Abstract
Genomic imprinting, a phenomenon by which genes are expressed in a monoallelic, parent-of-origin-dependent fashion, is critical for normal brain development. Expression of imprinted genes is regulated via epigenetic mechanisms, including DNA methylation (5-methylcytosine, 5mC), and disruptions in imprinting can lead to disease. Early-life exposure to the endocrine disrupting chemical bisphenol A (BPA) is associated with abnormalities in brain development and behavior, as well as with disruptions in epigenetic patterning, including 5mC and DNA hydroxymethylation (5-hydroxymethylcytosine, 5hmC). Using an established mouse model of perinatal environmental exposure, the objective of this study was to examine the effects of perinatal BPA exposure on epigenetic regulation of imprinted gene expression in adult mice. Two weeks prior to mating, dams were assigned to control chow or chow containing an environmentally relevant dose (50 µg/kg) of BPA. Exposure continued until offspring were weaned at post-natal day 21, and animals were followed until 10 months of age. Expression of three imprinted genes—Pde10a, Ppp1r9a, and Kcnq1, as well as three genes encoding proteins critical for regulation of 5mC and 5hmC—Dnmt1, Tet1, and Tet2, were evaluated in the right cortex and midbrain using qRT-PCR. Perinatal BPA exposure was associated with a significant increase in adult Kcnq1 (p = 0.04) and Dnmt1 (p = 0.02) expression in the right cortex, as well as increased expression of Tet2 in the midbrain (p = 0.03). Expression of Tet2 and Kcnq1 were positively correlated in the midbrain. Analysis of 5mC and 5hmC at the Kcnq1 locus was conducted in parallel samples using standard and oxidative bisulfite conversion followed by pyrosequencing. This analysis revealed enrichment of both 5mC and 5hmC at this locus in both brain regions. No significant changes in 5mC and 5hmC at Kcnq1 were observed with perinatal BPA exposure. Together, these data suggest that perinatal BPA exposure results in altered expression of Kcnq1, Dnmt1, and Tet2 in the adult mouse brain. Further studies with larger sample sizes are necessary to understand the mechanistic basis for these changes, as well as to determine the implications they have for brain development and function.
Highlights
The Developmental Origins of Health and Disease (DOHaD) hypothesis states that environmental exposures during critical windows of development influence the risk of diseases later in life (Barker, 2007)
Dams were exposed to bisphenol A (BPA) or control chow beginning two weeks prior to mating until weaning at post-natal day (PND) 21 (Figure 1)
BPA exposure resulted in a significant reduction in the number of pups per litter that survived at weaning (Kochmanski et al, 2017)
Summary
The Developmental Origins of Health and Disease (DOHaD) hypothesis states that environmental exposures during critical windows of development influence the risk of diseases later in life (Barker, 2007). DNA methylation is critical for establishment of tissuespecific gene expression patterns, regulation of imprinted genes, maintenance of genome stability, and silencing of transposable elements (Jones, 2012) Because it is stable, mitotically heritable, and undergoes rapid reprogramming during early development, DNA methylation is vulnerable to the effects of toxicant exposures (Dolinoy and Jirtle, 2008). 5mC and 5hmC undergo dynamic changes during brain development, and both marks play a critical role in neuronal function, including learning and memory, during development and adulthood (Spiers et al, 2015; Jobe and Zhao, 2017; Spiers et al, 2017) Alterations in these marks are associated with neurodegenerative and psychiatric illnesses, suggesting a role for 5mC and 5hmC in disease pathogenesis (Zhao et al, 2017; Cui and Xu, 2018)
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