Single-cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a proinflammatory metabolic signature in male mice at late adulthood

Apr 22, 2024Toxicological sciences : an official journal of the Society of Toxicology

Early-life BDE-99 exposure changes gut-liver communication to increase inflammation-related metabolism in older male mice

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Neonatal exposure to BDE-99 at 57 mg/kg altered liver gene expression in male mice by 15 months of age.

Exposure to BDE-99 down-regulated genes related to drug metabolism and lipid processing in the liver.
An increase in neutrophils and predicted macrophage signaling was observed in the liver following BDE-99 exposure.
Decreased levels of intestinal tight junction protein transcripts were associated with changes in the gut environment.
Dysregulation of inflammation-related metabolites was noted in mice exposed to BDE-99 during the neonatal period.
Germ-free mice studies indicated that a normal gut microbiome is necessary for maintaining liver immune tolerance.

AI simplified

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants that bioaccumulate in the environment. The gut microbiome is an important regulator of liver functions including xenobiotic biotransformation and immune regulation. We recently showed that neonatal exposure to polybrominated diphenyl ether-99 (BDE-99), a human breast milk-enriched PBDE congener, up-regulated proinflammation-related and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, the persistence of this dysregulation into late adulthood, differential impact among hepatic cell types, and the involvement of the gut microbiome from neonatal BDE-99 exposure remain unknown. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4. At 15 months of age, neonatal BDE-99 exposure down-regulated xenobiotic and lipid-metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also increased the hepatic proportion of neutrophils and led to a predicted increase of macrophage migration inhibitory factor signaling. This was associated with decreased intestinal tight junction protein (Tjp) transcripts, altered gut environment, and dysregulation of inflammation-related metabolites. ScRNA-seq using germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immune tolerance. Microbiota transplant to GF mice using large intestinal microbiome from adults neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed cell type-specific gene expression and cell-cell communication in liver towards proinflammation, and this may be partly due to the dysregulated gut environment.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text ↗

Single-cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a proinflammatory metabolic signature in male mice at late adulthood

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief