Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms

Abstract

Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

Keywords: acetylcholinesterase; brain; chlorpyrifos; development; learning; memory.

Fig. 1

Learning deficits presented by guinea pigs prenatally exposed to chlorpyrifos (CPF). Learning performance of offspring born to pregnant guinea pigs that had been injected with peanut oil (PO) or with CPF (25 mg/kg/day for 10 days starting on approximate GD53–55) was examined in the Morris water maze, as described in Mamczarz et al. (2016). (a) Swim paths of a vehicle (peanut oil)-exposed and a CPF-exposed male offspring on the 1st and 4th trials of the first and last days of training to find the hidden platform in the Morris water maze. The swim path of the male guinea pig prenatally exposed to peanut oil became shorter with training as the animal learned to use the contextual cues to find the platform. In contrast, the swim path of the male prenatally exposed to CPF did not improve substantially with training. (b and c) Graphs show mean escape latency (b) and distance (c) traveled by CPF- and peanut oil (PO)-exposed offspring per training day. Results are presented as mean ± standard error of the mean. A random effect ANOVA model revealed that: (i) among control animals, learning performance was sex dimorphic, with performance being better among control males than control females, and (ii) prenatal exposure to CPF impaired learning of male and female offspring, with the effect being more pronounced among males. According to Tukey– Kramer post hoc test for pairwise comparisons: *p < 0.05 PO males versus CPF males; †p < 0.05 PO males versus PO females. Details of the analysis are provided in the article by Mamczarz et al. (2016), from which this figure was adapted.

Fig. 2

Diffusion kurtosis imaging (DKI) parameters (mean diffusivity, MD and radial diffusivity, RD) obtained from the striatum of female guinea pigs prenatally exposed to chlorpyrifos (CPF) or peanut oil and correlation of these parameters with the learning performance of the animals. (a) Mean striatal RD and MD measured from female guinea pigs born to dams exposed to peanut oil or CPF (25 mg/kg/day for 10 days starting on approximate gestation day 53–55). Results are presented as mean and standard error of the mean. *p < 0.05; **p < 0.01. (b) Scatterplots of the correlation between striatal DKI measures and mean escape latency measures of CPF- and peanut oil-exposed offspring. Filled circles are data from CPF-exposed offspring, whereas open circles are data from peanut-oil exposed offspring. Details on the statistical analysis are provided in the article by Mullins et al. (2015), from which this figure was adapted.