Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to ...cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P<0.0001) and were significant predictors of tissue origin (P<0.0001). In solid tissues (n = 119) we found striking, highly significant CpG island-dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P<0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age- and exposure-related differences in tissue-specific methylation and significant age-associated methylation patterns which are CpG island context-dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference and disease-related epigenomes and in the interpretation of potentially pathologically important alterations.
Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many ...terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be non-toxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet.
In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge.
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•Seafood is a major source of organic arsenic exposure.•Arsenolipids and arsenosugars can be metabolized by humans.•Some organic arsenic compounds and their metabolites can produce cytotoxic effects.•Analytical standards for organic arsenic are a priority for advancing research.
Background: Methylmercury (MeHg) is a known neurotoxicant. Emerging evidence indicates it may have adverse effects on the neurologic and other body systems at common low levels of exposure. Impacts ...of MeHg exposure could vary by individual susceptibility or be confounded by beneficial nutrients in fish containing MeHg. Despite its global relevance, synthesis of the available literature on low-level MeHg exposure has been limited. Objectives: We undertook a synthesis of the current knowledge on the human health effects of low-level MeHg exposure to provide a basis for future research efforts, risk assessment, and exposure remediation policies worldwide. Data sources and extraction: We reviewed the published literature for original human epidemiologic research articles that reported a direct biomarker of mercury exposure. To focus on high-quality studies and those specifically on low mercury exposure, we excluded case series, as well as studies of populations with unusually high fish consumption (e.g., the Seychelles), marine mammal consumption (e.g., the Faroe Islands, circumpolar, and other indigenous populations), or consumption of highly contaminated fish (e.g., gold-mining regions in the Amazon). Data synthesis: Recent evidence raises the possibility of effects of low-level MeHg exposure on fetal growth among susceptible subgroups and on infant growth in the first 2 years of ufe. Low-level effects of MeHg on neurologic outcomes may differ by age, sex, and timing of exposure. No clear pattern has been observed for cardiovascular disease (CVD) risk across populations or for specific CVD end points. For the few studies evaluating immunologie effects associated with MeHg, results have been inconsistent. Conclusions: Studies targeted at identifying potential mechanisms of low-level MeHg effects and characterizing individual susceptibility, sexual dimorphism, and nonlinearity in dose response would help guide future prevention, policy, and regulatory efforts surrounding MeHg exposure.
Epidemiologic studies on the association between metals and body mass index (BMI) have been cross-sectional and have demonstrated inconsistent associations. Our study prospectively examined whether ...metals measured at baseline were associated with later BMI. We considered metals individually and as joint exposure to pre-defined metal groupings.
We measured concentrations of 16 metals in toenails collected at baseline (2003–2009) in a subset of 1221 women from the Sister Study. We calculated BMI from height and weight reported on a follow-up questionnaire an average of 5.2 years (range = 3.5–8.3) after baseline. Multivariable linear regression was used to estimate β coefficients and 95% confidence intervals (CIs) for associations between BMI and individual metals (with estimates given per interquartile range (IQR) increase or in quartiles). Quantile g-computation was used to examine joint associations between groups of metals and BMI. Groups considered were (1) all metals combined, and metals classified as (2) non-essential or (3) essential.
In individual metal models we found that, with the exception of cobalt, no single metal was strongly related to BMI. In our mixture analyses, a quartile increase in all non-essential metals was associated with higher BMI (β = 0.32; 95%CI: 0.00, 0.63 kg/m2), whereas essential metals were suggestively associated with lower BMI (β = −0.25; 95%CI: −0.58, 0.07 kg/m2).
In this population of women who were, on average, overweight, essential metals were jointly associated with slightly healthier, lower BMI whereas non-essential metals were jointly associated with slightly higher, unhealthier BMI, after controlling for other health indicators and predictors of metals exposures.
•This study prospectively examined whether metals were associated with BMI.•In single metal models cobalt was inversely associated with BMI.•Other metals were not strongly related to BMI individually.•Increasing all non-essential metals jointly was positively associated with BMI.•Results show the importance of a prospective design and examining metal mixtures.
Seaweed consumption has gained popularity due to its nutritional value and potential health benefits. However, concerns regarding the bioaccumulation of several trace elements highlight the need for ...comprehensive studies on exposure associated with seaweed consumption. To address this gap in knowledge, we carried out a feeding intervention study of three common edible seaweeds (Nori, Kombu, and Wakame) in 11 volunteers, aiming to elucidate the extent of both beneficial and harmful trace element exposure through seaweed consumption in humans. Concentrations of total arsenic, cobalt, copper, cadmium, iodine, molybdenum, selenium, and zinc were measured in urine samples before and following seaweed consumption. Elements concentrations were also measured in the seaweeds provided for the study. Descriptive analysis for each element were conducted and we used quantile g-computation approach to assess the association between the 8-element mixture and seaweed consumption. Differences in urine element concentrations and seaweed consumption were analyzed using generalized estimating equations (GEE). Urinary concentrations of iodine and total arsenic increased after seaweed consumption. When we analyze the 8-element mixture, the largest weight was observed for iodine after Kombu consumption while for total arsenic was observed after Wakame consumption. Similar results were observed when we compared the mean differences between the elements before and after seaweed consumption through the GEE. Seaweed consumption relates with increased urinary iodine and total arsenic concentrations, particularly after Kombu and Wakame consumption.
Although much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor ...features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated.
DNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided.
We observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72).
The homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.
Emerging data indicate that rice consumption may lead to potentially harmful arsenic exposure. However, few human data are available, and virtually none exist for vulnerable periods such as ...pregnancy. Here we document a positive association between rice consumption and urinary arsenic excretion, a biomarker of recent arsenic exposure, in 229 pregnant women. At a 6-mo prenatal visit, we collected a urine sample and 3-d dietary record for water, fish/seafood, and rice. We also tested women's home tap water for arsenic, which we combined with tap water consumption to estimate arsenic exposure through water. Women who reported rice intake (n = 73) consumed a median of 28.3 g/d, which is ∼0.5 cup of cooked rice each day. In general linear models adjusted for age and urinary dilution, both rice consumption (g, dry mass/d) and arsenic exposure through water (μg/d) were significantly associated with natural log-transformed total urinary arsenic (Formula , Formula , both P < 0.0001), as well as inorganic arsenic, monomethylarsonic acid, and dimethylarsinic acid (each P < 0.005). Based on total arsenic, consumption of 0.56 cup/d of cooked rice was comparable to drinking 1 L/d of 10 μg As/L water, the current US maximum contaminant limit. US rice consumption varies, averaging ∼0.5 cup/d, with Asian Americans consuming an average of >2 cups/d. Rice arsenic content and speciation also vary, with some strains predominated by dimethylarsinic acid, particularly those grown in the United States. Our findings along with others indicate that rice consumption should be considered when designing arsenic reduction strategies in the United States.
Consistent evidence at high levels of water arsenic (≥100 µg/l), and growing evidence at low-moderate levels (<100 µg/l), support a link with cardiovascular disease (CVD). The shape of the ...dose-response across low-moderate and high levels of arsenic in drinking water is uncertain and critical for risk assessment.
We conducted a systematic review of general population epidemiological studies of arsenic and incident clinical CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories. In a dose-response meta-analysis, we estimated the pooled association between log-transformed water arsenic (log-linear) and restricted cubic splines of log-transformed water arsenic (non-linear) and the relative risk of each CVD endpoint.
Twelve studies (pooled N = 408 945) conducted at high (N = 7) and low-moderate (N = 5) levels of water arsenic met inclusion criteria, and 11 studies were included in the meta-analysis. Compared with 10 µg/l, the estimated pooled relative risks 95% confidence interval (CI) for 20 µg/l water arsenic, based on a log-linear model, were 1.09 (1.03, 1.14) (N = 2) for CVD incidence, 1.07 (1.01, 1.14) (N = 6) for CVD mortality, 1.11 (1.05, 1.17) (N = 4) for CHD incidence, 1.16 (1.07, 1.26) (N = 6) for CHD mortality, 1.08 (0.99, 1.17) (N = 2) for stroke incidence and 1.06 (0.93, 1.20) (N = 6) for stroke mortality. We found no evidence of non-linearity, although these tests had low statistical power.
Although limited by the small number of studies, this analysis supports quantitatively including CVD in inorganic arsenic risk assessment, and strengthens the evidence for an association between arsenic and CVD across low-moderate to high levels.
Dietary supplements sourced from marine environments, such as fish oils and seaweed-based supplements, are widely consumed to boost nutrient intakes, including by vulnerable populations such as ...pregnant women. Like other marine foods, these supplements are also a potential source of exposure to arsenic, including the known toxic species, inorganic arsenic, and the cytotoxic, lipid-soluble arsenic compounds, arsenic hydrocarbons. A study of 32 marine-sourced supplements found higher total arsenic concentrations (>1000 ng g−1) in supplements made from seaweed, krill and calanus oil, and in fish and fish liver products marketed as “unprocessed”. Inorganic arsenic was only detectable in the seaweed samples, and was elevated (8900 ng g−1) in one product. Arsenic hydrocarbons were not detected in krill oil samples but were present at concentrations from 169 to 2048 ng g−1 in “unprocessed” fish and fish liver oil, and calanus oil. Survey data from the New Hampshire Birth Cohort Study (NHBCS) found 13.5% of pregnant women (n = 1997) reported taking fish oil supplements; and of those, most did so daily (75.6%, 6 or more times per week). Only a small percentage (9%) of those who reported consuming fish oil used products associated with higher arsenic levels. Higher urinary arsenic concentrations were found among women who consumed fish oil compared with those who did not, and specifically higher arsenobetaine and dimethyl arsenic concentrations. Dietary supplements are becoming common components of modern diets, and some marine-sourced dietary supplements are a source of inorganic arsenic and arsenic hydrocarbons.
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•Fish oils and seaweed-based dietary supplements can be a source of arsenic exposure.•Seaweed-based supplements can be a source of inorganic arsenic exposure.•Some krill oil and unprocessed fish oils contain elevated concentrations of arsenolipids.•Fish oil supplementation in a pregnancy cohort was associated with healthy diet choices.•Fish oil intake was associated with higher levels of some urinary arsenic species.
The gut microbiome has an important role in infant health and immune development and may be affected by early-life exposures. Maternal diet may influence the infant gut microbiome through vertical ...transfer of maternal microbes to infants during vaginal delivery and breastfeeding. We aimed to examine the association of maternal diet during pregnancy with the infant gut microbiome 6 weeks post-delivery in mother-infant dyads enrolled in the New Hampshire Birth Cohort Study. Infant stool samples were collected from 145 infants, and maternal prenatal diet was assessed using a food frequency questionnaire. We used targeted sequencing of the 16S rRNA V4-V5 hypervariable region to characterize infant gut microbiota. To account for differences in baseline and trajectories of infant gut microbial profiles, we stratified analyses by delivery mode.
We identified three infant gut microbiome clusters, characterized by increased abundance of Bifidobacterium, Streptococcus and Clostridium, and Bacteroides, respectively, overall and in the vaginally delivered infant stratum. In the analyses stratified to infants born vaginally and adjusted for other potential confounders, maternal fruit intake was associated with infant gut microbial community structure (PERMANOVA, p < 0.05). In multinomial logistic regression analyses, increased fruit intake was associated with an increased odds of belonging to the high Streptococcus/Clostridium group among infants born vaginally (OR (95% CI) = 2.73 (1.36, 5.46)). In infants delivered by Cesarean section, we identified three clusters that differed slightly from vaginally delivered infants, which were characterized by a high abundance of Bifidobacterium, high Clostridium and low Streptococcus and Ruminococcus genera, and high abundance of the family Enterobacteriaceae. Maternal dairy intake was associated with an increased odds of infants belonging to the high Clostridium cluster in infants born by Cesarean section (OR (95% CI) = 2.36 (1.05, 5.30)). Linear models suggested additional associations between maternal diet and infant intestinal microbes in both delivery mode strata.
Our data indicate that maternal diet influences the infant gut microbiome and that these effects differ by delivery mode.
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