Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood (Part 2/2)

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 BDE-99, a human breast milk-enriched PBDE congener,
up-regulated pro-inflammation- and down-regulated drug metabolism-related
genes predominantly in males in young adulthood.  However, it
remains unknown regarding the persistence of dysregulation into late
adulthood, differential impact of hepatic cell types, and the involvement
of the gut microbiome from neonatal BDE-99 exposure.  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 key xenobiotic- and lipid metabolizing enzymes and
up-regulated genes involved in microbial influx in hepatocytes.
 Neonatal BDE-99 exposure also persistently 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, persistent dysbiosis,
and dysregulation of inflammation-related metabolites.  ScRNA-seq
using germ-free (GF) mice demonstrated the necessity of a normal gut
microbiome in maintaining hepatic immunotolerance. 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 the large intestine.  In conclusion, neonatal BDE-99
exposure reprogrammed cell type-specific gene expression and communication
in liver towards pro-inflammation, and BDE-99-mediated pro-inflammatory
signatures may be partly due to the dysregulated gut environment.