1639d Preclinical model of chlorpyrifos exposures and effects documented in egyptian pesticide applicators

Introduction Organophosphorus pesticide (OP)-induced neurotoxicity remains a significant occupational health concern, management of which is complicated by the lack of biomarkers that reliably identify at-risk individuals. To address this issue, we used a preclinical model of occupational OP exposure to evaluate the relationship between OP-induced cognitive deficits and expression of conventional and novel biomarkers of exposure and effect. Methods Adult male Long Evans rats were exposed to CPF (3 or 10 mg/kg/d, s.c.) or an equal volume of vehicle for up to 21 days. Previous PBPK modelling studies confirmed that this exposure paradigm resulted in urinary TCPy levels and blood cholinesterase activity within the range of those observed in exposed Egyptian pesticide applicators. Learning and memory were assessed using appetitive Pavlovian discrimination between two tones and by Pavlovian fear conditioning. Tissues were collected for quantification of peripheral and central biomarkers of CPF exposure, inflammation and oxidative stress. Results Subchronic CPF exposure for 21 d interfered with the maintenance and reversal of appetitive behaviour, but these effects were not reliable. In contrast, CPF caused robust and reproducible dose-dependent deficits in Pavlovian fear conditioning at 21 but not 4, 10 or 15 days of exposure. CPF also increased urinary TCPy levels, caused a delayed decrease in blood and brain cholinesterase activity, increased urinary and brain F2-isoprostanes and upregulated expression of multiple oxidative stress biomarkers in brain and in the periphery. Of these biomarkers, only oxidative stress biomarkers correlated with cognitive deficits. Moreover, CPF-induced cognitive deficits were prevented by co-administration of the antioxidant Trolox (1 mg/kg, i.p.). Conclusion These findings demonstrate that subchronic exposures to CPF at levels that do not cause systemic cholinergic toxicity impair learning and memory via effects on the amygdala and hippocampus. Biomarker analyses suggest that oxidative stress, but not cholinesterase inhibition, contribute to CPF-induced cognitive deficits. Funding: R01 ES016308