A study has revealed that parental alcohol consumption prior to conception may predispose male offspring to an increased risk of developing hepatocellular carcinoma.
In the study, published in the Aging and Disease and conducted at Texas A&M University, researchers demonstrated that both maternal and paternal alcohol use can program lasting alterations in offspring mitochondrial function and immune response.
"Chronic parental alcohol use alters mitochondrial complex I activity and immune function, predisposing male offspring to a proinflammatory precancerous state," reported lead study author Alison Basel, of the Department of Veterinary Physiology & Pharmacology at Texas A&M University, and her colleagues.
Using a multiplex mouse model study, the researchers examined offspring from four treatment groups: control, maternal alcohol exposure, paternal alcohol exposure, and dual-parental alcohol exposure. When challenged with the hepatocellular carcinoma (HCC) inducer diethylnitrosamine (DEN), male offspring showed increased tumor incidence, multiplicity, and size—with dual-parental exposure producing the most severe outcomes.
The researchers identified specific molecular mechanisms driving this increased cancer susceptibility. Offspring of alcohol-exposed parents exhibited compromised mitochondrial complex I activity, resulting in a decreased NAD-positive/NADH ratio and increased oxidative stress. This correlated with activation of transforming growth factor–beta signaling pathways and elevated production of the inflammatory cytokine interleukin-6.
Notably, the researchers found that maternal and paternal alcohol exposures can interact additively. "Some adverse outcomes of dual-parental offspring exceeded those caused by either maternal or paternal alcohol use alone," the study authors note.
The findings suggested that individuals with fetal alcohol spectrum disorder may inherit heightened susceptibility to HCC through epigenetic mechanisms rather than direct alcohol exposure, underscoring the need for expanded public health messaging about preconception alcohol use to include both men and women.
The study utilized a voluntary "Drinking in the Dark" model where mice consumed either water or 10% ethanol. Male mice received an average daily dose of 1.91 g/kg, whereas females received 2.30 g/kg during preconception and 2.34 g/kg during early gestation—amounts correlating to 1.25 to 1.8 times the legal blood alcohol limit in humans.
"For the first time, we demonstrate that HCC development and susceptibility in the offspring of alcohol-exposed parents can arise through presumptive epigenetic mechanisms instead of direct alcohol exposure," the study authors concluded.
The work was supported by grants from the W.M. Keck Foundation and National Institute on Alcohol Abuse and Alcoholism. Disclosures were not made available at time of publishing.