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Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice.

ABSTRACT: Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders and manifests inattention, hyperactivity, and impulsivity symptoms in childhood that can last throughout life. Genetic and environmental studies implicate the dopamine system in ADHD pathogenesis. Work from our group and that of others indicates that deltamethrin insecticide and stress exposure during neurodevelopment leads to alterations in dopamine function, and we hypothesized that exposure to both of these factors together would lead to synergistic effects on DNA methylation of key genes within the midbrain, a highly dopaminergic region, that could contribute to these findings. Through targeted next-generation sequencing of a panel of cortisol and dopamine pathway genes, we observed hypermethylation of the glucocorticoid receptor gene, Nr3c1, in the midbrain of C57/BL6N males in response to dual deltamethrin and corticosterone exposures during development. This is the first description of DNA methylation studies of Nr3c1 and key dopaminergic genes within the midbrain in response to a pyrethroid insecticide, corticosterone, and these two exposures together. Our results provide possible connections between environmental exposures that impact the dopamine system and the hypothalamic-pituitary-adrenal axis via changes in DNA methylation and provides new information about the presence of epigenetic effects in adulthood after exposure during neurodevelopment.

SUBMITTER: Vester AI

PROVIDER: S-EPMC7457745 | biostudies-literature | 2020 Jul - Aug

REPOSITORIES: biostudies-literature

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Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice.

Vester Aimée I AI Hermetz Karen K Burt Amber A Everson Todd T Marsit Carmen J CJ Caudle William M WM

Neurotoxicology and teratology 20200426

Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders and manifests inattention, hyperactivity, and impulsivity symptoms in childhood that can last throughout life. Genetic and environmental studies implicate the dopamine system in ADHD pathogenesis. Work from our group and that of others indicates that deltamethrin insecticide and stress exposure during neurodevelopment leads to alterations in dopamine function, and we hypothesized that exposure ...[more]

PMID: 32348866

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Project description:RATIONALE:Effort-related choice tasks are used to study aspects of motivation in both rodents and humans (Der-Avakian and Pizzagalli Biol Psychiatry 83(11):932-939, 2018). Various dopaminergic manipulations and antidepressant treatments can shift responding to these tasks (Randall et al. Int J Neuropsychopharmacol 18(2), 2014; Yohn et al. Psychopharmacology 232(7):1313-1323, 2015). However, while chronic stress can precipitate mood disorders in humans, there is relatively little known about whether chronic stress elicits maladaptive behaviors in rodent effort-related choice tasks. OBJECTIVES:Chronic corticosterone (CORT) elicits an increase in negative maladaptive behaviors in male mice (David et al. Neuron 62(4):479-493, 2009; Gourley et al. Biol Psychiatry 64(10):884-890, 2008; Olausson et al. Psychopharmacology 225(3):569-577, 2013). We hypothesized that chronic CORT administration to male mice would reduce motivation for a higher effort, higher reward option, and shift responding to a less effortful, but a lesser reward. METHODS:Adult male C57BL/6J mice were administered either vehicle (n = 10) or CORT (n = 10) (~ 9.5 mg/kg/day) in their drinking water for 4 weeks, and then throughout all behavioral experiments (15 weeks total), and were tested in a Y-Maze barrier task and a fixed ratio concurrent (FR/chow) choice task. RESULTS:Chronic CORT reduced Y-maze HR arm choice when more effort was required to obtain the 4 food pellets (15-cm barrier in the high-reward (HR) arm, p < 0.001; 20-cm barrier in HR arm, p < 0.001) and shifted choice to the low reward (LR) arm where only 2 pellets were available. Chronic CORT also reduced lever pressing for food pellets in FR30/chow sessions of the concurrent choice task (p = 0.009), without impacting lab chow consumed. CONCLUSIONS:Chronic stress induces maladaptive shifts in effort-related choice behavior in the Y-maze barrier task in male mice. Furthermore, males subjected to chronic CORT administration show reduced lever pressing in FR30/chow sessions where lab chow is concurrently available. These data demonstrate that chronic corticosterone reduces motivation to work for and obtain a highly rewarding reinforcer when a lesser reinforcer is concurrently available.

Project description:Attention-deficit hyperactivity disorder (ADHD) is one of the most 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.

Project description:AimsRestraint stress is one of the most widely used experimental methods for generating rodent models of stress-induced neuropsychiatric disorders, such as depression and anxiety. Although various types of restraint apparatuses have been used to expose animals to stress, the magnitudes of the effects of stress exposure via different types of restraint apparatuses on physiology and behavior have not been compared in the same environment. Here, we investigated the effects of stress exposure via two types of restraint apparatuses on body weight, locomotor activity, anxiety- and depression-related behaviors, and plasma corticosterone levels in mice.MethodsAdult male BALB/cAJcl mice were restrained by placing them in either a well-ventilated plastic conical tube or a tapered plastic film envelope for 6 hours per day for 10 or 21 consecutive days. Mice were weighed during and after the stress period and were subjected to a battery of behavioral tests, including light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, and sucrose preference tests, starting on the day after the last stress session. Plasma corticosterone levels were measured in another cohort of mice on the 1st and the 21st stress sessions and after the Porsolt forced swim test.ResultsExposure to repeated stress via the two above mentioned types of restraint apparatuses caused body weight loss, heightened locomotor activity, altered immobility during forced swim, and increased plasma corticosterone levels, and some of these results differed between the restraint stress protocols. Film-restraint-stressed mice had significantly lower body weights than tube-restraint-stressed mice. Film-restraint-stressed mice exhibited significantly higher or lower immobility during forced swim than tube-restraint-stressed mice, depending on the test time. Additionally, the stress-induced increase in plasma corticosterone levels was found to be higher in film-restraint-stressed mice than in tube-restraint-stressed mice.ConclusionOur results indicate that film-restraint stress has more pronounced effects on body weight, depression-related behavior, and corticosterone response than tube-restraint stress in mice. These findings may help guide which restraint stress procedures to use, depending on the objectives of a given study, in generating animal models of stress-induced neuropsychiatric disorders.

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Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice.

Publications

Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice.

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