DNA methylation changes in the placenta are associated with fetal manganese exposure

Maccani, Jennifer Z.J.; Koestler, Devin C.; Houseman, E. Andrés; Armstrong, David A.; Marsit, Carmen J.; Kelsey, Karl T.

doi:10.1016/j.reprotox.2015.05.002

Cited by 47 publications

(38 citation statements)

References 81 publications

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“…Within each batch, samples with concentrations below the limit of detection were assigned a value equal to half of the lowest observed value in that batch. 21 Similar to previous reports from this study population, 22 the number of samples with concentrations below the minimal detection levels varied for each metal, ranging from 1% (Zn) to 68% (As).…”

Section: Metals Exposuresupporting

confidence: 68%

“…Several recent epigenome-wide association studies have linked prenatal exposure to arsenic, mercury, cadmium, and manganese to methylation across several loci, [21][22][23][24][25][26][27][28] including sites related to central nervous system development and behavioral disorders. 21,22 Moreover, patterning in methylation at these sites was prospectively linked to poor infant neurobehavior 22 and lower birthweight, 21 both considered sentinels of later life cognitive and behavioral problems.…”

Section: Introductionmentioning

confidence: 99%

“…21,22 Moreover, patterning in methylation at these sites was prospectively linked to poor infant neurobehavior 22 and lower birthweight, 21 both considered sentinels of later life cognitive and behavioral problems. 29,30 Other studies of in utero exposure to arsenic, cadmium, and lead have found similar associations with LINE-1, 31,32 Alu, 32 and global DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

2017

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Epigenetic alterations related to prenatal neurotoxic metals exposure may be key in understanding the origins of cognitive and neurobehavioral problems in children. Placental glucocorticoid receptor (NR3C1) methylation has been linked to neurobehavioral risk in early life, but has not been examined in response to neurotoxic metals exposure despite parallel lines of research showing metals exposure and NR3C1 methylation each contribute to a similar set of neurobehavioral phenotypes. Thus, we conducted a study of prenatal neurotoxic metals exposure and placental NR3C1 methylation in a cohort of healthy term singleton pregnancies from Rhode Island, USA (n D 222). Concentrations of arsenic (As; median 0.02 ug/g), cadmium (Cd; median 0.03 mg/g), lead (Pb; median 0.40 mg/g), manganese (Mn; median 0.56 mg/g), mercury (Hg; median 0.02 mg/g), and zinc (Zn; 145.18 mg/g) measured in infant toenails were categorized as tertiles. Multivariable linear regression models tested the independent associations for each metal with NR3C1 methylation, as well as the cumulative risk of exposure to multiple metals simultaneously. Compared to the lowest exposure tertiles, higher levels of As, Cd, Pb, Mn, and Hg were each associated with increased placental NR3C1 methylation (all P<0.02). Coefficients for these associations corresponded with a 0.71-1.41 percent increase in NR3C1 methylation per tertile increase in metals concentrations. For Zn, the lowest exposure tertile compared with the highest tertile was associated with 1.26 percent increase in NR3C1 methylation (PD0.01). Higher cumulative metal risk scores were marginally associated with greater NR3C1 methylation. Taken together, these results indicate that prenatal exposure to neurotoxic metals may affect the offspring's NR3C1 activity, which may help explain cognitive and neurodevelopmental risk later in life.

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Section: Metals Exposuresupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

2017

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“…A great body of literature has made efforts to understand what epigenetic variations can be induced by what environmental factors throughout the lifetime [12,23–26]. In particular, with the growth of high-throughput technology, epigenome-wide studies allow us a holistic insight into the epigenetic programming in response to specific environmental factors [27–31]. …”

Section: Introductionmentioning

confidence: 99%

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

Tian

Marsit

2018

Curr Epidemiol Rep

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Purpose of Review Epigenetic processes represent important mechanisms underlying developmental plasticity in response to environmental exposures. The current review discusses three classes of environmentally-induced epigenetic changes reflecting two aspects of that plasticity, toxicity effects as well as adaptation in the process of development. Recent findings Due to innate resilience, epigenetic changes caused by environmental exposures may not always lead impairments but may allow the organisms to achieve positive developmental outcomes through appropriate adaptation and a buffering response. Thus, some epigenetic adaptive responses to an immediate stimulus or exposure early in life would be expected to have a survival advantage but these same responses may also result in adverse developmental outcomes as they persists into later life stage. Although accumulating literature has identified environmentally induced epigenetic changes and linked them to health outcomes, we currently face challenges in the interpretation of the functional impact of their epigenetic plasticity. Summary Current environmental epigenetic research suggest that epigenetic processes may serve as a mechanism for resilience, and that they can be considered in terms of their impact on toxicity as a negative outcome, but also on adaptation for improved survival or health. This review encourages epigenetic environmental studies to move deeper inside into the functional meaning of epigenetic plasticity in the development.

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“…The nuclear factor kappa-light-chain-enhancer of active B cell (NF-κβ) pathway is a major regulator of cytokine production and is affected by manganese [14, 15]. Additionally, previous human studies have shown that manganese is associated with changes in patterns of DNA methylation [16, 17] although no studies have examined the effects of manganese on epigenetic regulation of the NF-κβ pathway. To date, the inflammatory potential of dietary manganese intake or the effects of dietary manganese on DNA methylation have yet to be examined.…”

Section: Introductionmentioning

confidence: 99%

The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men

Kresovich

Bulka

Joyce

et al. 2017

Biol Trace Elem Res

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Manganese is an essential nutrient that may play a role in the production of inflammatory biomarkers. We examined associations between estimated dietary manganese intake from food/beverages and supplements with circulating biomarkers of inflammation. We further explored whether estimated dietary manganese intake affects DNA methylation of selected genes involved in the production of these biomarkers. We analyzed 1023 repeated measures of estimated dietary manganese intakes and circulating blood inflammatory biomarkers from 633 participants in the Normative Aging Study. Using mixed-effect linear regression models adjusted for covariates, we observed positive linear trends between estimated dietary manganese intakes and three circulating interleukin proteins. Relative to the lowest quartile of estimated intake, concentrations of IL-1β were 46% greater (95% CI − 5, 126), IL-6 52% greater (95% CI − 9, 156). and IL-8 32% greater (95% CI 2, 71) in the highest quartiles of estimated intake. Estimated dietary manganese intake was additionally associated with changes in DNA methylation of inflammatory biomarker-producing genes. Higher estimated intake was associated with higher methylation of NF-κβ member activator NKAP (Q4 vs Q1: β = 3.32, 95% CI − 0.6, 7.3). When stratified by regulatory function, higher manganese intake was associated with higher gene body methylation of NF-κβ member activators NKAP (Q4 vs Q1: β = 10.10, 95% CI − 0.8, 21) and NKAPP1 (Q4 vs Q1: β = 8.14, 95% CI 1.1, 15). While needed at trace amounts for various physiologic functions, our results suggest estimated dietary intakes of manganese at levels slightly above nutritional adequacy contribute to inflammatory biomarker production.

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DNA methylation changes in the placenta are associated with fetal manganese exposure

Cited by 47 publications

References 81 publications

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men

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