DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium

Lozano, Manuel; Yousefi, Paul; Broberg, Karin; Soler-Blasco, Raquel; Miyashita, Chihiro; Pesce, Giancarlo; Kim, Woo Jin; Rahman, Mohammad L.; Bakulski, Kelly M.; Haug, Line Småstuen; Ikeda‐Araki, Atsuko; Huel, Guy; Park, Jaehyun; Relton, Caroline L; Vrijheid, Martine; Rifas‐Shiman, Sheryl L.; Oken, Emily; Dou, John; Kishi, Reiko; Gützkow, Kristine B.; Annesi‐Maesano, Isabella; Won, Sungho; Hivert, Marie‐France; Fallin, M. Daniele; Vafeiadi, Marina; Ballester, Ferrán; Llop, Sabrina

doi:10.1016/j.envres.2021.112093

Cited by 15 publications

(9 citation statements)

References 76 publications

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“…In human SH-SY5Y cells, exposure to MeHg 8 nM led to a significant increase ( p = 0.00175, adjusted p = 0.0385) in DNA methylation of one of the CpG sites in MED31 ( Figure 1A ). This CpG is located 3 base pairs (bp) from cg24184221, which was the one identified in Lozano et al (2022) to be more methylated with higher exposure to MeHg. A similar, but non-significant ( p = 0.0988, adjusted p = 1) change was found on DNA methylation of cg15288800 ( Figure 1B ), another CpG in the MED31 identified by Lozano et al (2022) to be more methylated with higher exposure to MeHg.…”

Section: Resultsmentioning

confidence: 99%

“…This CpG is located 3 base pairs (bp) from cg24184221, which was the one identified in Lozano et al (2022) to be more methylated with higher exposure to MeHg. A similar, but non-significant ( p = 0.0988, adjusted p = 1) change was found on DNA methylation of cg15288800 ( Figure 1B ), another CpG in the MED31 identified by Lozano et al (2022) to be more methylated with higher exposure to MeHg. Exposure to 40 nM MeHg did not produce significant changes on MED31 methylation nor was MED31 expression significantly altered, although a trend towards downregulation was observed ( Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

“…Several epidemiological studies have also reported associations between exposure to MeHg and altered DNA methylation at specific loci ( Bakulski et al, 2015 ; Appleton et al, 2017 ; Cediel Ulloa et al, 2021 ; Nishizawa-Jotaki et al, 2021 ). A recent large epigenome-wide association study (EWAS) by Lozano et al (2022) demonstrated associations between prenatal exposure to MeHg and altered DNA methylation at several loci in blood from newborns (n = 1,462) and children (n = 883), further supporting epidemiological associations between developmental exposure to MeHg and altered DNA methylation. Nonetheless, associations in human data can be confounded by other factors and implications on gene expression and biological functions remain unknown.…”

Section: Introductionmentioning

confidence: 87%

“…MeHgCl (Alfa Aesar, CAS 115-09-3) was dissolved in DMSO in polypropylene Eppendorf tubes and stock solutions of 1 mM were stored at −20°C until use. In order to cover the range of MeHg concentrations (2–8.5 μg/L) in cord blood observed in Lozano et al (2022) , SH-SY5Y cells were exposed to 8 and 40 nM of MeHg. These concentrations were calculated based on a molecular weight of 213.63 g/ml for MeHgCl and are equivalent to 1.7 and 8.5 μg/L respectively.…”

Section: Methodsmentioning

confidence: 99%

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Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence

Cediel-Ulloa

Yu²,

Hinojosa³

et al. 2022

Front. Genet.

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Methylmercury (MeHg) is a developmental neurotoxicant, and one potential mechanism of MeHg toxicity is epigenetic dysregulation. In a recent meta-analysis of epigenome-wide association studies (EWAS), associations between prenatal MeHg exposure and DNA methylation at several genomic sites were identified in blood from newborns and children. While EWASs reveal human-relevant associations, experimental studies are required to validate the relationship between exposure and DNA methylation changes, and to assess if such changes have implications for gene expression. Herein, we studied DNA methylation and gene expression of five of the top genes identified in the EWAS meta-analysis, MED31, MRPL19, GGH, GRK1, and LYSMD3, upon MeHg exposure in human SH-SY5Y cells exposed to 8 or 40 nM of MeHg during differentiation, using bisulfite-pyrosequencing and qPCR, respectively. The concentrations were selected to cover the range of MeHg concentrations in cord blood (2–8.5 μg/L) observed in the cohorts included in the EWAS. Exposure to MeHg increased DNA methylation at MED31, a transcriptional regulator essential for fetal development. The results were in concordance with the epidemiological findings where more MED31 methylation was associated with higher concentrations of MeHg. Additionally, we found a non-significant decrease in DNA methylation at GGH, which corresponds to the direction of change observed in the EWAS, and a significant correlation of GGH methylation with its expression. In conclusion, this study corroborates some of the EWAS findings and puts forward candidate genes involved in MeHg’s effects on the developing brain, thus highlighting the value of experimental validation of epidemiological association studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

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Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence

Cediel-Ulloa

Yu²,

Hinojosa³

et al. 2022

Front. Genet.

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“…DNA methylation is an epigenetic mechanism for gene expression modulation and can be used as a predictor of future disease risks. Several large-scale studies have evaluated the association between prenatal chemical exposure and DNA methylation [32][33][34]. Most of those studies have measured the site-specific, not the global, DNA methylation status by using a bead-chip DNA microarray.…”

Section: Discussionmentioning

confidence: 99%

Global DNA Methylation in Cord Blood as a Biomarker for Prenatal Lead and Antimony Exposures

Okamoto¹,

Iwai-Shimada²,

Nakai³

et al. 2022

Preprint

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DNA methylation is an epigenetic mechanism for gene expression modulation and can be used as a predictor of future disease risks. A prospective birth cohort study was performed to clarify the effects of neurotoxicants on child development, namely, the Tohoku Study of Child Development, in Japan. This study aimed to evaluate the association of prenatal exposure to five toxic metals—arsenic, cadmium, mercury, lead (Pb), antimony (Sb), and polychlorinated biphenyls (PCBs, N = 166)—with global DNA methylation in umbilical cord blood DNA. DNA methylation markers, 5-methyl-2’-deoxycytidine (mC) and 5-hydroxymethyl-2’-deoxycytidine (hmC), were determined using liquid chromatography-tandem mass spectrometry. The mC content in cord blood DNA was positively correlated with Pb and Sb levels (r = 0.442 and 0.288, respectively) but not with cord blood PCBs. We also observed significant positive correlations among Pb levels, maternal age, and hmC content (r = 0.159 and 0.243, respectively). The multiple regression analysis among the potential predictors demonstrated consistent positive associations between Pb and Sb levels and mC and hmC content. Our results suggest that global DNA methylation is a promising biomarker for prenatal exposure to Pb and Sb.

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Influence of Environmental Factors on the Epigenome

Christensen

Everson

Marsit

et al. 2022

Epigenetic Epidemiology

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DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium

Cited by 15 publications

References 76 publications

Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence

Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence

Global DNA Methylation in Cord Blood as a Biomarker for Prenatal Lead and Antimony Exposures

Influence of Environmental Factors on the Epigenome

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