PMID- 34600989
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20230202
IS  - 1879-1026 (Electronic)
IS  - 0048-9697 (Print)
IS  - 0048-9697 (Linking)
VI  - 806
IP  - Pt 2
DP  - 2022 Feb 1
TI  - Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a 
      mouse model of glutathione deficiency.
PG  - 150703
LID - S0048-9697(21)05781-8 [pii]
LID - 10.1016/j.scitotenv.2021.150703 [doi]
AB  - 1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial 
      solvents. Recent occurrence data show widespread and significant contamination of 
      drinking water with DX in the US. DX is classified by the International Agency 
      for Research on Cancer as a group 2B carcinogen with the primary target organ 
      being the liver in animal studies. Despite the exposure and cancer risk, US EPA 
      has not established a drinking water Maximum Contaminant Level (MCL) for DX and a 
      wide range of drinking water targets have been established across the US and by 
      Health Canada. The DX carcinogenic mechanism remains unknown; this information 
      gap contributes to the varied approaches to its regulation. Our recent mice study 
      indicated alterations in oxidative stress response accompanying DNA damage as an 
      early change by high dose DX (5000 ppm) in drinking water. Herein, we report a 
      follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine 
      ligase modifier subunit (Gclm)-null mice to investigate the role of redox 
      homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and 
      wild-type mice were exposed to DX for one week (1000 mg/kg/day by oral gavage) or 
      three months (5000 ppm in drinking water). Subchronic exposure of high dose DX 
      caused mild liver cytotoxicity. DX induced assorted molecular changes in the 
      liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 
      (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive 
      CYP2E1 induction, (iii) development of oxidative stress, as evidenced by 
      persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid 
      peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA 
      damage and DNA repair response. These DX-elicited changes were exaggerated in 
      GSH-deficient mice. Collectively, the current study provides additional evidence 
      linking redox dysregulation to DX liver genotoxicity, implying oxidative stress 
      as a candidate mechanism of DX liver carcinogenicity.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Chen, Ying
AU  - Chen Y
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA. Electronic address: ying.chen@yale.edu.
FAU - Wang, Yewei
AU  - Wang Y
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA.
FAU - Charkoftaki, Georgia
AU  - Charkoftaki G
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA.
FAU - Orlicky, David J
AU  - Orlicky DJ
AD  - Department of Pathology, School of Medicine, University of Colorado Anschutz 
      Medical Center, University of Colorado, Aurora, CO 80045, USA.
FAU - Davidson, Emily
AU  - Davidson E
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA; Department of Cellular & Molecular 
      Physiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
FAU - Wan, Fengjie
AU  - Wan F
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA.
FAU - Ginsberg, Gary
AU  - Ginsberg G
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA.
FAU - Thompson, David C
AU  - Thompson DC
AD  - Department of Clinical Pharmacy, Skaggs School of Pharmacy & Pharmaceutical 
      Sciences, University of Colorado, Aurora, CO 80045, USA.
FAU - Vasiliou, Vasilis
AU  - Vasiliou V
AD  - Department of Environmental Health Sciences, Yale School of Public Health, Yale 
      University, New Haven, CT 06510, USA. Electronic address: 
      vasilis.vasiliou@yale.edu.
LA  - eng
GR  - UL1 TR001863/TR/NCATS NIH HHS/United States
GR  - P42 ES033815/ES/NIEHS NIH HHS/United States
GR  - K01 AA025093/AA/NIAAA NIH HHS/United States
GR  - R24 AA022057/AA/NIAAA NIH HHS/United States
GR  - P30 DK034989/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20210930
PL  - Netherlands
TA  - Sci Total Environ
JT  - The Science of the total environment
JID - 0330500
RN  - 0 (Dioxanes)
RN  - GAN16C9B8O (Glutathione)
RN  - J8A3S10O7S (1,4-dioxane)
SB  - IM
MH  - Animals
MH  - *DNA Damage
MH  - Dioxanes
MH  - Follow-Up Studies
MH  - Glutathione/metabolism
MH  - Liver/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - *Oxidative Stress
PMC - PMC8633123
MID - NIHMS1746576
OTO - NOTNLM
OT  - CYP2E1
OT  - Liver carcinogenicity
OT  - Mechanism of action
OT  - Oxidative DNA damage
OT  - Water contaminant
COIS- Declaration of competing interest The authors declare that they have no conflict 
      of interest with the contents of the article.
EDAT- 2021/10/04 06:00
MHDA- 2021/12/15 06:00
PMCR- 2023/02/01
CRDT- 2021/10/03 20:39
PHST- 2021/06/15 00:00 [received]
PHST- 2021/09/27 00:00 [revised]
PHST- 2021/09/27 00:00 [accepted]
PHST- 2021/10/04 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/10/03 20:39 [entrez]
PHST- 2023/02/01 00:00 [pmc-release]
AID - S0048-9697(21)05781-8 [pii]
AID - 10.1016/j.scitotenv.2021.150703 [doi]
PST - ppublish
SO  - Sci Total Environ. 2022 Feb 1;806(Pt 2):150703. doi: 
      10.1016/j.scitotenv.2021.150703. Epub 2021 Sep 30.