Late onset of metabolic liver disease from early life flame retardant exposure and adulthood western diet

PROJECT SUMMARY Metabolic-associated fatty liver disease (MAFLD) is a fatty liver disease with dysregulated metabolic phenotype but without excessive alcohol consumption and is a significant public health concern worldwide. The pathogenesis of MAFLD involve multiple cell types and usually accompanied by decreased metabolic capacity

as well as increased inflammation and oxidative stress in the liver. The intestinal environment (i.e., gut microbiome, host intestinal cell types) also contributes to MAFLD via the gut-liver axis. MAFLD has traditionally been linked to nutritional imbalances, such as a western diet (WD). However, the pathogenesis of complex

metabolic disorders, such as MAFLD, is rarely caused by only one risk factor. Early life exposure to environmental stressors is an emerging contributor to the delayed onset of metabolic diseases later in life. Among various environmental stressors, epidemiological and animal studies showed that legacy and current-use flame

retardants (i.e., polybrominated diphenyl ethers [PBDEs] and tetrabromobisphenol A [TBBPA]) are associated with altered carbohydrate and lipid metabolism, which are hallmarks of MAFLD. PBDEs and TBBPA can activate important xenobiotic-sensing nuclear receptors, namely the pregnane X receptor (PXR) and constitutive

androstane receptor (CAR) in the liver and intestine. PBDEs and TBBPA are enriched in breast milk and can cross the placenta making neonates especially susceptible to flame retardant-induced toxicities. I demonstrated that neonatal exposure to BDE-99 (i.e., human breast milk enriched PBDE congener) persistently up-regulated

proinflammation- but down-regulated lipid metabolism-related genes in mouse livers, which was accompanied by a dysbiotic gut microbiome at young adulthood. Furthermore, I observed immune cell infiltration in the liver with compromised xenobiotic and lipid metabolism pathways in hepatocytes at later adulthood from neonatal

exposure to BDE-99. Large intestinal microbiota transplantation using donors that were neonatally exposed to BDE-99 showed altered the immunological landscape of the gut environment towards proinflammation in the germ-free recipients, suggesting the involvement of the gut microbiome in the dysregulated gut-liver axis later in

life. Building on these findings, my central hypothesis is that early life exposure to legacy and current use flame retardants predisposes MAFLD development later in life, modulated by the gut microbiome. Specifically, the flame retardant-induced proinflammatory gut environment leads to the exacerbation of liver injuries later in life

by. I will use a novel humanized transgenic mouse model with human PXR and CAR as well as their targeted human CYP3A genes to test my hypothesis with 2 specific aims: 1) early life PBDE or TBBPA exposure exacerbates MAFLD following WD; 2) altered gut environment from early life toxicant exposure critically

regulates aggravation of WD induced MAFLD. The proposed work lay the foundation for how the gut microbiome, environmental stressors, and secondary risk factors interact in complex diseases.