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

Abstract

The early onset and incidence of liver disease and hepatocellular carcinoma have doubled in the last two decades and are primarily attributed to an unhealthy lifestyle. However, emerging studies suggest that increases in these age-related pathologies may link to heritable alterations in the control of cellular bioenergetics induced by the parental environment. Because our preclinical studies examining the fetal offspring of alcohol-exposed males and females have consistently identified epigenetic alterations in mitochondrial activity, we hypothesized that chronic parental alcohol exposure programs an increased predisposition of offspring to develop liver disease and hepatocellular carcinoma induced by an environmental toxicant. Here, we employed a multiplex mouse model to compare the sensitivities of male offspring derived from maternal, paternal, and dual-parental alcohol exposures to the potent hepatocellular carcinoma inducer Diethylnitrosamine and determine their predisposition for tumor formation and growth. Our analysis reveals that parental alcohol exposures disrupt the activity of offspring mitochondrial complex I in the liver, promoting enduring oxidative stress and activating Transforming Growth Factor β signaling. This lasting imbalance correlates with increased Interleukin 6 production, promoting an inflammatory precancerous state. In male offspring, chronic parental alcohol consumption leads to increased tumor incidence, multiplicity, and size. Significantly, maternal and paternal alcohol use interact in driving the progression of toxicant-induced liver disease, with some adverse outcomes of dual-parental offspring exceeding those caused by either maternal or paternal alcohol use alone. We conclude that chronic parental alcohol use alters mitochondrial complex I activity and immune function, predisposing male offspring to a proinflammatory precancerous state.