PARP Inhibitor Affects Long-term Heat-stress Response via Changes in DNA Methylation

Resilience to stress can be obtained by adjusting the stress-response set point during postnatal sensory development. Recent studies have implemented epigenetic mechanisms to play leading roles in improving resilience. We previously found that better resilience to heat stress in chicks can be achieved by conditioning them to moderate heat stress during their critical developmental period of thermal control establishment, 3 days posthatch. Furthermore, the expression level of corticotropin-releasing hormone (CRH) was found to play a direct role in determining future resilience or vulnerability to heat stress by alterations in its DNA-methylation and demethylation pattern. Here we demonstrate how intraperitoneal injection of poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) influences the DNA methylation pattern, thereby affecting the long-term heat-stress response. Single PARPi administration, induced a reduction in both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), without affecting body temperature. The accumulated effect of three PARPi doses brought about a long-term decrease in 5mC% and 5hmC%. These changes coincided with a reduction in body temperature in non-conditioned chicks, similar to that occurring in moderately conditioned heat-stress-resilient chicks. The observed changes in DNA methylation can be explained by decreased activity of the enzyme DNA methyltransferase as a result of the PARPi injection. Furthermore, evaluation of the DNA-methylation pattern along the CRH intron showed a reduction in 5mC% as a result of PARPi treatment, alongside a reduction in CRH mRNA expression. Thus, PARPi treatment can affect DNA methylation, which can alter hypothalamic-pituitary-adrenal (HPA) axis anchors such as CRH, thereby potentially enhancing long-term resilience to heat stress.