Neurobehavioral and metabolic effects of prenatal low-dose chlorpyrifos in C57BL/6J mice

Chlorpyrifos is an organophosphorus insecticide known to produce severe neurotoxicity following early developmental exposure. So far, little data describes the neurobehavioral and metabolic consequences of low-dose exposures, near the threshold to produce cholinesterase inhibition. The purpose of the current study was to characterize the impact of prenatal exposure to a low dose of chlorpyrifos, at 0.5 mg/kg/day, and compare observed neurobehavioral and metabolic changes to a well-defined daily dose of 5 mg/kg. Pregnant C57BL/6 J dams were exposed to either 0, 0.5, or 5 mg/kg/day chlorpyrifos from gestation day 6.5-17.5. A metabolic profile was determined in dams and pups at the end of exposure and behavior was analyzed in offspring during late adolescence and early adulthood. Exposure to 5 mg/kg chlorpyrifos disrupted metabolites associated with the oxidative stress response and with energy metabolism within the brain and produced long-term impairment in spontaneous behavior and learning in offspring. Exposure to the lower dose of 0.5 mg/kg/day reduced levels of metabolites downstream of ornithine, a process that was also disrupted with exposure to 5 mg/kg/day. Further, 0.5 mg/kg/day chlorpyrifos impaired spontaneous behavior in offspring during adulthood, though no significant effects on learning or reversal were seen. These findings support a conclusion that prenatal low dose chlorpyrifos exposure produces long-term metabolic and neurobehavioral impairment that resemble deficits seen with high dose exposure.