Metabolite profiling of the effect of prenatal stimuli across postnatal treatments in the liver

Hepatic molecular mechanisms can be modulated by pro- and anti-inflammatory signals associated with infections and nutritional changes that can, in turn, affect the endocrine system. The sex-specific interplay between stimuli on hepatic pathways was studied using a biomedical model. The liver metabolome of pigs exposed to a prenatal immune activation from maternal infection was compared to that of matching female and male controls. Within prenatal treatment and sex group, the postnatal treatments were synthetic inflammatory factor, feeding deprivation (fasting), or saline. Liquid chromatography mass spectrometry enabled the detection of 2554 metabolites with significant (False Discovery Rate-adjusted p-value <0.05) sex, prenatal, and postnatal treatment effects. The glycine, serine, and threonine metabolism, RNA metabolism, and neurotransmitter transporters pathways included metabolites with prenatal-by-postnatal treatment interaction effects, such as alanine, arginine, and ketobutyric acid. These disruptions can impact hepatic detoxification, protein synthesis, and methylation. The synergistic interaction for adenosylhomocysteine was characterized by higher levels in the postnatal fasted relative to the saline-treated group, whereas this trend was 4.5-fold higher in the prenatal immune-activated group compared to controls. The antagonistic interaction for chenodeoxycholyltaurine was characterized by higher levels in prenatal-activated relative to controls under saline conditions, whereas this trend declined 2.2-fold in the postnatal-stimulated groups. Sex-specific effects were observed for glutamic acid, with differences between prenatal groups 4.7 times higher in males than in females. These findings offer insights into the interplay between sex, prenatal, and postnatal stimuli across pathways that must be considered in the development of therapies to optimize liver function.