Several lines of evidence indicate that the etiology of late-onset Alzheimer's disease (LOAD) is complex, with significant contributions from both genes and environmental factors. Recent research ...suggests the importance of epigenetic mechanisms in defining the relationship between environmental exposures and LOAD. In epidemiologic studies of adults, cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition. In addition, research in animal models suggests a causal association between Pb exposure during early life, epigenetics, and LOAD. There are multiple challenges to human epidemiologic research evaluating the relationship between epigenetics, LOAD, and Pb exposure. Epidemiologic studies are not well-suited to accommodate the long latency period between exposures during early life and onset of Alzheimer's disease. There is also a lack of validated circulating epigenetics biomarkers and retrospective biomarkers of Pb exposure. Members of our research group have shown bone Pb is an accurate measurement of historical Pb exposure in adults, offering an avenue for future epidemiologic studies. However, this would not address the risk of LOAD attributable to early-life Pb exposures. Future studies that use a cohort design to measure both Pb exposure and validated epigenetic biomarkers of LOAD will be useful to clarify this important relationship.
Epigenome-wide association studies of disease widely use DNA methylation measured in blood as a surrogate tissue. Cell proportions can vary between people and confound associations of exposure or ...outcome. An adequate reference panel for estimating cell proportions from adult whole blood for DNA methylation studies is available, but an analogous cord blood cell reference panel is not yet available. Cord blood has unique cell types and the epigenetic signatures of standard cell types may not be consistent throughout the life course. Using magnetic bead sorting, we isolated cord blood cell types (nucleated red blood cells, granulocytes, monocytes, natural killer cells, B cells, CD4
+
T cells, and CD8
+
T cells) from 17 live births at Johns Hopkins Hospital. We confirmed enrichment of the cell types using fluorescence assisted cell sorting and ran DNA from the separated cell types on the Illumina Infinium HumanMethylation450 BeadChip array. After filtering, the final analysis was on 104 samples at 429,794 probes. We compared cell type specific signatures in cord to each other and methylation at 49.2% of CpG sites on the array differed by cell type (F-test P < 10
−8
). Differences between nucleated red blood cells and the remainder of the cell types were most pronounced (36.9% of CpG sites at P < 10
−8
) and 99.5% of these sites were hypomethylated relative to the other cell types. We also compared the mean-centered sorted cord profiles to the available adult reference panel and observed high correlation between the overlapping cell types for granulocytes and monocytes (both r=0.74), and poor correlation for CD8
+
T cells and NK cells (both r=0.08). We further provide an algorithm for estimating cell proportions in cord blood using the newly developed cord reference panel, which estimates biologically plausible cell proportions in whole cord blood samples.
The prenatal environment influences lifetime health; epigenetic mechanisms likely predominate. In 2016, the first international consortium paper on cigarette smoking during pregnancy and offspring ...DNA methylation identified extensive, reproducible exposure signals. This finding raised expectations for epigenome-wide association studies (EWAS) of other exposures.
We review the current state-of-the-science for DNA methylation associations across prenatal exposures in humans and provide future recommendations.
We reviewed 134 prenatal environmental EWAS of DNA methylation in newborns, focusing on 51 epidemiological studies with meta-analysis or replication testing. Exposures spanned cigarette smoking, alcohol consumption, air pollution, dietary factors, psychosocial stress, metals, other chemicals, and other exogenous factors. Of the reproducible DNA methylation signatures, we examined implementation as exposure biomarkers.
Only 19 (14%) of these prenatal EWAS were conducted in cohorts of 1,000 or more individuals, reflecting the still early stage of the field. To date, the largest perinatal EWAS sample size was 6,685 participants. For comparison, the most recent genome-wide association study for birth weight included more than 300,000 individuals. Replication, at some level, was successful with exposures to cigarette smoking, folate, dietary glycemic index, particulate matter with aerodynamic diameter
and
, nitrogen dioxide, mercury, cadmium, arsenic, electronic waste, PFAS, and DDT. Reproducible effects of a more limited set of prenatal exposures (smoking, folate) enabled robust methylation biomarker creation.
Current evidence demonstrates the scientific premise for reproducible DNA methylation exposure signatures. Better powered EWAS could identify signatures across many exposures and enable comprehensive biomarker development. Whether methylation biomarkers of exposures themselves cause health effects remains unclear. We expect that larger EWAS with enhanced coverage of epigenome and exposome, along with improved single-cell technologies and evolving methods for integrative multi-omics analyses and causal inference, will expand mechanistic understanding of causal links between environmental exposures, the epigenome, and health outcomes throughout the life course. https://doi.org/10.1289/EHP12956.
Alzheimer's disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer's disease and related dementias is partially attributable to ...environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer's disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer's disease specifically though two studies have reported a link between cadmium and Alzheimer's disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer's disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer's disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer's disease and related dementias and makes recommendations of critical areas of future investment.
Chronic lead (Pb) exposure causes long term health effects. While recent exposure can be assessed by measuring blood lead (half-life 30 days), chronic exposures can be assessed by measuring lead in ...bone (half-life of many years to decades). Bone lead measurements, in turn, have been measured non-invasively in large population-based studies using x-ray fluorescence techniques, but the method remains limited due to technical availability, expense, and the need for licensing radioactive materials used by the instruments. Thus, we developed prediction models for bone lead concentrations using a flexible machine learning approach--Super Learner, which combines the predictions from a set of machine learning algorithms for better prediction performance. The study population included 695 men in the Normative Aging Study, aged 48 years and older, whose bone (patella and tibia) lead concentrations were directly measured using K-shell-X-ray fluorescence. Ten predictors (blood lead, age, education, job type, weight, height, body mass index, waist circumference, cumulative cigarette smoking (pack-year), and smoking status) were selected for patella lead and 11 (the same 10 predictors plus serum phosphorus) for tibia lead using the Boruta algorithm. We implemented Super Learner to predict bone lead concentrations by calculating a weighted combination of predictions from 8 algorithms. In the nested cross-validation, the correlation coefficients between measured and predicted bone lead concentrations were 0.58 for patella lead and 0.52 for tibia lead, which has improved the correlations obtained in previously-published linear regression-based prediction models. We evaluated the applicability of these prediction models to the National Health and Nutrition Examination Survey for the associations between predicted bone lead concentrations and blood pressure, and positive associations were observed. These bone lead prediction models provide reasonable accuracy and can be used to evaluate health effects of cumulative lead exposure in studies where bone lead is not measured.
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•Bone lead is an indicator of cumulative lead exposure.•Bone lead measurement is limited in large population-based studies due to technical availability and expense.•We developed prediction models for bone lead concentrations using Super Learner.•The model provides reasonable accuracy and can be used to evaluate health effects of cumulative lead exposure.
We investigated the complex relations of socioeconomic status (SES) and healthy lifestyles with cognitive functions among older adults in 1313 participants, aged 60 years and older, from the National ...Health and Nutrition Examination Survey 2011-2014. Cognitive function was measured using an average of the standardized z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Word Learning and delayed recall tests, the Animal Fluency Test, and the Digit Symbol Substitution Test. Latent class analysis of family income, education, occupation, health insurance, and food security was used to define composite SES (low, medium, high). A healthy lifestyle score was calculated based on smoking, alcohol consumption, physical activity, and the Healthy-Eating-Index-2015. In survey-weighted multivariable linear regressions, participants with 3 or 4 healthy behaviors had 0.07 (95% CI 0.005, 0.14) standard deviation higher composite cognitive z-score, relative to those with one or no healthy behavior. Participants with high SES had 0.37 (95% CI 0.29, 0.46) standard deviation higher composite cognitive z-score than those with low SES. No statistically significant interaction was observed between healthy lifestyle score and SES. Our findings suggested that higher healthy lifestyle scores and higher SES were associated with better cognitive function among older adults in the United States.
The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism ...Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate q-value <0.1), near the genes CYP24A1, ASCL2, FAT1, SNX31, NKX6-2, LRC4C, BMP7, HOXC11, PCDH7, ZSCAN18, and VIPR2. Lead-associated sites were enriched (FDR q-value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR q-value <0.1), one of which was near the gene ARID2. Manganese-associated sites were enriched for cellular metabolism pathways (FDR q-value<0.1). Effect estimates for DNA methylation sites associated (p < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.
Epigenetic changes underlie developmental and age related biology. Promising epidemiologic research implicates epigenetics in disease risk and progression, and suggests epigenetic status depends on ...environmental risks as well as genetic predisposition. Epigenetics may represent a mechanistic link between environmental exposures, or genetics, and many common diseases, or may simply provide a quantitative biomarker for exposure or disease for areas of epidemiology currently lacking such measures. This great promise is balanced by issues related to study design, measurement tools, statistical methods, and biological interpretation that must be given careful consideration in an epidemiologic setting. This article describes the promises and challenges for epigenetic epidemiology, and suggests directions to advance this emerging area of molecular epidemiology.
Integration of emerging epigenetic information with autism spectrum disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. Here we ...use the genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists). Additionally, we use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; P < 0.001) and peripheral blood meQTLs (OR = 1.58; P < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.
Prenatal testosterone (T)-treated female sheep manifest adipose depot-specific disruptions in inflammatory/oxidative state, adipocyte differentiation and thermogenic adipocyte distribution. The ...objective of this study was to identify common and divergent gene pathways underlying prenatal T excess-induced adipose depot-specific disruptions. RNA sequencing and network analyses were undertaken with visceral (VAT), subcutaneous (SAT), epicardiac (ECAT) and perirenal (PRAT) adipose tissues from control and prenatal T-treated (100 mg T propionate twice a week from days 30–90 of gestation) female sheep at 21 months of age. Increased expression of adiposity and inflammation-related genes in VAT and genes that promote differentiation of white adipocytes in SAT were congruous with their metabolic roles with SAT favoring uptake/storage of free fatty acids and triglycerides and VAT favoring higher rate of fatty acid turnover and lipolysis. Selective upregulation of cardiac muscle and renoprotection genes in ECAT and PRAT respectively are suggestive of protective paracrine actions. Expression profile in prenatal T-treated sheep paralleled depot-specific dysfunctions with increased proinflammatory genes in VAT, reduced adipocyte differentiation genes in VAT and SAT and increased vascular related gene expression in PRAT. The high expression of genes involved in cardiomyocyte function in ECAT is suggestive of cardioprotective function being maintained to overcome the prenatal T-induced cardiac dysfunction and hypertension. These findings coupled with changes in gene pathways and networks involved in chromatin modification, extracellular matrix, immune and mitochondrial function, and endoplasmic reticulum to Golgi transport suggest that dysregulation in gene expression underlie prenatal T-treatment induced functional differences among adipose depots and manifestation of metabolic dysfunction.
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•Adult female sheep VAT, SAT, ECAT and PRAT depots showed distinct gene expression.•ECAT and PRAT expressed genes that influence cardiac and renal function, respectively.•Prenatal T excess reduced WAT differentiation genes distinctly in VAT and SAT.•Prenatal T excess increased cardiac muscle function-related genes in ECAT depots.•Prenatal T induced depot-specific chromatin/immune/mitochondrial/Golgi pathways.
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