Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead
Open accessAbstract
Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend toward negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice.
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Developmental lead exposure (3, 30 ppm) resulted in over 1000 differentially methylated CpG sites, predominantly DNA hypermethylation, in regions corresponding to 117 unique genes in the adult female mouse hippocampus whereas no changes were observed in male mice.
“In this study, developmental lead exposure (3, 30 ppm) resulted in over 1000 differentially methylated CpG sites, predominantly DNA hypermethylation, in regions corresponding to 117 unique genes in the adult female mouse hippocampus whereas no changes were observed in male mice [ 43 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [43]
The functional consequence of lead-induced DNA hypermethylation in this context has yet to be defined but may account for changes in gene expression important for synapse and memory formation.
“The functional consequence of lead-induced DNA hypermethylation in this context has yet to be defined but may account for changes in gene expression important for synapse and memory formation [ 43 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [43]
Differential DNA methylation is retained when blood levels of lead from developmentally exposed animals have returned to levels of unexposed control animals.
“Importantly, differential DNA methylation is retained when blood levels of lead from developmentally exposed animals have returned to levels of unexposed control animals [ 43 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [43]
Developmental exposure to more physiologically relevant levels of lead (3, 30 ppm) has been reported to cause differential DNA methylation in male versus female cortex and hippocampus of young adult mice.
“However, consistent with these findings, developmental exposure to more physiologically relevant levels of lead (3, 30 ppm) has been reported to cause differential DNA methylation in male versus female cortex and hippocampus of young adult mice [ 43 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [43]
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References 56 · Cited by 43
- Authors
- Sánchez-Martín, F. J., Lindquist, D. M., Landero-Figueroa, J., Zhang, X., Chen, J., Cecil, K. M., Medvedovic, M., & Puga, A.
- Affiliations
- University of Cincinnati (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Puga, Alvaro
- ORCID
- Venue
- NeuroToxicology
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 46
- Pages
- 92-100
- ISSN
- 0161-813X (ISSN-L)
- PMC
- PMC4339411
- OpenAlex
- W1980857834
- Cited by
- 43
- References
- 56
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 1
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroToxicology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R21 ES020048)
- Center for Environmental Genetics (P30 ES06096)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- perinatal lead exposure, DNA methylation, sex differences, hippocampus, cerebral cortex, differentially methylated regions, epigenetic plasticity, lead acetate, gene expression, brain development, mouse model
- MeSH terms
- Animals, Animals, Newborn, Brain, Chromosome Mapping, Female, Lead, Male, Mice, Inbred C57BL, RNA, Messenger, Sex Characteristics, Gene Expression Regulation, Developmental, CpG Islands, DNA Methylation, Mice
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