Prevention of aberrant DNA methylation induced by caregiver maltreatment in early life
Date
2019
Authors
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Publisher
University of Delaware
Abstract
Parental care is a critical buffer for normative mammalian development. While nurturing care can protect offspring from environmental stressors, poor care can have dire consequences for offspring physical and mental health. Research over the last few decades has begun to illuminate biological mechanisms involved in the influence of parental care on development, with epigenetics at its forefront. One type of epigenetic alteration that alters gene expression, DNA methylation, often increases as a result of experiencing maltreatment in early life. DNA methylation occurs when DNA methyltransferases (DNMTs) attach methyl groups to DNA, typically rendering it less accessible for transcription. DNA methylation is also causally related to behavior, making it a prime candidate for pharmacological intervention of the effects of maltreatment. The goals of this thesis were to: 1) establish an effective dose of 5-aza-2’-deoxycytidine (5-aza) that normalizes locus-specific DNA methylation in infant rats exposed to brief and repeated bouts of maltreatment; and, 2) measure the effects of the drug intervention on global DNA methylation, DNMT gene expression, and the stress hormone corticosterone. Chapter 1 reviews evidence of the influence of the epigenome in mediating the effects of early environmental influences on the brain and behavior. A major underlying theme of the chapter is the importance of animal models in establishing relationships between epigenetic mechanisms and behavior and the translational relevance of important discoveries in the field of behavioral epigenetics. Chapter 2 consists of the experimental findings of using 5-aza to prevent aberrant methylation and gene outcomes of maltreatment. This study established an effective dose of 5-aza that successfully lowered methylation levels in Long-Evans rat pups when administered daily concurrent with maltreatment. Gene expression of DNMTs, global methylation, and corticosterone concentration were measured to shed light on the effects of 5-aza on the developing pups. Results indicate that 5-aza elicited a condition- and sex-specific effect on corticosterone concentration, but no effect on DNMT expression or global methylation. From this work, we have provided additional evidence showing that even brief bouts of early life maltreatment have an impact on cortical DNA methylation. We also show that pharmacological substances can be effective at preventing aberrant changes in DNA methylation induced by maltreatment. However, this project has also revealed some unexpected consequences of the pharmacological agent later in development. Future projects in the lab will investigate whether other pharmacological substances can prevent aberrant DNA methylation induced by early life maltreatment, how they affect other biological measures, and their long-term consequences for behavior.