PMID- 38309623
OWN - NLM
STAT- MEDLINE
DCOM- 20240308
LR  - 20240311
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 81
DP  - 2024 Mar
TI  - The aryl hydrocarbon receptor in beta-cells mediates the effects of TCDD on glucose 
      homeostasis in mice.
PG  - 101893
LID - S2212-8778(24)00024-3 [pii]
LID - 10.1016/j.molmet.2024.101893 [doi]
LID - 101893
AB  - OBJECTIVE: Chronic exposure to persistent organic pollutants (POPs) is associated 
      with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin 
      secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs 
      that exert cellular toxicity through activation of the aryl hydrocarbon receptor 
      (AhR). We previously showed that a single high-dose injection of 
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 mug/kg) in vivo reduced 
      fasted and glucose-stimulated plasma insulin levels for up to 6 weeks in male and 
      female mice. TCDD-exposed male mice were also modestly hypoglycemic and had 
      increased insulin sensitivity, whereas TCDD-exposed females were transiently 
      glucose intolerant. Whether these effects are driven by AhR activation in beta-cells 
      requires investigation. METHODS: We exposed female and male beta-cell specific Ahr 
      knockout (betaAhr(KO)) mice and littermate Ins1-Cre genotype controls (betaAhr(WT)) to 
      a single high dose of 20 mug/kg TCDD and tracked the mice for 6 weeks. RESULTS: 
      Under baseline conditions, deleting AhR from beta-cells caused hypoglycemia in 
      female mice, increased insulin secretion ex vivo in female mouse islets, and 
      promoted modest weight gain in male mice. Importantly, high-dose TCDD exposure 
      impaired glucose homeostasis and beta-cell function in betaAhr(WT) mice, but these 
      phenotypes were largely abolished in TCDD-exposed betaAhr(KO) mice. CONCLUSION: Our 
      study demonstrates that AhR signaling in beta-cells is important for regulating 
      baseline beta-cell function in female mice and energy homeostasis in male mice. We 
      also show that beta-cell AhR signaling largely mediates the effects of TCDD on 
      glucose homeostasis in both sexes, suggesting that the effects of TCDD on beta-cell 
      function and health are driving metabolic phenotypes in peripheral tissues.
CI  - Copyright (c) 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.
FAU - Hoyeck, Myriam P
AU  - Hoyeck MP
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Angela Ching, Ma Enrica
AU  - Angela Ching ME
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Basu, Lahari
AU  - Basu L
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - van Allen, Kyle
AU  - van Allen K
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Palaniyandi, Jana
AU  - Palaniyandi J
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Perera, Ineli
AU  - Perera I
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Poleo-Giordani, Emilia
AU  - Poleo-Giordani E
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Hanson, Antonio A
AU  - Hanson AA
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada.
FAU - Ghorbani, Peyman
AU  - Ghorbani P
AD  - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, 
      Centre for Infection, Immunity and Inflammation, Ottawa Institute of Systems 
      Biology, Ottawa, ON, Canada.
FAU - Fullerton, Morgan D
AU  - Fullerton MD
AD  - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, 
      Centre for Infection, Immunity and Inflammation, Ottawa Institute of Systems 
      Biology, Ottawa, ON, Canada; Centre for Catalysis Research and Innovation, 
      University of Ottawa, Ottawa, ON, Canada.
FAU - Bruin, Jennifer E
AU  - Bruin JE
AD  - Department of Biology & Institute of Biochemistry, Carleton University, Ottawa, 
      ON, Canada. Electronic address: jenny.bruin@carleton.ca.
LA  - eng
PT  - Journal Article
DEP - 20240202
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Dioxins)
RN  - IY9XDZ35W2 (Glucose)
RN  - 0 (Polychlorinated Dibenzodioxins)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Ahr protein, mouse)
SB  - IM
MH  - Animals
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice
MH  - *Diabetes Mellitus, Type 2/chemically induced
MH  - *Dioxins
MH  - Glucose
MH  - Homeostasis
MH  - *Polychlorinated Dibenzodioxins/toxicity
MH  - Receptors, Aryl Hydrocarbon/genetics/metabolism
PMC - PMC10867573
OTO - NOTNLM
OT  - Aryl hydrocarbon receptor
OT  - Cre-loxP knockout
OT  - Dioxins
OT  - Environmental pollutants
OT  - Type 2 diabetes
OT  - beta-cells
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2024/02/04 00:42
MHDA- 2024/03/08 06:43
PMCR- 2024/02/02
CRDT- 2024/02/03 19:34
PHST- 2023/11/13 00:00 [received]
PHST- 2024/01/24 00:00 [revised]
PHST- 2024/01/30 00:00 [accepted]
PHST- 2024/03/08 06:43 [medline]
PHST- 2024/02/04 00:42 [pubmed]
PHST- 2024/02/03 19:34 [entrez]
PHST- 2024/02/02 00:00 [pmc-release]
AID - S2212-8778(24)00024-3 [pii]
AID - 101893 [pii]
AID - 10.1016/j.molmet.2024.101893 [doi]
PST - ppublish
SO  - Mol Metab. 2024 Mar;81:101893. doi: 10.1016/j.molmet.2024.101893. Epub 2024 Feb 
      2.