Developmental and behavioral effects of fetal and neonatal exposure to the phenylpyrazole pesticide fipronil in mice

Fipronil (FPN), a phenylpyrazole pesticide widely used in agriculture and households, acts as a noncompetitive antagonist of gamma-aminobutyric acid (GABA)-gated chloride channels. Although originally considered relatively safe for mammals at low doses, FPN is metabolized into fipronil sulfone (FPNS), a more toxic and persistent metabolite. Both FPN and FPNS have been detected in human biological samples, raising concerns about chronic exposure during critical developmental windows. In this study, pregnant mice were administered FPN orally at 0.43 mg/kg/day from gestational day 1.5 through weaning. In Experiment 1, which was designed to evaluate fetal transfer, FPN and FPNS were detected in all fetal samples, with FPNS concentrations exceeding those of FPN and the levels of both compounds being higher in fetuses than in dams, suggesting placental transfer and fetal accumulation. In Experiment 2, behavioral and endocrine effects were assessed in male offspring at 3 and 10 weeks of age. Behavioral tests included the open field, elevated plus maze, and novel object recognition test. FPN-exposed offspring exhibited increased locomotor activity, reduced anxiety-like behavior, and impaired short-term memory and object recognition. Blood analyses revealed the presence of FPN and FPNS in exposed offspring, with FPNS levels peaking at 3 weeks. Histamine and progesterone levels were elevated at 3 weeks, while progesterone and 17-hydroxyprogesterone levels were decreased at 10 weeks. These findings suggest that fetal and neonatal exposure to FPN can disrupt neurobehavioral and endocrine development in mice.