Early postnatal parathion exposure in rats causes sex-selective cognitive impairment and neurotransmitter defects which emerge in aging

Abstract

Developmental exposure of rats to the organophosphate (OP) pesticides leads to altered neurobehavioral function in juvenile and young adult stages. The current study was conducted to determine whether effects of neonatal parathion exposure on cognitive performance persist in older adult and aged rats, and the relationship of behavioral changes to underlying cholinergic and serotonergic mechanisms. We administered parathion to rat pups on postnatal days 1-4, at doses spanning the threshold for the initial signs of systemic toxicity and for barely-detectable cholinesterase inhibition (0.1 or 0.2 mg/kg/day). Beginning at 14 months of age and continuing until 19 months, the rats were trained in the 16-arm radial maze. Controls showed the normal sex difference in this spatial learning and memory task, with the males committing significantly fewer working memory errors than females. Neonatal parathion exposure eliminated the sex difference primarily by causing impairment in males. In association with the effects on cognitive performance, neonatal parathion exposure elicited widespread abnormalities in indices of serotonergic and cholinergic synaptic function, characterized by upregulation of 5HT 2 receptors and the 5HT transporter, deficits in choline acetyltransferase activity and nicotinic cholinergic receptors, and increases in hemicholinium-3 binding to the presynaptic choline transporter. Within-animal correlations between behavior and neurochemistry indicated a specific correlation between working memory performance and hippocampal hemicholinium-3 binding; parathion exposure destroyed this relationship. Like the behavioral effects, males showed greater effects of parathion on neurochemical parameters. This study demonstrates the sex-selective, long-term behavioral alterations caused by otherwise nontoxic neonatal exposure to parathion, with effects persisting into the beginning of senescence.

Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?

“…Future work should address whether premating and/or gestational exposure to secondhand smoke could result in earlier onset of the impairments associated with senescence. Indeed, we have already shown this to be the case for organophosphate pesticides, that like TSE, cause damage to ACh and 5HT circuits (Levin et al, 2010).…”

Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age

“…Thus, only one sex may be sensitive to a specific exposure for a specific outcome. In animal studies, sex-selective disturbances in brain development and behavior have been reported for several pesticides including some organophosphates (Levin et al 2010), endosulfan (Lafuente and Pereiro 2013), prochloraz (Vinggaard et al 2005), and mixture of fungicides (Jacobsen et al 2012). In humans, sexually dimorphic response profiles have been reported in relation to prenatal exposure to endocrine disruptors.…”

“…Sex-selective disturbances in brain development after gestational exposure have also been reported in animal studies of other organophosphates (Levin et al 2010) and for anti-androgenic fungicides (Bisenius et al 2006;Vinggaard et al 2005). …”

Environmental Chemical Substances in Relation to Neurodevelopmental Disorders: A Systematic Literature Review

“…However, it became now clear that these agents act as developmental neurotoxicants through a number of differential mechanisms. Some of which operate at exposures below the threshold for cholinesterase inhibition may differ in their effects on brain development and their consequent impacts on behavioral performance (Paul et al 1994;Cohn and MacPhail 1997;Itoh et al 1997aItoh et al , 1997bPalumbo et al 2001;Castillo et al 2002;Levin et al 2002 Levin et al 2010). A series of studies with toxico-dynamically equivalent exposures in neonatal rats showed that chlorpyrifos, diazinon and parathion (PRT) elicit behavioral abnormalities in association with adverse effects on acetylcholine (ACh) and serotonin (5HT) circuits, but that the underlying defects and behavioral outcomes differ among the three OPs.…”