Abstract 6458: Maternal and paternal alcohol exposures program higher incidence of hepatocellular carcinoma in offspring
Authors: Basel Alison , Bhadsavle Sanat S. , Thomas Kara N. , Zimmel Katherine N. , Roach Alexis N. , Gaytan Matthew , Parkey Grace , Golding Michael C. 
Published: June 2023

Environmental exposures during development are known to influence adult health and disease. Specifically, early developmental exposures have been shown to increase susceptibility to cancer in adults through epigenetic mechanisms. Alcohol is a potent environmental carcinogen and teratogen, causing a wide range of health problems across the life course of an individual. Current literature examining early life exposures solely focuses on maternal exposures despite recent efforts to recognize paternal epigenetic contributions. Thus, we investigated the influence of preconception paternal, maternal, and dual parental alcohol exposures on offspring’s predisposition to develop liver disease and hepatocellular carcinoma (HCC). We hypothesized that dual-parental alcohol exposure would exacerbate the incidence of liver cancer in adult offspring.

Using an established mouse model, we exposed male and female adult C57BL/6J mice to control (0% EtOH) or alcohol (10% EtOH) preconception treatments. Next, we randomly assigned pups from each treatment to either a single injection of Diethylnitrosamine (DEN; 25mg/kg) to promote liver tumors, or saline control. Finally, we sacrificed offspring on postnatal day 182 and collected organs and blood for enzyme analysis.

DEN-treated males display an increased liver-to-body weight ratio compared to saline males while also exhibiting lower body weight. The male progeny from the dual-parental treatment group exhibited a significant increase in tumor incidence and burden in DEN-treated males, exceeding those measured for the maternal and paternal treatments. Further, offspring from the dual-parental group had high levels of alanine transaminase (ALT) and aspartate transaminase (AST) compared to the other treatment groups. Oil Red-O and Sirius Red staining of liver sections revealed increased hepatic steatosis and fibrosis in DEN males compared to saline males. Again, the dual-parental exposed offspring exhibited the most aberrant phenotype. Blind scoring of H&E-stained liver sections identified increases in steatosis, fibrosis, and HCC lesions, with the highest scores emerging in DEN-treated dual-parental offspring.

These findings demonstrate that preconception paternal and gestational maternal alcohol exposures program a predisposition to adult-onset chronic diseases including alcoholic fatty liver disease, hepatic fibrosis, and HCC. These experiments not only confirm our hypothesis that dual-parental exposed offspring exhibit an exacerbated hepatic abnormality phenotype, but also highlight the importance of both maternal and paternal environmental exposures on disease risk in offspring. While the negative effects of maternal alcohol consumption have been well established, our novel finding that paternal alcohol exposure also promotes hepatocellular carcinoma in offspring has potentially profound clinical implications.

Citation Format: Alison Basel, Sanat S. Bhadsavle, Kara N. Thomas, Katherine N. Zimmel, Alexis N. Roach, Matthew Gaytan, Grace Parkey, Michael C. Golding. Maternal and paternal alcohol exposures program higher incidence of hepatocellular carcinoma in offspring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6458.