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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.

SUBMITTER: Vester AI

PROVIDER: S-EPMC6630986 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A variety of contaminants find their way to the marine sediments from different sources, and these contaminants can pose serious risks to the natural marine flora and fauna. For example, pyrethroids, which are a potent pesticide family, are often used in agriculture fields worldwide, and these find their way into the marine environment through run off. Further, pyrethroids are used in farmed Atlantic salmon cages in Chile, Great Britain and Norway. Ammonia is another contaminant that is used in agriculture in form of ammonia-rich fertilizer and can be carried during run-offs to localized rivers and streams. Ammonia is also detectable after emission of effluents from sewage treatment plants and industrial plants like oil refineries and meat processing plants. Contaminants may have short and long term effects on non-target organisms living in the water column or in the marine sediment. Importantly, the sediment ecosystem houses a variety of plants, animals and crustaceans, including the American lobster Homarus americanus. Lobster is the most fished crustacean in New Brunswick and Quebec and its resale and exportation produced over $1.6 billion in 2011. Due to its economic and environmental importance, it is essential to study the effects of contaminants present in its ecosystem. Sediment samples are often used as pollution markers during toxicity testing due to their tendency to accumulate hydrophobic contaminants. To better understand the possible effects of contaminants in sediment, a total gene expression study was developed using the marine amphipod Eohaustorius estuarius. A 10 day spike-in exposure was performed using ammonia and two pyrethroids, namely cypermethrin and deltamethrin. As pyrethroids and ammonia are known to have vastly different mechanisms of action in living organisms, we compared global gene expression patterns following exposure to ammonia against the patterns observed following exposure to pyrethroids. Total gene expression was measured by oligonucleotide microarray. The expression of five genes of interest involved in different biological processes such as metabolism, transcription, translation, immunity and stress, which were found to be differently expressed by microarray, was validated by RT-qPCR. A set of genes was identified that showed differential expression levels in a treatment-dependent manner, thus further highlighting the different mechanisms of action of ammonia and pyrethroids in the marine sediment. This study provides a proof of concept for the use of DNA microarrays with model crustaceans for the study of marine sediment contaminants.

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A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure.

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