Embryonic catalase protects against ethanol embryopathies in acatalasemic mice and transgenic human catalase-expressing mice in embryo culture

Miller-Pinsler, Lutfiya; Wells, Peter G.

doi:10.1016/j.taap.2015.06.007

Cited by 15 publications

(14 citation statements)

References 42 publications

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“…Also, the EtOH dose/response and concentration/response relationships often are shifted in different species (e.g., rats vs. mice, where mice are more sensitive than rats) and strains (e.g., outbred CD‐1 mice vs. inbred C57BL/6 or C3H mice, where different inbred strains exhibit variable sensitivity, and inbred mice are usually more sensitive than outbred mice), requiring some caution in comparing studies. Results from our laboratory reflect “threshold” models, which for example in vivo , result in neurodevelopmental deficits following a single EtOH dose administered during the fetal period, that does not cause gross morphological birth defects when administered during the embryonic period (Miller et al, ), or a single dose that causes deficits in −/− knockout or mutant progeny but not their wild‐type (+/+) littermates (Miller et al, ; Miller‐Pinsler et al, ), or a concentration in embryo culture that is embryopathic in +/− knockout or mutant progeny but does not affect +/+ littermates (Miller‐Pinsler and Wells, ; Shapiro et al, ). Studies involving chronic EtOH exposures at higher doses or concentrations may yield different results.…”

Section: Ethanol‐initiated Birth Defects and Postnatal Neurodevelopmementioning

confidence: 66%

“…In particular, enhanced ROS formation has been implicated (Fig. ) in EtOH‐initiated embryopathies, teratogenesis (Tables ), and neurodevelopmental deficits (Table ), based upon evidence of enhanced conceptal ROS formation, oxidative macromolecular damage, and protection by inhibitors of ROS formation, by antioxidants and antioxidative enzymes, and by enzymes involved in the repair of oxidatively damaged DNA (Brocardo et al, ; Miller‐Pinsler et al, ; Miller‐Pinsler and Wells, ; Miller‐Pinsler and Wells, ). ROS‐mediated developmental toxicity would involve as yet undetermined molecular mechanisms and risk factors, distinctly different from those for other mechanisms of FASD.…”

Section: Ethanol‐initiated Birth Defects and Postnatal Neurodevelopmementioning

confidence: 99%

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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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Section: Ethanol‐initiated Birth Defects and Postnatal Neurodevelopmementioning

confidence: 66%

Section: Ethanol‐initiated Birth Defects and Postnatal Neurodevelopmementioning

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

Self Cite

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“…In the case of catalase, although its activity is only about 5% of maternal activity (Wells et al, ; Wells et al, ), studies in embryo culture and in vivo employing mutant catalase‐deficient mice and transgenic mice expressing human catalase show that even the low embryonic level of endogenous catalase is critically protective against EtOH‐initiated embryonic DNA oxidation and abnormal morphological development in embryo culture and teratogenicity in vivo (Miller, Shapiro, & Wells, ; Miller‐Pinsler & Wells, ). Treatment of catalase‐deficient pregnant dams with stabilized polyethylene glycol (PEG)‐conjugated catalase prior to explanting embryos, which increases the level of embryonic catalase activity, blocked the increase in EtOH‐initiated embryopathies in cultured catalase‐deficient embryos (Miller‐Pinsler & Wells, ), and in catalase‐deficient fetuses at the end of gestation (Miller, Shapiro, & Wells, ). Endogenous catalase similarly protects the embryo and fetus from DNA oxidation and the embryopathic effects of both physiological ROS and drug‐enhanced ROS in the case of phenytoin (a ROS‐initiating drug), including both morphological abnormalities in embryo culture and in vivo (Abramov & Wells, ; Abramov & Wells, ), and neurodevelopmental abnormalities (Abramov et al, ).…”

Section: Pathways Involved In Conceptal Ros Detoxification and Protecmentioning

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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“…CYP2E1-mediated metabolism of ethanol has also been shown to generate ROS as a byproduct [23] . ROS levels are increased in embryos and fetuses exposed in utero to ethanol, evidenced by DCF fluorescence and oxidatively damaged DNA [15] , [22] , [24] , [25] , [26] . Structural and cognitive changes caused by ethanol in vivo are prevented with pretreatment by the free radical scavenging agent α-phenyl-N-tert-butylnitrone (PBN) [27] .…”

Section: Introductionmentioning

confidence: 99%

Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies

2016

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The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/−) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, our results show BRCA1 plays a broader biological role in protecting the embryo from oxidative stress. Sox2-promoted Cre-expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/− brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS)-initiating drug ethanol (EtOH). Untreated +/− brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2'-deoxyguanosine, γH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2'-deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1-normal littermates. These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis.

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Embryonic catalase protects against ethanol embryopathies in acatalasemic mice and transgenic human catalase-expressing mice in embryo culture

Cited by 15 publications

References 42 publications

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

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

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

Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies

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