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

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2024 · $45,574

## Abstract

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 foundat...

## Key facts

- **NIH application ID:** 10996387
- **Project number:** 1F31DK139707-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jongpyo Joe Lim
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,574
- **Award type:** 1
- **Project period:** 2024-08-06 → 2026-08-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996387

## Citation

> US National Institutes of Health, RePORTER application 10996387, Late onset of metabolic liver disease from early life flame retardant exposure and adulthood western diet (1F31DK139707-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10996387. Licensed CC0.

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