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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.
Aimée I. Vester; Merry Chen; Carmen J. Marsit; W. Michael Caudle. A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure. Toxics 2019, 7, 24 .
AMA StyleAimée I. Vester, Merry Chen, Carmen J. Marsit, W. Michael Caudle. A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure. Toxics. 2019; 7 (2):24.
Chicago/Turabian StyleAimée I. Vester; Merry Chen; Carmen J. Marsit; W. Michael Caudle. 2019. "A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure." Toxics 7, no. 2: 24.
Identifying functional non-coding variation is critical for defining the genetic contributions to human disease. While single-nucleotide polymorphisms (SNPs) within cis-acting transcriptional regulatory elements have been implicated in disease pathogenesis, not all cell types have been assessed and functional validations have been limited. In particular, the cells of the peripheral nervous system have been excluded from genome-wide efforts to link non-coding SNPs to altered gene function. Addressing this gap is essential for defining the genetic architecture of diseases that affect the peripheral nerve. We developed a computational pipeline to identify SNPs that affect regulatory function (rSNPs) and evaluated our predictions on a set of 144 regions in Schwann cells, motor neurons, and muscle cells. We identified 28 regions that display regulatory activity in at least one cell type and 13 SNPs that affect regulatory function. We then tailored our pipeline to one peripheral nerve cell type by incorporating SOX10 ChIP-Seq data; SOX10 is essential for Schwann cells. We prioritized 22 putative SOX10 response elements harboring a SNP and rapidly validated two rSNPs. We then selected one of these elements for further characterization to assess the biological relevance of our approach. Deletion of the element from the genome of cultured Schwann cells—followed by differential gene expression studies—revealed Tubb2b as a candidate target gene. Studying the enhancer in developing mouse embryos revealed activity in SOX10-positive cells including the dorsal root ganglia and melanoblasts. Our efforts provide insight into the utility of employing strict conservation for rSNP discovery. This strategy, combined with functional analyses, can yield candidate target genes. In support of this, our efforts suggest that investigating the role of Tubb2b in SOX10-positive cells may reveal novel biology within these cell populations. The online version of this article (10.1186/s12864-018-4692-z) contains supplementary material, which is available to authorized users.
William D. Law; Elizabeth A. Fogarty; Aimée Vester; Anthony Antonellis. A genome-wide assessment of conserved SNP alleles reveals a panel of regulatory SNPs relevant to the peripheral nerve. BMC Genomics 2018, 19, 311 .
AMA StyleWilliam D. Law, Elizabeth A. Fogarty, Aimée Vester, Anthony Antonellis. A genome-wide assessment of conserved SNP alleles reveals a panel of regulatory SNPs relevant to the peripheral nerve. BMC Genomics. 2018; 19 (1):311.
Chicago/Turabian StyleWilliam D. Law; Elizabeth A. Fogarty; Aimée Vester; Anthony Antonellis. 2018. "A genome-wide assessment of conserved SNP alleles reveals a panel of regulatory SNPs relevant to the peripheral nerve." BMC Genomics 19, no. 1: 311.