Comparative developmental and maternal neurotoxicity following acute gestational exposure to chlorpyrifos in rats

Abstract

Chlorpyrifos (CPF), an organophosphorus (OP) insecticide, exerts toxicity through inhibition of acetylcholinesterase (AChE). In the present study, pregnant Sprague‐Dawley rats were given CPF (200 mg/kg, sc) as a single dose on gestation d 12 (GD12) and then sacrificed on either GD16, GD20, or postnatal d 3 (PND3) for measurement of maternal and developmental indicators of toxicity. While most CPF‐treated rats exhibited no overt signs, a subset (4/28) showed moderate to severe signs of “cholinergic” toxicity at 2–3 d after treatment, and these rats were omitted from further studies. Extensive AChE inhibition (82–88%) was noted in maternal brain at all three time points following acute exposures. At GD16 and GD20, fetal brain AChE activity was inhibited 42–44%. While some degree of recovery in AChE activity was noted in pup brain by PND3, AChE activity was still inhibited (30%) in treated pups cross‐fostered to control dams. In vitro inhibition of maternal and fetal (GD20) brain AChE activity by the active metabolite, chlorpyrifos oxon, suggested that the prenatal brain AChE activity was somewhat more sensitive (IC50 at 37.0°C, 20 min: dam, 26.6 ± 1.8 × 10⁻⁹ M; fetus, 6.7 ± 0.4 × 10⁻⁹ M). Maternal brain muscarinic receptor binding was more extensively reduced (30–32%) at GD20 and PND3 as compared to the developing brain at GD20 (16%) and PND3 (11 %). A simple postnatal reflex test (righting reflex) was transiently altered by CPF. The results suggest that CPF exposure to dams during gestation produces more extensive neurotoxicological effects in the dam relative to the developing fetus.