Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure

Abstract

Several studies have demonstrated that exposure to arsenic in drinking water adversely affects brain development and cognitive function in adulthood. While the mechanism by which arsenic induces adverse neurological outcomes remains elusive, studies suggest a link between reduced levels of histone acetylation and impaired performance on a variety of behavioral tasks following arsenic exposure. Using our developmental arsenic exposure (DAE) paradigm, we have previously reported reduced histone acetylation and associated histone acetyltransferase enzyme expression in the frontal cortex of C57BL/6J adult male mice, with no changes observed in the female frontal cortex. In the present study, we sought to determine if DAE produced sex-dependent deficits in frontal cortical executive function using the Y-maze acquisition and reversal learning tasks, which are specific for assessing cognitive flexibility. Further, we tested whether the administration of valproic acid, a class I–IIa histone deacetylase inhibitor, was able to mitigate behavioral and biochemical changes resulting from DAE. As anticipated, DAE inhibited acquisition and reversal learning performance in adult male, but not female, mice. Valproate treatment for 2 weeks restored reversal performance in the male arsenic-exposed offspring, while not affecting female performance. Protein levels of HDACs 1, 2, and 5 were elevated following behavioral assessment but only in DAE male mice; restoration of appropriate HDAC levels occurred after valproate treatment and was concurrent with improved behavioral performance, particularly during reversal learning. Female frontal cortical levels of HDAC enzymes were not impacted by DAE or valproate treatment. Finally, mRNA expression levels of brain-derived neurotrophic factor, Bdnf, which has been implicated in the control of frontal cortical flexibility and is regulated by HDAC5, were elevated in DAE male mice and restored to normal levels following HDACi treatment. Levels of mRNA encoding glutamate receptor ionotropic NMDA type subunits, which have been linked to cognitive flexibility, were not related to the reversal learning deficit in the DAE mice and were not altered by HDACi treatments. These findings demonstrate that DAE alters frontal cortical HDAC levels and Bdnf expression in males, but not females, and that these molecular changes are associated with sex-dependent differences in cognitive flexibility in a reversal-learning task.

Developmental arsenic exposure is associated with sex differences in the epigenetic regulation of stress genes in the adult mouse frontal cortex

“…In this study we show a glimpse of the different epigenetic changes male and female mice make in response to damage caused by perinatal arsenic exposure. In our previous publications we show that DAE caused severe executive dysfunction in male but not female adult (PN70) mice, tested in a Y-Maze alternation task ( Tyler et al, 2018 ). In the present study, we focused on the H3K9 modification states on key stress regulatory genes.…”

“…The house keeping gene, hydorxyxanthine phosphoribosyltransferase (Hprt), was used as an endogenous control for all mRNA assays. Hprt was not altered by prenatal exposure to arsenic, making it an acceptable housekeeping gene ( Tyler et al, 2018 ). The variation in efficiency between Hprt and target primers was below 5%.…”

“…Many publications focus on global changes to epigenetic markers and modifying proteins caused by recent arsenic exposure ( Cronican et al, 2013 ; Zhou et al, 2008 ), with few exploring if this epigenetic dysregulation is sex-dependent ( Winterbottom et al, 2019 ; Howe et al, 2017 ; Bommarito et al, 2017 ). In our past work we have found that perinatal arsenic alters levels of histone deacetylase (HDAC) 1, 2, and 5 in male but not female adult frontal cortex ( Tyler et al, 2018 ). In the same study, we found that males, but not females, showed impairment in executive function (Y-Maze alternation task).…”

Inhibition of DNA Methylation in Picochlorum soloecismus Alters Algae Productivity

“…Algae were treated with 0-20 µM 5AZA and the dose response was determined (Supplementary Figure 2). Drug treatment pharmacodynamics follow an inverted-U dose response with low and high concentrations of the same drug not eliciting a significant response (Tyler et al, 2018). We assessed 0-80 µM of 5AZA treatment and found this inverted -U dose response (data not shown); 20 µM 5AZA induced the most distinct growth response.…”

Sex chromosome complement affects multiple aspects of reversal‐learning task performance in mice

“…In studies of otherwise healthy subjects, evidence is highly inconsistent for sex differences in performance of the RLT or related tasks that include a reversal learning component (e.g., Wisconsin Card Sorting Task, attentional‐set shifting). Many studies detected no sex difference in either humans 21‐30 or animal models, 31‐43 and a minority finding that males performed better under reversal conditions in humans 44 and animal models 44‐48 …”