Neonatal Exposure to BPA, BDE-99, and PCB Produces Persistent Changes in Hepatic Transcriptome Associated with Gut Dysbiosis in Adult Mouse Livers

Joe Jongpyo Lim, Moumita Dutta, Joseph L. Dempsey, Hans Joachim Lehmler, James Macdonald, Theo Bammler, Cheryl Walker, Terrance J. Kavanagh, Haiwei Gu, Sridhar Mani, Julia Yue Cui

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Recent evidence suggests that complex diseases can result from early life exposure to environmental toxicants. Polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) and remain a continuing risk to human health despite being banned from production. Developmental BPA exposure mediated-adult onset of liver cancer via epigenetic reprogramming mechanisms has been identified. Here, we investigated whether the gut microbiome and liver can be persistently reprogrammed following neonatal exposure to POPs, and the associations between microbial biomarkers and disease-prone changes in the hepatic transcriptome in adulthood, compared with BPA. C57BL/6 male and female mouse pups were orally administered vehicle, BPA, BDE-99 (a breast milk-enriched PBDE congener), or the Fox River PCB mixture (PCBs), once daily for three consecutive days (postnatal days [PND] 2-4). Tissues were collected at PND5 and PND60. Among the three chemicals investigated, early life exposure to BDE-99 produced the most prominent developmental reprogramming of the gut-liver axis, including hepatic inflammatory and cancer-prone signatures. In adulthood, neonatal BDE-99 exposure resulted in a persistent increase in Akkermansia muciniphila throughout the intestine, accompanied by increased hepatic levels of acetate and succinate, the known products of A. muciniphila. In males, this was positively associated with permissive epigenetic marks H3K4me1 and H3K27, which were enriched in loci near liver cancer-related genes that were dysregulated following neonatal exposure to BDE-99. Our findings provide novel insights that early life exposure to POPs can have a life-long impact on disease risk, which may partly be regulated by the gut microbiome.

Original languageEnglish (US)
Pages (from-to)83-103
Number of pages21
JournalToxicological Sciences
Volume184
Issue number1
DOIs
StatePublished - Nov 1 2021

Keywords

  • adverse health outcomes
  • bioinformatics
  • environmental chemicals
  • epigenetic
  • microbiome
  • toxicogenomics

ASJC Scopus subject areas

  • Toxicology

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