Neurodevelopmental Effects of Chlorpyrifos Depend on Age of Exposure and Maturational Stage: an In Vivo MR and Behavioral Study

Abstract

Exposure to chlorpyrifos (CPF), an organophosphorus pesticide, is a serious worldwide health concern. Aside from issues of acute toxicity, a major focus of this concern is its harmful long-term effects on neurodevelopment in humans and animals. By employing MR techniques as well as standard animal behavioral tasks, we test the hypothesis that exposure to a sub-lethal dose of CPF causes neurodevelopmental deficits that are dependent on both the developmental stage of exposure and the extent of maturity after exposure. The scope of this hypothesis necessitates the examination of these neurodevelopmental effects in a guinea pig animal model over a range of neurodevelopmental stages, from gestation to maturation. In addition to studying normal development as a baseline, our investigation focused on the neurological deficits associated with CPF exposure in the prenatal and prepubertal periods, and examined the persistence of these effects into maturity. Our results demonstrated that normal development of the guinea pig brain was characterized by clear age-related increases in overall brain volume, white matter integrity, and microstructural complexity. Prenatal exposure to CPF resulted in decreases in forebrain volume, grey and white matter integrity, and spatial learning performance, with these effects being primarily associated with the integrity of the striatum and amygdalae. Prepubertal exposure to CPF yielded more complex results over development, which depends on the age of the animal at the time of examination. Significant spatial memory impairments and reductions in hippocampal myo-inositol were observed in mature animals a year after prepubertal exposure to CPF, while at the adolescent and young adult stages there were instead behavioral signs of anxiety, cytotoxic edema in the corpus callosum, striatum, and thalamus, and oxidative stress in the cerebral cortex. In the hippocampus there was a potentially neuroprotective glutamine response that may explain the lower severity of the effects in the young adult age compared to the more severely afflicted mature adults. These findings provide compelling evidence in support of the above neurodevelopmental CPF hypothesis. The key findings of these experiments are that lifelong deficits in brain function result from even a single exposure to CPF, vary greatly depending on the neurodevelopmental stage at time of exposure, and increase in severity as the animal matures. This knowledge of the complex neurodevelopmental effects of CPF aids future preventive measures, informs human translational research, and acts as a solid basis for further mechanistic animal studies.