Nitrosatable Drug Exposure During Early Pregnancy and Neural Tube Defects in Offspring

Brender, Jean D.; Werler, Martha M.; Kelley, Katherine E.; Vuong, Ann M.; Shinde, Mayura; Zheng, Qi; Huber, John C.; Sharkey, Joseph R.; Griesenbeck, Joachim; Romitti, Paul A.; Langlois, Peter H.; Suarez, Lucina; Canfield, Mark A.

doi:10.1093/aje/kwr254

Cited by 47 publications

(39 citation statements)

References 30 publications

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“…However, several studies suggest that deficiency of ascorbate is linked to certain types of developmental defects. For example, women at high risk for neural tube defect (NTD) recurrence tend to have lower leucocyte ascorbate levels compared with low-risk women (3, 77). Genetic variation in SVCT2, which might affect intracellular ascorbate levels, is also associated with the risk of preterm birth (16).…”

Section: Vitamin C and Dna Demethylationmentioning

confidence: 99%

Regulation of the Epigenome by Vitamin C

Young¹,

2015

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Emerging evidence suggests that ascorbate, the dominant form of vitamin C under physiological pH conditions, influences the genome activity via regulating epigenomic processes. Ascorbate serves as a cofactor for ten-eleven translocation (TET) dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), further to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which are ultimately replaced by unmodified cytosine. The JmjC domain-containing histone demethylases also require ascorbate as a cofactor for histone demethylation. Thus, by primarily participating in the demethylation of both DNA and histones, ascorbate appears to be a mediator of the interface between the genome and environment. Furthermore, redox status has a profound impact on the bioavailability of ascorbate in the nucleus. In order to bridge the gap between redox biology and genomics, we suggest an interdisciplinary research field that can be termed “Redox Genomics” to study dynamic redox processes in health and diseases. This review examines the evidence and potential molecular mechanism of ascorbate in demethylation of the genome, while highlighting potential epigenetic roles of ascorbate in various diseases.

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Section: Vitamin C and Dna Demethylationmentioning

confidence: 99%

Regulation of the Epigenome by Vitamin C

Young¹,

2015

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“…Ascorbate deficiency has been linked to certain types of developmental defects. For example, women at a high risk for neural tube defect (NTD) recurrence tend to have lower leucocyte ascorbate levels compared with low-risk women [13, 125]. Lower intake of ascorbate also increases the risk of gastroschisis in infants, which is a congenital defect of the abdominal wall [147].…”

Section: Epigenetic Regulation Of Ascorbate In Embryonic Developmentmentioning

confidence: 99%

The epigenetic role of vitamin C in health and disease

Camarena

Wang

2016

Cell. Mol. Life Sci.

183

125

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Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation.

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“…N- Nitroso compounds have been found to be teratogens in animal models (Nagao et al 1991; Platzek et al 1983). These compounds are formed to a greater extent in the presence of a nitrosatable compound if nitrite concentration is high (Choi 1985); and when combined with higher nitrite, nitrosatable compounds have been reported to be more strongly associated with exencephaly and skeletal malformations in mice (Teramoto et al 1980) and with NTDs (Brender et al 2004, 2011b) and other types of birth defects in humans (Brender et al 2012). In a small case–control study of Mexican-American women, nitrosatable drug exposure was more strongly associated with NTDs in offspring of women whose drinking-water nitrate measured ≥ 3.5 mg/L than among births to women with lower measured nitrate in their drinking water (Brender et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Prenatal Nitrate Intake from Drinking Water and Selected Birth Defects in Offspring of Participants in the National Birth Defects Prevention Study

Brender¹,

Weyer²,

Romitti³

et al. 2013

Environ Health Perspect

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134

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Background: Previous studies of prenatal exposure to drinking-water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs.Objectives: We examined the relation between prenatal exposure to drinking-water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure.Methods: With data from the National Birth Defects Prevention Study, we linked addresses of 3,300 case mothers and 1,121 control mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work.Results: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. < 0.91 mg) than control mothers. During 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily (vs. < 1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects.Conclusions: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects.Citation: Brender JD, Weyer PJ, Romitti PA, Mohanty BP, Shinde MU, Vuong AM, Sharkey JR, Dwivedi D, Horel SA, Kantamneni J, Huber JC Jr., Zheng Q, Werler MM, Kelley KE, Griesenbeck JS, Zhan FB, Langlois PH, Suarez L, Canfield MA, and the National Birth Defects Prevention Study. 2013. Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the National Birth Defects Prevention Study. Environ Health Perspect 121:1083–1089; http://dx.doi.org/10.1289/ehp.1206249

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Nitrosatable Drug Exposure During Early Pregnancy and Neural Tube Defects in Offspring

Cited by 47 publications

References 30 publications

Regulation of the Epigenome by Vitamin C

Regulation of the Epigenome by Vitamin C

The epigenetic role of vitamin C in health and disease

Prenatal Nitrate Intake from Drinking Water and Selected Birth Defects in Offspring of Participants in the National Birth Defects Prevention Study

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