Parental Alcohol Use Disrupts Offspring Mitochondrial Activity, Promoting Susceptibility to Toxicant-Induced Liver...

Area of Science:

• Hepatology
• Toxicology
• Epigenetics

Background:

• Liver disease and hepatocellular carcinoma incidence have doubled, linked to lifestyle and potentially heritable epigenetic changes.
• Parental environmental exposures, like alcohol, may induce epigenetic alterations affecting offspring's cellular bioenergetics and disease predisposition.

Purpose of the Study:

• To investigate if chronic parental alcohol exposure predisposes male offspring to liver disease and hepatocellular carcinoma.
• To compare the effects of maternal, paternal, and dual-parental alcohol exposure on offspring's susceptibility to a carcinogen.

Main Methods:

• Utilized a multiplex mouse model to assess male offspring from alcohol-exposed parents.
• Exposed offspring to Diethylnitrosamine, a potent hepatocellular carcinoma inducer.
• Analyzed liver mitochondrial complex I activity, oxidative stress, TGF-β, and IL-6 signaling.

Main Results:

• Parental alcohol exposure disrupted offspring liver mitochondrial complex I activity, causing oxidative stress and activating TGF-β signaling.
• This imbalance promoted inflammation via increased IL-6, creating a precancerous state.
• Male offspring from alcohol-exposed parents showed increased tumor incidence, multiplicity, and size, with dual-parental exposure showing synergistic adverse effects.

Conclusions:

• Chronic parental alcohol use alters mitochondrial function and immune responses in male offspring.
• This leads to a proinflammatory, precancerous state, increasing susceptibility to toxicant-induced liver disease and cancer.
• Maternal and paternal alcohol exposure interact, with combined exposure potentially causing more severe outcomes than individual exposure.