Developmental heptachlor exposure increases susceptibility of dopamine neurons to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)in a gender-specific manner

Abstract

Parkinson's disease (PD) is primarily thought of as a disease of aging. However recent evidence points to the potential for exposure to xenobiotics during development to increase risk of PD. Here, we report that developmental exposure to the organochlorine pesticide heptachlor alters the dopamine system and increases neurotoxicity in an animal model of PD. Exposure of pregnant mice to heptachlor led to increased levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) levels at both the protein and mRNA level in their offspring. Increased DAT and VMAT2 levels were accompanied by alterations of mRNA levels of nuclear transcription factors that control dopamine neuron development and regulate DAT and VMAT2 levels in adulthood. At 12 weeks of age, control and heptachlor-exposed offspring were administered a moderate dose (2×10 mg/kg) of the parkinsonism-inducing agent MPTP. Greater neurotoxicity as evidenced by a greater loss of striatal dopamine and potentiation of increased levels of glial fibrillary acidic protein and α-synuclein was observed in heptachlor-exposed offspring. The neurotoxicity observed was greater in the male offspring than the female offspring, suggesting that males are more susceptible to the longterm effects of developmental heptachlor exposure. These data suggest that developmental heptachlor exposure causes long-term alterations of the dopamine system thereby rendering it more susceptible to dopaminergic damage in adulthood. 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. Although most cases of PD are observed later in life, there is evidence that the disease process begins long before the disease has progressed to the point at which it is diagnosed (Calne and Langston, 1983;Fearnley and Lees, 1991;Di Paola and Uitti, 1996). The presence of a lengthy preclinical phase and the linkage of environmental exposures to increased risk of PD has led to speculation that early life exposures to environmental toxicants may enhance dopaminergic neurodegeneration or increase vulnerability of the dopamine system in adulthood leading to an increased risk of PD (Carvey et al., 2003;Cory-Slechta et al., 2005;Richardson et al., 2006;Barlow et al., 2007). NIH Public AccessPesticide exposure has been on of the most studied environmental risk factors for PD (Semchuk et al., 1992;Tanner and Goldman, 1996;Le Couteur et al., 1999;Priyadarshi et al., 2000; Asherio et al., 2006). However, the possibility that developmental pesticide exposure contributes to PD has only recently begun to be explored. Early postnatal exposure of mice to the ...

Developmental exposure to the organochlorine insecticide endosulfan damages the nigrostriatal dopamine system in male offspring

“…Previous work has shown exposure to the organochlorine insecticides heptachlor and dieldrin cause significant alterations to the nigrostriatal dopamine system of offspring exposed throughout gestation and lactation (Caudle et al , 2005; Richardson et al , 2006; Richardson et al , 2008). This damage is further exacerbated following a subsequent exposure to the dopaminergic neurotoxin, MPTP.…”

Neurochemical changes following a single dose of polybrominated diphenyl ether 47 in mice

“…Mariussen and Fonnum (2003) found that DE-71 inhibited the vesicular uptake of dopamine (DA) in rat brain synaptosome preparations. Altered levels of specific neurotransmitters (especially DA), receptors, and/or transporters were noted following developmental exposure to other chemicals, including structurally similar polychlorinated biphenyls (PCBs), persistent organic pollutants, and pesticides (Bortolozzi et al, 2003;Caudle et al, 2006;Lazarini et al, 2001;Nasuti et al, 2007;Richardson and Miller, 2004;Richardson et al, 2006Richardson et al, , 2008. These findings are especially interesting, given the role of the dopaminergic system in motor function and activity, changes in which have been a behavioral hallmark of rodents developmentally exposed to PBDEs.…”

Effects of Developmental Deltamethrin Exposure on White Adipose Tissue Gene Expression

“…Upon identification of a vaginal plug, males were removed and single-housed female mice were administered 0 (control), 1, or 3 mg/kg BW deltamethrin (ChemSer-vice, West Chester, PA), dissolved in corn oil and mixed with peanut butter (~100 mg; Skippy Creamy Peanut Butter) every 3 days throughout gestation and lactation as described previously [16][17][18]. Mice were monitored to ensure total consumption of the treatment dose, which generally occurred within 10 min.…”

“…Mice were monitored to ensure total consumption of the treatment dose, which generally occurred within 10 min. This administration method reduces handling stress associated with injections during pregnancy and most closely mimics human oral exposure conditions [16,17].…”