Methylmercury (MeHg) exposure during gestation causes perseverative responding, impaired acquisition of choice, impulsivity, and other markers of impaired cortical function. These effects appear in adulthood and aging in animal models in which no overt toxicity is present and occurs at environmentally relevant exposures. Moreover, the effects are reversible with experience and early developmental is an especially sensitive window of exposure. Together, these observations raise the possibility that MeHg's developmental neurotoxicity is mediated by epigenetic changes in the brain. Adolescence is a life stage that is sensitive to events that disrupt cortical development and those that also have epigenetic consequences, but we know very little about MeHg exposure during this potentially vulnerable developmental period.
Under Aim 1, the behavioral and epigenetic consequences of gestational MeHg exposure will be examined in a mouse model. Whole genome analyses will be conducted from prefrontal cortex in adult mice exposed to MeHg during gestation via maternal drinking water. Analyses will focus on RNA, methylation, and acetylation and will identify candidate genes for further study. Additional mice will be exposed similarly and exposed to one of three interventions designed to investigate the reversibility of MeHg-induced behavioral and epigenetic disturbances: Paired- housing (Control group), environmental enrichment, and administration of a histone deacetylation (HDAC) inhibitor, Na-butyrate. The mice will be examined on a Spatial Discrimination Reversal procedure as adults to determine the behavioral impact of these rescue attempts, after which the expression of candidate genes identified in the whole epigenome analysis will be examined.
Under Aim 2, adolescent MeHg exposure will be examined in studies that otherwise mirror those conducted under Aim 1. The proposed studies will advance our understanding of the behavioral epigenetic consequences of developmental MeHg exposure, the relative vulnerability of two important exposure windows, and the potential for rescue by enrichment or HDAC inhibition.
Fetal exposure to methylmercury results in perseverative responding and deficits in choice and decision-making in adulthood, suggestive of cortical dysfunction. The fetal basis of an adult disorder suggests that methylmercury exposure may have epigenetic consequences. Adolescence is an important developmental period, both for epigenetics and for cortical development. We will examine the epigenetic basis of fetal and adolescent methylmercury exposure and the possibility that environmental enrichment or direct modification of epigenetic markers can reverse its behavioral neurotoxicity.
|Boomhower, Steven R; Newland, M Christopher (2018) Adolescent methylmercury exposure: Behavioral mechanisms and effects of sodium butyrate in mice. Neurotoxicology 70:33-40|
|Boomhower, Steven R; Newland, M Christopher (2017) Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice. Exp Clin Psychopharmacol 25:64-73|
|Shen, Andrew Nathanael; Cummings, Craig; Pope, Derek et al. (2016) A bout analysis reveals age-related methylmercury neurotoxicity and nimodipine neuroprotection. Behav Brain Res 311:147-159|
|Boomhower, Steven R; Newland, M Christopher (2016) Adolescent methylmercury exposure affects choice and delay discounting in mice. Neurotoxicology 57:136-144|