Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an ...intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles.
Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (
,
,
,
in whole blood leukocytes of children ages 11-18 years of age.
Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (
) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (
) and 5mC only; 5hmC is estimated by subtraction.
Participants were 51% male, and mean maternal blood lead levels (BLL) were
in Trimester 1 (T1),
in Trimester 2 (T2), and
in Trimester 3 (T3). In addition, 5hmC levels were calculated for
(
,
),
(G/C:
; GG:
),
(
), and
(
). Furthermore, 5mC levels were measured in
(
),
(heterozygotes:
; GG homozygotes:
),
(
), and
(
). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in
(
,
) and 5hmC in
(
,
); T2 BLLs with 5mC in
(
,
) and 5hmC in
(
,
); and T3 BLLs with 5mC in
(
,
) and
(
,
) and 5hmC in
(
,
).
5mC was negatively correlated with gene expression (Pearson
,
), whereas 5hmC was positively correlated (
,
).
These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the ...effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
End-of-life spending and healthcare utilization among older adults with COPD have not been previously described.
We examined data on Medicare beneficiaries aged 65 years or older with chronic ...obstructive pulmonary disease (COPD) who died during the period of 2013-2014. End-of-life measures were retrospectively reviewed for 2 years prior to death. Hospital referral regions (HRRs) were categorized into quintiles of age-sex-race-adjusted overall spending during the last 2 years of life. Geographic quintile variation in spending and healthcare utilization was examined across the continuum.
We investigated data on 146,240 decedents with COPD from 306 HRRs. Age-sex-race-adjusted overall spending per decedent during the last 2 years of life varied significantly nationwide ($61,271±$11,639 per decedent; range: $48,288±$3,665 to $79,453±$9,242). Inpatient care accounted for 40.2% of spending ($24,626±$6,192 per decedent). Overall, 82%±4% of decedents were admitted to the hospital for 13.7±3.1 days, and 55%±11% were admitted to an intensive care unit for 5.4±2.5 days. Compared with HRRs in the lowest spending quintile, HRRs in the highest spending quintile had a 1.5-fold longer hospital length of stay. Skilled nursing facilities accounted for 11.6% of spending ($7101±$2403 per decedent), and these facilities were utilized by 38%±7% of decedents for 18.7±4.9 days. Hospice accounted for 10.3% of spending ($6,307±$2,201 per decedent) and was utilized by 47%±9% of decedents for 39.7±14.8 days. Significant geographic variation in hospice utilization existed nationwide.
End-of-life spending and healthcare utilization among older adults with COPD varied substantially nationwide. Decedents with COPD frequently utilized acute care near the end of life. Hospice utilization was higher than expected, with significant geographic disparities.
Background Social risk factors influence rehospitalization rates yet are challenging to incorporate into prediction models. Integration of social risk factors using natural language processing (NLP) ...and machine learning could improve risk prediction of 30-day readmission following an acute myocardial infarction. Methods and Results Patients were enrolled into derivation and validation cohorts. The derivation cohort included inpatient discharges from Vanderbilt University Medical Center between January 1, 2007, and December 31, 2016, with a primary diagnosis of acute myocardial infarction, who were discharged alive, and not transferred from another facility. The validation cohort included patients from Dartmouth-Hitchcock Health Center between April 2, 2011, and December 31, 2016, meeting the same eligibility criteria described above. Data from both sites were linked to Centers for Medicare & Medicaid Services administrative data to supplement 30-day hospital readmissions. Clinical notes from each cohort were extracted, and an NLP model was deployed, counting mentions of 7 social risk factors. Five machine learning models were run using clinical and NLP-derived variables. Model discrimination and calibration were assessed, and receiver operating characteristic comparison analyses were performed. The 30-day rehospitalization rates among the derivation (n=6165) and validation (n=4024) cohorts were 15.1% (n=934) and 10.2% (n=412), respectively. The derivation models demonstrated no statistical improvement in model performance with the addition of the selected NLP-derived social risk factors. Conclusions Social risk factors extracted using NLP did not significantly improve 30-day readmission prediction among hospitalized patients with acute myocardial infarction. Alternative methods are needed to capture social risk factors.
Acute kidney injury (AKI) is a common complication of cardiac surgery. Postprocedural AKI is a risk factor for 30-day readmission. We sought to examine the association of AKI and kidney injury ...biomarkers with readmission after cardiac surgery.
Patients alive at discharge who underwent cardiac surgery from the Translational Research Investigating Biomarker Endpoints-AKI cohort were enrolled from six medical centers in the United States and Canada. AKI duration was defined as the total number of days AKI was present during index admission (no AKI, 1–2, 3–6, and 7+ days). Preoperative and postoperative urinary levels were collected for interleukin-18, neutrophil gelatinase–associated lipocalin, kidney injury molecule-1, liver-fatty-acid-binding protein, cystatin C, microalbumin, creatinine, and albumin-to-creatinine ratio. Readmission and death events were identified through US (Medicare) and Canadian administrative databases at 30 days and 365 days after discharge.
Of 968 patients 15.9% were readmitted or died within 30 days of discharge and 35.9% were readmitted or died within 365 days. AKI duration of 3 to 6 days was significantly associated with 30-day readmission or death (adjusted odds ratio, 1.82%; 95% confidence interval, 1.08–3.05). Patients with AKI duration ≥ 7 days had increased odds of readmission or death at both 30 days (adjusted odds ratio, 2.49%; 95% confidence interval, 1.15–5.43) and 365 days (adjusted odds ratio, 3.67%; 95% confidence interval, 1.73–7.79). Urinary biomarkers had no association with readmission and death.
AKI duration ≥ 3 days, and not kidney biomarkers, was strongly associated with readmission or death. These clinical outcomes are potentially due to cardiovascular or hemodynamic causes rather than intrinsic injury to the kidney parenchyma.
The developing epigenome changes rapidly, potentially making it more sensitive to toxicant exposures. DNA modifications, including methylation and hydroxymethylation, are important parts of the ...epigenome that may be affected by environmental exposures. However, most studies do not differentiate between these two DNA modifications, possibly masking significant effects.
To investigate the relationship between DNA hydroxymethylation and developmental exposure to common contaminants, a collaborative, NIEHS-sponsored consortium, TaRGET II, initiated longitudinal mouse studies of developmental exposure to human-relevant levels of the phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP), and the metal lead (Pb). Exposures to 25 mg DEHP/kg of food (approximately 5 mg DEHP/kg body weight) or 32 ppm Pb-acetate in drinking water were administered to nulliparous adult female mice. Exposure began 2 weeks before breeding and continued throughout pregnancy and lactation, until offspring were 21 days old. At 5 months, perinatally exposed offspring blood and cortex tissue were collected, for a total of 25 male mice and 17 female mice (
= 5-7 per tissue and exposure). DNA was extracted and hydroxymethylation was measured using hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq). Differential peak and pathway analysis was conducted comparing across exposure groups, tissue types, and animal sex, using an FDR cutoff of 0.15.
DEHP-exposed females had two genomic regions with lower hydroxymethylation in blood and no differences in cortex hydroxymethylation. For DEHP-exposed males, ten regions in blood (six higher and four lower) and 246 regions (242 higher and four lower) and four pathways in cortex were identified. Pb-exposed females had no statistically significant differences in blood or cortex hydroxymethylation compared to controls. Pb-exposed males, however, had 385 regions (all higher) and six pathways altered in cortex, but no differential hydroxymethylation was identified in blood.
Overall, perinatal exposure to human-relevant levels of two common toxicants showed differences in adult DNA hydroxymethylation that was specific to sex, exposure type, and tissue, but male cortex was most susceptible to hydroxymethylation differences by exposure. Future assessments should focus on understanding if these findings indicate potential biomarkers of exposure or are related to functional long-term health effects.
Abstract
Early-life lead (Pb) exposure has been linked to adverse neurodevelopmental outcomes. Recent evidence has indicated a critical role of DNA methylation (DNAm) in cognition, and Pb exposure ...has also been shown to alter DNAm. However, it is unknown whether DNAm is part of the mechanism of Pb neurotoxicity. This longitudinal study investigated the associations between trimester-specific (T1, T2, and T3) maternal blood Pb concentrations, gene-specific DNAm in umbilical cord blood, and infant neurodevelopmental outcomes at 12 and 24 months of age (mental development index, psychomotor development index, and behavioral rating scale of orientation/engagement and emotional regulation) among 85 mother–infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study. In the mediation analysis for this pilot study, P < 0.1 was considered significant. DNAm at a locus in CCSER1 (probe ID cg02901723) mediated the association between T2 Pb on 24-month orientation/engagement indirect effect estimate 4.44, 95% confidence interval (−0.09, 10.68), P = 0.06 and emotional regulation 3.62 (−0.05, 8.69), P = 0.05. Cg18515027 (GCNT1) DNAm mediated the association of T1 Pb −4.94 (−10.6, −0.77), P = 0.01 and T2 Pb −3.52 (−8.09, −0.36), P = 0.02 with 24-month EMOCI, but there was a positive indirect effect estimate between T2 Pb and 24-month psychomotor development index 1.25 (−0.11, 3.32), P = 0.09. The indirect effect was significant for cg19703494 (TRAPPC6A) DNAm in the association between T2 Pb and 24-month mental development index 1.54 (0, 3.87), P = 0.05. There was also an indirect effect of cg23280166 (VPS11) DNAm on T3 Pb and 24-month EMOCI 2.43 (−0.16, 6.38), P = 0.08. These associations provide preliminary evidence for gene-specific DNAm as mediators between prenatal Pb and adverse cognitive outcomes in offspring.
In the US, more than 600 000 adults will experience an acute myocardial infarction (AMI) each year, and up to 20% of the patients will be rehospitalized within 30 days. This study highlights the need ...for consideration of calibration in these risk models.
To compare multiple machine learning risk prediction models using an electronic health record (EHR)-derived data set standardized to a common data model.
This was a retrospective cohort study that developed risk prediction models for 30-day readmission among all inpatients discharged from Vanderbilt University Medical Center between January 1, 2007, and December 31, 2016, with a primary diagnosis of AMI who were not transferred from another facility. The model was externally validated at Dartmouth-Hitchcock Medical Center from April 2, 2011, to December 31, 2016. Data analysis occurred between January 4, 2019, and November 15, 2020.
Acute myocardial infarction that required hospital admission.
The main outcome was thirty-day hospital readmission. A total of 141 candidate variables were considered from administrative codes, medication orders, and laboratory tests. Multiple risk prediction models were developed using parametric models (elastic net, least absolute shrinkage and selection operator, and ridge regression) and nonparametric models (random forest and gradient boosting). The models were assessed using holdout data with area under the receiver operating characteristic curve (AUROC), percentage of calibration, and calibration curve belts.
The final Vanderbilt University Medical Center cohort included 6163 unique patients, among whom the mean (SD) age was 67 (13) years, 4137 were male (67.1%), 1019 (16.5%) were Black or other race, and 933 (15.1%) were rehospitalized within 30 days. The final Dartmouth-Hitchcock Medical Center cohort included 4024 unique patients, with mean (SD) age of 68 (12) years; 2584 (64.2%) were male, 412 (10.2%) were rehospitalized within 30 days, and most of the cohort were non-Hispanic and White. The final test set AUROC performance was between 0.686 to 0.695 for the parametric models and 0.686 to 0.704 for the nonparametric models. In the validation cohort, AUROC performance was between 0.558 to 0.655 for parametric models and 0.606 to 0.608 for nonparametric models.
In this study, 5 machine learning models were developed and externally validated to predict 30-day readmission AMI hospitalization. These models can be deployed within an EHR using routinely collected data.
Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to ...identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within PDGFRL associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within TRHR with tibia bone Pb (adjusted P-value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted P-value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.
In 1990, the US Congress amended the Clean Air Act (CAA) to reduce regional-scale ecosystem degradation from SO
x
and NO
x
emissions which have been responsible for acid deposition in regions such as ...the Adirondack Mountains of New York State. An ecosystem assessment project was conducted from 1994 to 2012 by the Darrin Fresh Water Institute to determine the effect of these emission reduction policies on aquatic systems. The project investigated water chemistry and biota in 30 Adirondack lakes and ponded waters. Although regulatory changes made in response to the 1990 CAA amendments resulted in a reduction of acid deposition within the Adirondacks, the ecosystem response to these reductions is complicated. A statistical analysis of SO
4
, pH, Al, and DOC data collected during this project demonstrates positive change in response to decreased deposition. The changes in water chemistry also have lowered the risk of Al toxicity to brook trout (
Salvelinus fontinalis
Mitchill), which allowed the re-introduction of this species to Brooktrout Lake from which it had been extirpated. However, pH and labile aluminum (Al
im
) fluctuate and are not strongly correlated to changes in acid deposition. As such, toxicity to
S. fontinalis
also is cyclic and provides rationale for the difficulties inherent in re-establishing resident populations in impacted aquatic environments. Overall, aquatic ecosystems of the Adirondacks show a positive response to reduced deposition driven by changes in environmental policy, but the response is more complex and indicates an ecosystem-wide interaction between aquatic and watershed components of the ecosystem.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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