Polychlorinated biphenyl exposures differentially regulate hepatic metabolism and pancreatic function: Implications for nonalcoholic steatohepatitis and diabetes.
Animals
Aroclors
/ toxicity
Diabetes Mellitus
/ chemically induced
Disease Models, Animal
Endocrine Disruptors
/ toxicity
Fibrosis
Humans
Lipid Metabolism
/ drug effects
Liver
/ drug effects
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
/ chemically induced
Pancreas
/ drug effects
Phospholipases A2, Calcium-Independent
/ metabolism
Polychlorinated Biphenyls
/ toxicity
AhR
FGF21
Islet Identity
PCB
Pnpla3
Journal
Toxicology and applied pharmacology
ISSN: 1096-0333
Titre abrégé: Toxicol Appl Pharmacol
Pays: United States
ID NLM: 0416575
Informations de publication
Date de publication:
15 01 2019
15 01 2019
Historique:
received:
16
05
2018
revised:
25
09
2018
accepted:
08
10
2018
pubmed:
13
10
2018
medline:
19
7
2019
entrez:
13
10
2018
Statut:
ppublish
Résumé
The endocrine disrupting chemicals, polychlorinated biphenyls (PCBs), have been associated with nonalcoholic steatohepatitis (NASH) and diabetes. However, an integrative analysis of the effects of PCBs on the liver and pancreas has never been performed for the two major PCB subtypes, dioxin-like (DL) and nondioxin-like (NDL), and a mixture of NDL/DL PCBs. Therefore, male C57BL/6 J mice fed a control synthetic diet were treated with either a NDL PCB mixture, Aroclor 1260 (20 mg/kg); a single DL PCB congener, PCB 126 (20 μg/kg); a NDL/DL mixture, Aroclor 1260 plus PCB 126; or vehicle control for 2 weeks. PCB126 had the greatest impact on hepatic lipid metabolism. It caused steatosis due to increased hepatic lipid import with associated hypolipidemia. However, all PCB exposures impacted expression of hepatic lipid metabolism genes in different manners. The 'NASH gene', Pnpla3, was elevated by Aroclor 1260, but decreased by all other exposures. The expression of hepatokines implicated in metabolic syndrome (Fgf21, Igf1, and betatrophin) were differentially regulated. The NDL/DL PCB mixture had the greatest effects on pancreatic histology, including acinar cell atrophy, mild steatosis, and fibrosis without ductal changes or immune cell infiltration. It decreased expression of insulin and altered the expression of genes regulating islet identity. None of these exposures was associated with altered HOMA-IR or HOMA-B. In summary, PCB exposures differentially regulated liver and pancreas structure and function. Novel mechanisms for PCB-induced endocrine/metabolic disruption included altered hepatokines and Pnpla3 as well as 'PCB pancreatopathy' that was associated with altered expression of pancreatic islet identity factors. More research is required to understand fully these findings in the context of human NASH and diabetes.
Identifiants
pubmed: 30312631
pii: S0041-008X(18)30469-1
doi: 10.1016/j.taap.2018.10.011
pmc: PMC7059560
mid: NIHMS1010404
pii:
doi:
Substances chimiques
Aroclors
0
Endocrine Disruptors
0
aroclor 1260
11096-82-5
Polychlorinated Biphenyls
DFC2HB4I0K
PNPLA3 protein, mouse
EC 3.1.1.3
Phospholipases A2, Calcium-Independent
EC 3.1.1.4
3,4,5,3',4'-pentachlorobiphenyl
TSH69IA9XF
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
22-33Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM113226
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA024337
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES021375
Pays : United States
Organisme : NIEHS NIH HHS
ID : F31 ES028982
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES028373
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES023716
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2018. Published by Elsevier Inc.
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