Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits

Abstract

Organophosphates are developmental neurotoxicants but recent evidence also points to metabolic dysfunction. We determined whether neonatal parathion exposure in rats has long-term effects on regulation of adipokines and lipid peroxidation. We also assessed the interaction of these effects with increased fat intake. Rats were given parathion on postnatal days 1-4 using doses (0.1 or 0.2 mg/kg/ day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard chow or switched to a high-fat diet for seven weeks. We assessed serum leptin and adiponectin, tumor necrosis factor-α (TNFα) in adipose tissues, and thiobarbituric acid reactive species (TBARS) in peripheral tissues and brain regions. Neonatal parathion exposure uncoupled serum leptin levels from their dependence on body weight, suppressed adiponectin and elevated TNFα in white adipose tissue. Some of the effects were offset by a high-fat diet. Parathion reduced TBARS in the adipose tissues, skeletal muscle and temporal/occipital cortex but not in heart, liver, kidney or frontal/parietal cortex; it elevated TBARS in the cerebellum; the high-fat diet again reversed many of the effects. Neonatal parathion exposure disrupts the regulation of adipokines that communicate metabolic status between adipose Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. tissues and the brain, while also evoking an inflammatory adipose response. Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain. Conflict of Interest NIH Public Access

The Effects of Endocrine Disruptors on Adipogenesis and Osteogenesis in Mesenchymal Stem Cells: A Review

“…Perinatal and prenatal exposures have also been shown to result in excessive weight gain and adipose tissue mass in offspring (30, 31, 38–47). Human studies have demonstrated a positive association between EDC exposures and obesity, increased weight circumference, or increased body mass index (28, 30, 40, 42, 48–65). …”

“…EDCs including diazinon, parathion, malathion, BPA, PCB-77, PCB-153, and PCB-180 increase the levels of pro-inflammatory cytokines, such as TNF-α and interleukin 6 in adipose tissue (34, 37, 48, 71, 74, 81, 84, 88, 130–134). Together, these EDC effects induce a pro-inflammatory phenotype in adipose tissue.…”

“…Together, these EDC effects induce a pro-inflammatory phenotype in adipose tissue. Animal studies have also demonstrated an increase in pro-inflammatory cytokines in adipose tissue following exposure to parathion and PCB-77 (48, 130). …”

Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum

“…At lower doses administered during development, chlorpyrifos also produces excess weight gain and dysregulation of leptin [11], along with a metabolic profile resembling prediabetes [24]. Similarly, when we exposed neonatal rats to parathion at doses straddling the threshold for barely-detectable cholinesterase inhibition, we found later emergence of a prediabetes-like state, involving excessive weight gain, hyperglycemia, abnormalities of lipid metabolism and adipose tissue inflammation [12,13]. Further, many of the metabolic effects of early-life OP exposure were exacerbated when animals were switched to a high-fat diet in adulthood, including a much greater fat-induced weight gain than that with the equivalent dietary change in controls [12,13,20].…”

Pesticide use and incident diabetes among wives of farmers in the Agricultural Health Study

“…Organophosphate exposure may contribute to diabetes via disruption of adipokine signalling and metabolic regulation 14. Recent experimental studies have demonstrated excess weight gain, hyperlipidaemia and hyperinsulinaemia persisting into adulthood in rats exposed neonatally to the organophosphate chlorpyrifos; the magnitude of these effects differs between males and females 15 16.…”