Abstract
Background
Exposure to endocrine-disrupting chemicals (EDCs) during fetal life is associated with reproductive disorders in humans. While research has largely focused on environmental EDCs and developmental exposure, some pharmaceuticals, including commonly used antifungal agents, also possess endocrine-disrupting properties. We investigate whether prenatal exposure to over-the-counter antifungal drugs is associated with altered fetal and postnatal steroidogenesis and reproductive development.Methods
We combined epidemiological, experimental, and translational approaches using data from a prospective mother-child cohort (n = 589), ex vivo human fetal adrenal cultures, and in vivo rat models. Maternal antifungal use during pregnancy was assessed prospectively, and associations with fetal growth, anogenital distance (AGD), penile measurements, and circulating steroid hormone levels during infancy were evaluated. Experimental studies examined the effects of selected antifungal agents on steroidogenesis in cultured human fetal adrenals and gestationally exposed Sprague-Dawley rats.Results
Early-pregnancy antifungal exposure is associated with reduced circulating steroid hormone levels and indicators of diminished androgen action, including decreased penile width at infancy. In contrast, exposure during mid-to-late pregnancy is associated with elevated steroid hormone levels and longer AGD in both female fetuses and male infants. Consistent with these observations, the antifungal agent clotrimazole reduces progesterone levels in human fetal adrenal cultures and in gestationally exposed rats, whereas miconazole increases AGD in rats.Conclusions
These translational findings suggest that commonly used antifungal agents alter fetal adrenal steroidogenesis and influence reproductive development, with effects persisting into postnatal life. Given their widespread use and over-the-counter availability, the safety of topical azole use during pregnancy may warrant re-evaluation.