TY - JOUR
T1 - Neonatal Exposure to BPA, BDE-99, and PCB Produces Persistent Changes in Hepatic Transcriptome Associated with Gut Dysbiosis in Adult Mouse Livers
AU - Lim, Joe Jongpyo
AU - Dutta, Moumita
AU - Dempsey, Joseph L.
AU - Lehmler, Hans Joachim
AU - Macdonald, James
AU - Bammler, Theo
AU - Walker, Cheryl
AU - Kavanagh, Terrance J.
AU - Gu, Haiwei
AU - Mani, Sridhar
AU - Cui, Julia Yue
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
KW - adverse health outcomes
KW - bioinformatics
KW - environmental chemicals
KW - epigenetic
KW - microbiome
KW - toxicogenomics
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U2 - 10.1093/toxsci/kfab104
DO - 10.1093/toxsci/kfab104
M3 - Article
C2 - 34453844
AN - SCOPUS:85119583901
SN - 1096-6080
VL - 184
SP - 83
EP - 103
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -