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Neonatal Oral Exposure to Environmental Chemicals Produces Persistent Dysbiosis Corresponding to Hepatic Epigenetic Reprogramming in Adult Mice
Abstract   Peer reviewed

Neonatal Oral Exposure to Environmental Chemicals Produces Persistent Dysbiosis Corresponding to Hepatic Epigenetic Reprogramming in Adult Mice

Joseph L Dempsey, Xiajian Shi, Haiwei Gu, Hans‐Joachim Lehmler, Joseph Petrosino, Cheryl Walker, Terrance J Kavanagh and Julia Yue Cui
The FASEB journal, Vol.33(S1), pp.lb23-lb23
04/2019
DOI: 10.1096/fasebj.2019.33.1_supplement.lb23

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Abstract

Background Mechanistic research establishing a causal relationship between gut dysbiosis and developmental origins of health and disease (DOHaD) is lacking. The ontogeny of many liver genes is modulated by distinct epigenetic mechanisms through microbial metabolites, such as histone acetylation and short‐chain fatty acids (SCFAs). Early life exposure to bisphenol A (BPA) has been linked to epigenetic reprogramming in adults, but little is known regarding the potentially persistent effects of other environmental toxicants (e.g. polybrominated diphenyl ethers [PBDEs] and polychlorinated biphenyls [PCBs]) on the gut‐liver axis. The present study tested the hypothesis that neonatal oral exposure to these compounds causes persistent dysbiosis, leading to epigenetic reprogramming of hepatic xenobiotic biotransformation genes by microbial metabolites. Experimental Design Male and female C57BL/6J mouse pups were sublingually exposed to corn oil, BDE‐99, BPA, or Fox River PCB mixture once daily at postnatal days (PND) 2–4. Feces and host tissues were collected at PND 5 and 60 (n=5 per group). Microbial DNA from feces and intestines (duodenum, jejunum, ileum, and large intestine) was subjected to 16S rDNA sequencing. Whole transcriptome sequencing (RNA‐Seq) and location of epigenetic marks (ChIP‐Seq) were conducted in livers of PND 60 mice. SCFAs were quantified in livers of PND 60 mice using gas chromatography‐mass spectrometry (GC‐MS). Results Neonatal chemical exposure persistently decreased the richness of the bacterial community (alpha diversity) in feces of adult mice. Interestingly, BDE‐99, but not BPA or PCB, profoundly increased the percentage of the SCFA‐generating Akkermensia muciniphilia in both male and female PND60 mice (0.55%‐6%) in duodenum, jejunum, large intestine, and feces. Corresponding to the increase in A. muciniphila, in BDE‐99 neonatal exposed mice, there was a persistent increase in the relative abundance of the hepatic SCFAs succinate and lactate, as well as an increasing trend in the known HDAC inhibitor acetate in adult age. In addition, adult male mice that were neonatally exposed to BDE‐99 had 12,606 more peaks for the permissive gene transcription mark histone 3 lysine 27 acetylation (H3K27ac; p<0.01; MACS2) associated with 4,495 protein‐coding genes (threshold: ±10kb of the gene loci; PAVIS). Examples of these genes include cytochrome P450s as well as genes involved in circadian entrainment. Conclusion Neonatal exposure to BDE‐99, BPA, and PCBs persistently altered the gut microbiome composition, correlating with altered hepatic SCFAs and epigenetic reprogramming, demonstrating the importance of the gut‐liver axis in DOHaD. Support or Funding Information Funding provided by NIH grants P30ES007033 and P30 ES023512‐04S2 (Center admin supplement), as well as GM111381. This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.

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