Oxidative Stress and Species Differences in the Metabolism, Developmental Toxicity, and Carcinogenic Potential of Methanol and Ethanol

Wells, Peter G.; McCallum, Gordon P.; Miller, Lutfiya; Siu, Michelle; Sweeting, J. Nicole

doi:10.1002/9781118353110.ch7

Cited by 12 publications

(5 citation statements)

References 160 publications

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“…Humans metabolize methanol differently than all other animals, including the non-human primates [21]. Elucidation of methanol's toxicity has been impeded by the conundrum that in all non-human animals the first metabolite of methanol, formaldehyde, is produced by catalase safely in the peroxisome where its conversion to formic acid and then carbon dioxide can proceed easily via the same enzyme [22]. Unfortunately the human peroxisome has no such protective mechanism, leaving methanol's conversion to formaldehyde to the free floating alcohol dehydrogenase class 1 (ADH) enzyme in the cytosol of many non-hepatic cells such as the Purkinje in the cerebellum and the lining of the blood vessels of the brain [23].…”

Section: Discussionmentioning

confidence: 99%

“…Humans bear a genetic defect of the catalase detoxification complex that guarantees any formaldehyde produced from methanol's first oxidation is randomly released into cell cytoplasm [22]. Formaldehyde causes embryo lethality in vitro at a nearly 1000-fold lower concentration (0.004 mg/ml) than either methanol itself or its second metabolite, formic acid [33].…”

Section: Discussionmentioning

confidence: 99%

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Dietary methanol and autism

Walton¹,

Monte

2015

Medical Hypotheses

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The authors sought to establish whether maternal dietary methanol during pregnancy was a factor in the etiology of autism spectrum disorders. A seven item questionnaire was given to women who had given birth to at least one child after 1984. The subjects were solicited from a large primary care practice and several internet sites and separated into two groups - mothers who had given birth to a child with autism and those who had not. Average weekly methanol consumption was calculated based on questionnaire responses. 550 questionnaires were completed by women who gave birth to a non-autistic child. On average these women consumed 66.71mg. of methanol weekly. 161 questionnaires were completed by women who had given birth to an autistic child. The average estimated weekly methanol consumption for this group was 142.31mg. Based on the results of the Wilcoxon rank sum-test, we see a significant difference between the reported methanol consumption rates of the two groups. This study suggests that women who have given birth to an autistic child are likely to have had higher intake of dietary sources of methanol than women who have not. Further investigation of a possible link of dietary methanol to autism is clearly warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dietary methanol and autism

Walton¹,

Monte

2015

Medical Hypotheses

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“…Reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide, and hydroxyl radicals (Halliwell & Gutteridge, ; Wells et al, ; Wells, Miller‐Pinsler, & Shapiro, ), are unstable, are produced naturally in the embryo and fetus, and are essential for normal development (Dennery, ; Wells, McCallum, Miller, Siu, & Sweeting, ). ROS can be formed via several mechanisms including superoxide leakage from the mitochondrial electron transport chain, and production via NADPH oxidases (NOXs; Abdel‐Rahman et al, ; Ali et al, ; Chen, Kirber, Xiao, Yang, & Keaney Jr., ; Wells et al, , , ; Figure ). ROS normally participate in intracellular signaling pathways (Finkel, ; Hansen & Harris, ) by acting as messenger molecules affecting processes such as the activity of enzymes involved in long‐term potentiation and modulating learning and memory (Massaad & Klann, ).…”

Section: The Relationship Between Reactive Oxygen Species Oxidative mentioning

confidence: 99%

“…Many of the same ROS‐forming pathways that are enhanced by xenobiotics are also responsible for physiological ROS formation, and imbalances between conceptal ROS formation versus detoxification and the repair of oxidatively damaged DNA can have pathogenic consequences even under normal conditions in the absence of xenobiotic exposures. Abbreviations: ATM, ataxia telangiectasia mutated; BRCA1, breast cancer 1; CSB, Cockayne syndrome B; CYPs, cytochromes P450; Fe, iron; G‐6‐P, glucose‐6‐phosphate; GSH, glutathione; GSSG, glutathione disulfide; LPOs, lipoxygenases; NADP+, nicotinamide adenine dinucleotide phosphate; OGG1, oxoguanine glycosylase 1; PHSs, prostaglandin H synthases; SOD, superoxide dismutase (Wells et al, )…”

Section: The Relationship Between Reactive Oxygen Species Oxidative mentioning

confidence: 99%

Oxidative stress and DNA damage in the mechanism of fetal alcohol spectrum disorders

Bhatia

Drake

Miller

et al. 2019

Birth Defects Research

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This review covers molecular mechanisms involving oxidative stress and DNA damage that may contribute to morphological and functional developmental disorders in animal models resulting from exposure to alcohol (ethanol, EtOH) in utero or in embryo culture. Components covered include: (a) a brief overview of EtOH metabolism and embryopathic mechanisms other than oxidative stress; (b) mechanisms within the embryo and fetal brain by which EtOH increases the formation of reactive oxygen species (ROS); (c) critical embryonic/fetal antioxidative enzymes and substrates that detoxify ROS; (d) mechanisms by which ROS can alter development, including ROS-mediated signal transduction and oxidative DNA damage, the latter of which leads to pathogenic genetic (mutations) and epigenetic changes; (e) pathways of DNA repair that mitigate the pathogenic effects of DNA damage; (f) related indirect mechanisms by which EtOH enhances risk, for example by enhancing the degradation of some DNA repair proteins; and, (g) embryonic/fetal pathways like NRF2 that regulate the levels of many of the above components. Particular attention is paid to studies in which chemical and/or genetic manipulation of the above mechanisms has been shown to alter the ability of EtOH to adversely affect development. Alterations in the above components are also discussed in terms of: (a) individual embryonic and fetal determinants of risk and (b) potential risk biomarkers and mitigating strategies. FASD risk is likely increased in progeny which/who are biochemically predisposed via genetic and/or environmental mechanisms, including enhanced pathways for ROS formation and/or deficient pathways for ROS detoxification or DNA repair.

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“…Many of the same ROS‐forming pathways that are enhanced by xenobiotics are also responsible for endogenous ROS formation, and imbalances between conceptal ROS formation versus detoxification and the repair of oxidatively damaged DNA can have pathogenic consequences even under physiological conditions in the absence of xenobiotic exposures. Abbreviations: ATM, ataxia telangiectasia mutated; BRCA1, breast cancer 1; CSB, Cockayne syndrome B; CYPs, cytochromes P450; Fe, iron; G‐6‐P, glucose‐6‐phosphate; GSH, glutathione; GSSG, glutathione disulfide; LPOs, lipoxygenases; NADP+, nicotinamide adenine dinucleotide phosphate; OGG1, oxoguanine glycosylase 1; PHSs, prostaglandin H synthases; SOD, superoxide dismutase (Wells et al, ).…”

Section: Introduction and Background: Reactive Oxygen Species (Ros) mentioning

confidence: 99%

Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine

Wells

Bhatia

Drake

et al. 2016

Birth Defects Research Pt C

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In utero exposure of mouse progeny to alcohol (ethanol, EtOH) and methamphetamine (METH) causes substantial postnatal neurodevelopmental deficits. One emerging pathogenic mechanism underlying these deficits involves fetal brain production of reactive oxygen species (ROS) that alter signal transduction, and/or oxidatively damage cellular macromolecules like lipids, proteins, and DNA, the latter leading to altered gene expression, likely via non-mutagenic mechanisms. Even physiological levels of fetal ROS production can be pathogenic in biochemically predisposed progeny, and ROS formation can be enhanced by drugs like EtOH and METH, via activation/induction of ROS-producing NADPH oxidases (NOX), drug bioactivation to free radical intermediates by prostaglandin H synthases (PHS), and other mechanisms. Antioxidative enzymes, like catalase in the fetal brain, while low, provide critical protection. Oxidatively damaged DNA is normally rapidly repaired, and fetal deficiencies in several DNA repair proteins, including oxoguanine glycosylase 1 (OGG1) and breast cancer protein 1 (BRCA1), enhance the risk of drug-initiated postnatal neurodevelopmental deficits, and in some cases deficits in untreated progeny, the latter of which may be relevant to conditions like autism spectrum disorders (ASD). Risk is further regulated by fetal nuclear factor erythroid 2-related factor 2 (Nrf2), a ROS-sensing protein that upregulates an array of proteins, including antioxidative enzymes and DNA repair proteins. Imbalances between conceptal pathways for ROS formation, versus those for ROS detoxification and DNA repair, are important determinants of risk. Birth Defects Research (Part C) 108:108-130, 2016. © 2016 Wiley Periodicals, Inc.

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Oxidative Stress and Species Differences in the Metabolism, Developmental Toxicity, and Carcinogenic Potential of Methanol and Ethanol

Cited by 12 publications

References 160 publications

Dietary methanol and autism

Dietary methanol and autism

Oxidative stress and DNA damage in the mechanism of fetal alcohol spectrum disorders

Fetal oxidative stress mechanisms of neurodevelopmental deficits and exacerbation by ethanol and methamphetamine

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