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Title: A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol

Abstract

Oxidative stress and reactive oxygen species (ROS) have been implicated in the teratogenicity of methanol (MeOH) in rodents, both in vivo and in embryo culture. We explored the ROS hypothesis further in vivo in pregnant C57BL/6J mice. Following maternal treatment with a teratogenic dose of MeOH, 4 g/kg via intraperitoneal (ip) injection on gestational day (GD) 12, there was no increase 6 h later in embryonic ROS formation, measured by 2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA) fluorescence, despite an increase observed with the positive control ethanol (EtOH), nor was there an increase in embryonic oxidatively damaged DNA, quantified as 8-oxo-2′-deoxyguanosine (8-oxodG) formation. MeOH teratogenicity (primarily ophthalmic anomalies, cleft palate) also was not altered by pre- and post-treatment with varying doses of the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN). In contrast, pretreatment with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, depleted maternal hepatic and embryonic GSH, and enhanced some new anomalies (micrognathia, agnathia, short snout, fused digits, cleft lip, low set ears), but not the most common teratogenic effects of MeOH (ophthalmic anomalies, cleft palate) in this strain. These results suggest that ROS did not contribute to the teratogenic effects of MeOH in this in vivo mouse model, in contrast to resultsmore » in embryo culture from our laboratory, and that the protective effect of GSH in this model may arise from its role as a cofactor for formaldehyde dehydrogenase in the detoxification of formaldehyde. - Highlights: • In vivo, a free radical scavenger did not block methanol (MeOH) teratogenesis. • MeOH did not increase embryonic reactive oxygen species formation or DNA oxidation. • MeOH teratogenesis was enhanced by glutathione (GSH) depletion. • GSH may protect as the cofactor for formaldehyde dehydrogenase (ADH3). • Formaldehyde may be a ROS-independent proximate teratogenic species in vivo.« less

Authors:
;  [1];  [2]
  1. Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario (Canada)
  2. Division of Anatomy, Faculty of Medicine, University of Toronto, Toronto, Ontario (Canada)
Publication Date:
OSTI Identifier:
22285531
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 273; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALCOHOL DEHYDROGENASE; DMSO; DNA; ETHANOL; FLUORESCENCE; FORMALDEHYDE; FORMIC ACID; GLUTATHIONE; IN VIVO; LIVER; METHANOL; MICE; OXIDATION; STRESSES

Citation Formats

Siu, Michelle T., Shapiro, Aaron M., Wiley, Michael J., Wells, Peter G., E-mail: pg.wells@utoronto.ca, and Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario. A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.09.020.
Siu, Michelle T., Shapiro, Aaron M., Wiley, Michael J., Wells, Peter G., E-mail: pg.wells@utoronto.ca, & Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario. A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol. United States. https://doi.org/10.1016/J.TAAP.2013.09.020
Siu, Michelle T., Shapiro, Aaron M., Wiley, Michael J., Wells, Peter G., E-mail: pg.wells@utoronto.ca, and Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario. 2013. "A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol". United States. https://doi.org/10.1016/J.TAAP.2013.09.020.
@article{osti_22285531,
title = {A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol},
author = {Siu, Michelle T. and Shapiro, Aaron M. and Wiley, Michael J. and Wells, Peter G., E-mail: pg.wells@utoronto.ca and Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario},
abstractNote = {Oxidative stress and reactive oxygen species (ROS) have been implicated in the teratogenicity of methanol (MeOH) in rodents, both in vivo and in embryo culture. We explored the ROS hypothesis further in vivo in pregnant C57BL/6J mice. Following maternal treatment with a teratogenic dose of MeOH, 4 g/kg via intraperitoneal (ip) injection on gestational day (GD) 12, there was no increase 6 h later in embryonic ROS formation, measured by 2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA) fluorescence, despite an increase observed with the positive control ethanol (EtOH), nor was there an increase in embryonic oxidatively damaged DNA, quantified as 8-oxo-2′-deoxyguanosine (8-oxodG) formation. MeOH teratogenicity (primarily ophthalmic anomalies, cleft palate) also was not altered by pre- and post-treatment with varying doses of the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN). In contrast, pretreatment with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, depleted maternal hepatic and embryonic GSH, and enhanced some new anomalies (micrognathia, agnathia, short snout, fused digits, cleft lip, low set ears), but not the most common teratogenic effects of MeOH (ophthalmic anomalies, cleft palate) in this strain. These results suggest that ROS did not contribute to the teratogenic effects of MeOH in this in vivo mouse model, in contrast to results in embryo culture from our laboratory, and that the protective effect of GSH in this model may arise from its role as a cofactor for formaldehyde dehydrogenase in the detoxification of formaldehyde. - Highlights: • In vivo, a free radical scavenger did not block methanol (MeOH) teratogenesis. • MeOH did not increase embryonic reactive oxygen species formation or DNA oxidation. • MeOH teratogenesis was enhanced by glutathione (GSH) depletion. • GSH may protect as the cofactor for formaldehyde dehydrogenase (ADH3). • Formaldehyde may be a ROS-independent proximate teratogenic species in vivo.},
doi = {10.1016/J.TAAP.2013.09.020},
url = {https://www.osti.gov/biblio/22285531}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 273,
place = {United States},
year = {Sun Dec 15 00:00:00 EST 2013},
month = {Sun Dec 15 00:00:00 EST 2013}
}