PROJECT SUMMARY Bisphenol S (BPS), bisphenol F (BPF), and diisononylphthalate (DINP) are increasingly replacing the endocrine disrupting chemicals bisphenol A (BPA) and di-2-ethylhexylphthalate (DEHP), respectively. However, BPS, BPF, and DINP have not undergone safety testing. Perinatal exposures (in utero and during lactation) to BPA and DEHP are associated with the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, a common disease in children, is being diagnosed at increasingly younger ages and its prevalence is increasing in late adolescence. While BPA and DEHP have been extensively studied in this context, BPS/BPF and DINP have not. BPS exposure promoted NAFLD progression in zebrafish, and BPF serum levels are higher in NAFLD patients than in controls. BPS and BPF levels were associated with increased prevalence of obesity in children, a risk factor for NAFLD. DINP caused lipidomic disruption in neonatal mice, while phthalate exposure caused hepatic steatosis in adult mice. Thus, like BPA and DEHP, early-life BPS/BPF and DINP exposure may promote NAFLD development/progression. To date, the mechanisms by which bisphenols and phthalates, particularly as a mixture, trigger these long-term metabolic consequences are elusive. Here, we will test the hypothesis that early life exposure to a bisphenol/phthalate mixture activates RAGE signaling pathways, triggers a trained immune response in peripheral monocytes, and reprograms the epigenome/transcriptome in liver and in peripheral monocytes, thereby priming offspring for exaggerated metabolic dysfunction upon exposure to Western diet. This ViCTER consortium will address this novel hypothesis through integrated studies in mice and in human subjects.