Ethanol-induced changes in poly (ADP ribose) polymerase and neuronal developmental gene expression

Abstract

Prenatal alcohol exposure has profound effects on neuronal growth and development. Poly-ADP Ribose Polymerase (PARP) enzymes are perhaps unique in the field of epigenetics in that they directly participate in histone modifications, transcription factor modifications, DNA methylation/demethylation and are highly inducible by ethanol. It was our hypothesis that ethanol would induce PARP enzymatic activity leading to alterations in neurodevelopmental gene expression. Mouse E18 cortical neurons were treated with ethanol, PARP inhibitors, and nuclear hormone receptor transcription factor PPARγ agonists and antagonists. Subsequently, we measured PARP activity and changes in Bdnf, OKSM (Oct4, Klf4, Sox2, c-Myc), DNA methylating/demethylating factors, and Pparγ mRNA expression, promoter 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC), and PPARγ promoter binding. We found that ethanol reduced Bdnf4, 9a, and Klf4 mRNA expression, and increased c-Myc expression. These changes were reversed with a PARP inhibitor. In agreement with its role in DNA demethylation PARP inhibition increased 5MC levels at the c-Myc promoter. In addition, we found that elevated PARP enzymatic activity reduced PPARγ promoter binding, and this corresponded to decreased Bdnf and Klf4 mRNA expression. Our results suggest that PARP participates in DNA demethylation and reduces PPARγ promoter binding. The current study underscores the importance of PARP in ethanol-induced changes to neurodevelopmental gene expression.

Hesperidin promotes lysosomal biogenesis in chronically ethanol‐induced cardiotoxicity in rats: A proposed mechanisms of protection

“…PARP‐1 is involved in DNA repair processes and cell survival . Our data revealed that PARP‐1 activity in cardiac tissues were significantly enhanced in ethanol‐fed rats compared with both normal and hesperidin only treated control rats; well aligning with previous reports showing that ethanol causes induction of PARP enzymatic activity in alcoholic steatohepatitis and in the developing brain where it provokes neuronal cell death and alters neurodevelopmental gene expression . This effect might be indebted to the ethanol‐induced inflammation and oxidative/nitrative stress which can lead to DNA damage and consecutive increased PARP‐1 activity and poly (ADP‐ribose) polymers accumulation ending in energetic collapse and cell death .…”

Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice

“…Murai et al (2012) reported that PARP1 is responsible for 90-95% of PARP enzymatic activity while PARP2 contributes the remaining 5-10% (Murai et al, 2012). In mouse primary cortical neuronal cultures, we found that ethanol exposure increased PARP enzymatic activity and led to gene expression changes, and that PARP inhibitors rescued some of the ethanol-induced gene expression changes (Gavin et al, 2016), indicating that PARP enzymes may act as regulators in the biochemical response to ethanol exposure (Gavin et al, 2016).…”

Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

“…These results, together, support a crucial role of the TRPM2 channel in mediating EtOH-induced microglial cell death. It is known that exposure to alcohol leads to oxidative stress and activation of PARP [ 8 , 9 , 10 ] and, as introduced earlier, PARP activation is the major signaling mechanism for oxidative stress-induced TRPM2 channel activation, including in microglial cells [ 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 ]. As described in our recent study examining cell death induced by ROS or Zn 2+ in primary microglial cells [ 25 ], and in this study showing H 2 O 2 -induced cell death in BV2 microglial cells ( Figure 2 e–h), EtOH-induced microglial cell death was remarkably attenuated by treatment with PJ34 and DPQ, two structurally different PARP inhibitors ( Figure 3 ), supporting that PARP activation is critical in EtOH-induced TRPM2-mediated microglial cell death.…”

“…In addition, as has been well documented, alcohol intake causes the brain to promote further alcohol consumption [ 7 ]. Regarding how alcohol impacts the brain, multiple molecular and cellular mechanisms have been proposed, including increased poly(ADP-ribose) polymerase (PARP) activity and ensuing regulation of gene expression, induction of oxidative stress via NADPH oxidases (NOX)-mediated generation of reactive oxygen species (ROS), neurotoxicity, neuromodulation, and neuroinflammation [ 7 , 8 , 9 , 10 , 11 , 12 ].…”