A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure

Abstract

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.

Developmental pyrethroid exposure disrupts molecular pathways for MAP kinase and circadian rhythms in mouse brain

“…To follow up on these correlational findings in humans, mouse models of pyrethroid exposure have been developed 11,[17][18][19][20][21][22][23][24] . These models have established that exposure in mice to the pyrethroid deltamethrin during pregnancy and lactation at doses well below the EPA benchmark dose of 14.5 mg/kg is sufficient to cause broad male-biased changes in the brain and behavior of the resulting offspring.…”

Pesticide Residues in Fresh Fruit and Vegetables from Farm to Fork in the Kampala Metropolitan Area, Uganda

“… 23 , 24 Pyrethroids and neonicotinoids have high affinity to the soils with potential to bioaccumulate in the environment, but in humans are neurotoxins associated with poor development and neurological disorders. 25 - 27 …”

“…23,24 Pyrethroids and neonicotinoids have high affinity to the soils with potential to bioaccumulate in the environment, but in humans are neurotoxins associated with poor development and neurological disorders. [25][26][27] Quantifying pesticide residues in Ugandan foods can improve understanding of human exposure to pesticides in Uganda, providing evidence to inform policies intended to protect Uganda's community while at the same time supporting healthy food production practices. The very few studies that have examined pesticide residues in Ugandan produce have focussed on dithiocarbamate (Mancozeb) and organochlorines in tomatoes and carrots and reported levels that were above the Codex Alimentarius MRLs.…”

Applying a Fast-Scan Cyclic Voltammetry to Explore Dopamine Dynamics in Animal Models of Neuropsychiatric Disorders

“…For instance, just a few animal studies on Alzheimer's disease have reported on utilization of FSCV so far [161,162]. Similarly, there are few explorations of the role of DAT in attention deficit hyperactivity disorder-related animal models [135,163,164].…”