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.
