile sum regression and Bayesian kernel machine regression consistently showed positive associations between exposure to the NNIs and ICPP odds, with 5-hydroxy-IMI identified as the major contributor (46.8%). NNI exposure was linked to altered maternal steroid hormone profiles, with more pronounced disruptions in ICPP case mothers. Exploratory mediation analysis suggested that progesterone (P4) and 17α-hydroxyprogesterone (17α-OHP) may partially mediate the association between IMI exposure and ICPP, accounting for 27.6% and 20.2% of the total effect, respectively. These findings suggest that prenatal IMI exposure may elevate the odds of ICPP in girls, potentially through disruption of maternal steroid hormone homeostasis, underscoring the need for public health attention to mitigate the developmental risks of NNI exposure during vulnerable windows.