A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure

• Type of Material: Article
• Authors: Aimee Vester, Emory University; Merry Chen, Emory University; Carmen Marsit, Emory University; William Caudle, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2019 by the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/toxics7020024
• Title of Journal or Parent Work: Toxics
• Volume: 7
• Issue: 2
• Grant/Funding Information: Emory University School of Medicine; HERCULES Exposome Research Center (P30ES019776); National Institute of Environmental Health Sciences of the National Institutes of Health, grant numbers F30ES029018 (A.I.V.), T32ES012870 (A.I.V.), 1R01ES029212 (C.J.M., W.M.C.), and 1R01ES023829 (G.W.M.); Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378; Emory Neuroscience NINDS Core Facilities (P30NS055077)
• Keywords: Science & Technology; deltamethrin; SOCIOECONOMIC-STATUS; Environmental Sciences & Ecology; dopamine; Environmental Sciences; METHYLPHENIDATE TREATMENT; STRIATAL DOPAMINE TRANSPORTER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; Life Sciences & Biomedicine; corticosterone; pyrethroid; PESTICIDE EXPOSURE; Toxicology; DEVELOPMENTAL EXPOSURE; TERMINAL DIFFERENTIATION; URINARY CONCENTRATIONS; DEFICIT HYPERACTIVITY DISORDER; neurodevelopment; CORTICOSTERONE EXPOSURE
• Research Categories: Health Sciences, Toxicology; Biology, Neuroscience

Abstract

Attention-deficit hyperactivitydisorder (ADHD) is one of themost common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 μg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain Pitx3 expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations.