Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity?

Abstract

Human exposures to organophosphate insecticides are ubiquitous. Although regarded as neurotoxicants, increasing evidence points toward lasting metabolic disruption from early-life organophosphate exposures. We gave neonatal rats chlorpyrifos, diazinon or parathion in doses devoid of any acute signs of toxicity, straddling the threshold for barely-detectable cholinesterase inhibition. Organophosphate exposure during a critical developmental window altered the trajectory of hepatic adenylyl cyclase/cyclic AMP signaling, culminating in hyperresponsiveness to gluconeogenic stimuli. Consequently, the animals developed metabolic dysfunction resembling prediabetes. When the organophosphate-exposed animals consumed a high fat diet in adulthood, metabolic defects were exacerbated and animals gained excess weight compared to unexposed rats on the same diet. At the same time, the high fat diet ameliorated many of the central synaptic defects caused by organophosphate exposure, pointing to nonpharmacologic therapeutic interventions to offset neurodevelopmental abnormalities, as well as toward fostering dietary choices favoring high fat intake. These studies show how common insecticides may contribute to the increased worldwide incidence of obesity and diabetes.

Chronic exposure to chlorpyrifos triggered body weight increase and memory impairment depending on human apoE polymorphisms in a targeted replacement mouse model

“…Along the same lines, Karagiannides and colleagues described hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance in apoE3 knock-in mice fed a western-type diet for 24 weeks. Several epidemiological studies have provided evidence to suggest that there is a link between exposures to CPF on the one hand, and higher rates of obesity [68] and diabetes [47,64] on the other. However, the investigations assessing the metabolic effects arising from exposure to CPF in animal models have been carried out during development.…”

“…Heretofore, epidemiological studies have provided enough evidence supporting the existence of powerful links between OP exposure, long lasting cognitive impairments, and an increased risk of neurodegenerative diseases [3,23,31,46,78]. Besides, in recent years increasing references in the scientific literature point to lasting metabolic disturbances after perinatal exposure to CPF, and suggest that it is also an "endocrine disruptor" [43,68,69,76].…”

Obesity and Asthma

“…When the organophosphate-exposed animals consumed a high-fat diet in adulthood, metabolic defects were exacerbated and animals gained excess weight compared with unexposed rats on the same diet. 53 Liu and colleagues 54 recently reported that mice exposed to PM 2.5 pollutants produced insulin resistance by regulating visceral adipose tissue inflammation, hepatic lipid metabolism, and glucose use in skeletal muscle via both CCR2-dependent and CCR2-independent pathways, providing potential metabolic abnormalities underlying insulin resistance. The same group reported that a 10-month chronic exposure to PM 2.5 in mice induced macrophage infiltration and unfolded protein response in the white adipose tissue, 55 mediated early alterations in insulin resistance, and caused visceral inflammation and structural and functional alterations in the brown adipose tissue.…”

Changes in glucose metabolism and reversion of genes expression in the liver of insulin-resistant rats exposed to malathion. The protective effects of N-acetylcysteine

“…For instance, a study performed by Montgomery et al (2008) indicated extra incidence of diabetes among OPs applicators who worked between 1993 and 2003 in the US. Moreover, according to epidemiological reports (Rezg et al, 2010;Slotkin, 2011), clinical studies (Saldana et al, 2007;Raafat et al, 2012) and experimental data Mostafalou et al, 2012) OPs increase the risk of insulin resistance and type 2 diabetes induction.…”