Maternal metabolic syndrome induces liver injury and promotes tumor growth in the offspring

Abstract

Abstract Objective Obesity is a growing disease entity affecting a third of women of reproductive age. Epidemiological studies show that children of obese mothers suffer from obesity, long-term morbidity and an increased rate of childhood cancers. However, the mechanisms of disease transmission remain unknown. The aim of this study is to test this hypothesis in a mouse model and shed light on the involved mechanisms of vertical transmission. Methods Female mice were fed a high fat or standard diet (HFD/SD) for 16 weeks before being mated with mice fed a normal diet. Corresponding diet was continued until weaning, all offspring were thereafter fed a SD. Metabolic profile, weight gain, liver enzymes and the gut microbiota profile were assessed in the offspring (n = 24). Additional groups of offspring (n = 48) were injected with a carcinogen (diethylnitrosamine) at week two, tumor characteristics were assessed by computed tomography scan at week 36. Results Mothers fed HFD developed obesity and non-alcoholic fatty liver disease (NAFLD). Female offspring of mothers fed HFD gained significantly more weight (+33.7%, p = 0.001), had increased alanine transaminase levels (62 vs 18 IU/L, p = 0.003) and a significantly altered liver histology exemplified by an increased NAFLD activity score (3.8 vs 0.6, p = 0.016). Expression levels of several candidate genes were studied of which FGF21 showed the largest differential expression between HFD and SD offspring (9 vs 1 2^ΔΔCT, p = <0.001). However, epigenetic analysis of FGF21 in the liver revealed no changes in methylation level between HFD and SD offspring. Furthermore, offspring of HFD mothers had a distinctly altered gut microbiome with lower proportions of Bacteroides caccae, Bacteroidales and Parasutterella excrementihominis. Interestingly, the proportion of female offspring developing tumors was significantly higher in offspring of HFD mothers (83 vs 44%, p = 0.011), the average total tumor volume was larger (234 vs 3.5mm3, p = 0.022) and the offspring developed more tumors (3.5 vs 0.6, p = 0.010). Conclusion Maternal obesity promotes liver tumor growth in the offspring, alters metabolic patterns and induces liver suffering in the progeny in a sex-dependent manner. The gut microbiome seems to play a role in this transmission of disease. Yet further research is needed to determine the vectors of transmission and evaluate preventive interventions in obese mothers.