| Exposure of Neonatal Rats to Parathion Elicits Sex-Selective Reprogramming of Metabolism and Alters the Response to a High-Fat Diet in Adulthood T. Leon Lassiter,1 Ian T. Ryde,1 Emiko A. MacKillop,1 Kathleen K. Brown,2 Edward D. Levin,1,3 Frederic J. Seidler,1 and Theodore A. Slotkin1,3 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA; 2GlaxoSmithKline Inc., Research Triangle Park, North Carolina, USA; 3Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA Abstract
Background: Developmental exposures to organophosphate pesticides are virtually ubiquitous. These agents are neurotoxicants, but recent evidence also points to lasting effects on metabolism. Objectives: We administered parathion to neonatal rats. In adulthood, we assessed the impact on weight gain, food consumption, and glucose and lipid homeostasis, as well as the interaction with the effects of a high-fat diet. Methods: Neonatal 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 lab chow or switched to a high-fat diet for 7 weeks. Results: In male rats on a normal diet, the low-dose parathion exposure caused increased weight gain but also evoked signs of a prediabetic state, with elevated fasting serum glucose and impaired fat metabolism. The higher dose of parathion reversed the weight gain and caused further metabolic defects. Females showed greater sensitivity to metabolic disruption, with weight loss at either parathion dose, and greater imbalances in glucose and lipid metabolism. At 0.1 mg/kg/day parathion, females showed enhanced weight gain on the high-fat diet ; This effect was reversed in the 0.2-mg/kg/day parathion group, and was accompanied by even greater deficits in glucose and fat metabolism. Conclusions: Neonatal low-dose parathion exposure disrupts glucose and fat homeostasis in a persistent and sex-selective manner. Early-life toxicant exposure to organophosphates or other environmental chemicals may play a role in the increased incidence of obesity and diabetes. Key words: developing rat, diabetes, glucose homeostasis, high-fat diet, insulin, lipid homeostasis, obesity, organophosphate insecticides, parathion. Environ Health Perspect 116:1456–1462 (2008) . doi:10.1289/ehp.11673 available via http://dx.doi.org/ [Online 23 June 2008]
Address correspondence to T.A. Slotkin, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 681-8015. Fax: (919) 684-8197. E-mail: t.slotkin@duke.edu We thank B. Bodwell for technical assistance. This research was supported by grant ES10356 from the National Institutes of Health and by the Leon Golberg Postdoctoral Fellowship. T.A.S. and F.J.S. have provided expert witness testimony on behalf of government agencies, corporations, and/or individuals. The authors have no competing financial interests. Received 7 May 2008 ; accepted 20 June 2008.
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