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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\u2009ml\/kg) or BDE-99 (57\u2009mg\/kg) once daily from postnatal days 2\u20134. At 15\u2009months 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.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae047","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T18:46:21Z","timestamp":1713465981000},"page":"114-136","source":"Crossref","is-referenced-by-count":9,"title":["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"],"prefix":"10.1093","volume":"200","author":[{"given":"Joe Jongpyo","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, USA"},{"name":"Environmental Health and Microbiome Research Center (EHMBRACE) , Seattle, Washington 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Goedken","sequence":"additional","affiliation":[{"name":"Rutgers Research Pathology Services, Rutgers University , Piscataway, New Jersey 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jin","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University , Port St Lucie, Florida 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiwei","family":"Gu","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University , Port St Lucie, Florida 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Yue","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, USA"},{"name":"Environmental Health and Microbiome Research Center (EHMBRACE) , Seattle, Washington 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"key":"2024062607540750100_kfae047-B1","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s13567-021-00962-6","article-title":"Typhlitis induced by histomonas meleagridis affects relative but not the absolute Escherichia coli counts and invasion in the gut in turkeys","volume":"52","author":"Abdelhamid","year":"2021","journal-title":"Vet. 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