Journal
TOXICOLOGY LETTERS
Volume 356, Issue -, Pages 121-131Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2021.12.010
Keywords
Ethanol; Neurodevelopmental disorders; Oxoguanine glycosylase 1 (OGG1); Epigenetics; Histone deacetylase inhibition; Trichostatin A
Categories
Funding
- Canadian Institutes of Health Research [PJT-156023, MOP-115108]
- Faculty of Pharmacy, University of Toronto
- University of Toronto Centre for Pharmaceutical Oncology
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Oxoguanine glycosylase 1 (OGG1) is involved in DNA repair and epigenetic modification. This study investigates the effects of in utero ethanol exposure and postnatal treatment with a histone deacetylase inhibitor on behavior in OGG1-deficient mice. The results suggest that ethanol and the inhibitor improve memory and reverse ethanol-induced abnormalities, and the effects are dependent on sex and OGG1. The findings also indicate that the combined treatment reduces nesting material shredding in females and enhances rotarod performance in male OGG1-positive mice. These results suggest that targeting epigenetic modification may be a potential strategy for mitigating neurodevelopmental disorders.
Oxoguanine glycosylase 1 (OGG1) is both a DNA repair enzyme and an epigenetic modifier. We assessed behavioural abnormalities in OGG1-deficient progeny exposed once in utero to a low dose of ethanol (EtOH) and treated postnatally with a global histone deacetylase inhibitor, trichostatin A (TSA). The goal of this study was to determine if neurodevelopmental disorders initiated in the fetal brain by in utero exposure to EtOH could be mitigated by postnatal treatment with TSA. EtOH and TSA alone improved preference for novel location (short-term, 90 min) and novel object (long-term, 24 h) sex- and OGG1-dependently. Combined EtOH/TSA treatment reversed these effects in the short-term novel location test sex- and OGG1-dependently. In females but not males, the incidence of high shredders of nesting material was not altered by either TSA or EtOH alone, but was reduced by combined EtOH/TSA treatment in +/+ progeny. Similar but non-significant effects were observed in Ogg1 -/- females. Accelerated rotarod performance was enhanced by both EtOH and TSA alone in only male Ogg1 +/+ but not -/- progeny, and was not altered bycombined EtOH/TSA exposure. The OGG1-dependent effects of EtOH and TSA particularly on novel location and the incidence of high shredders, and the reversal of EtOH effects on these parameters by combined EtOH/TSA treatment, suggests both xenobiotics may alter behaviour via a mechanism involving OGG1 acting as an epigenetic modifier, in addition to repairing DNA damage. These preliminary results suggest that the postnatal use of more selective epigenetic modifying agents may constitute a novel strategy for mitigating some components of ROS-initiated neurodevelopmental disorders. (c) 2021 Elsevier B.V. All rights reserved.
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