Publications by authors named "Andrea Baccarelli"

470 Publications

The associations of phthalate biomarkers during pregnancy with later glycemia and lipid profiles.

Environ Int 2021 May 6;155:106612. Epub 2021 May 6.

School of Global Public Health, New York University, NY, USA.

Background: Pregnancy induces numerous cardiovascular and metabolic changes. Alterations in these sensitive processes may precipitate long-term post-delivery health consequences. Studies have reported associations between phthalates and metabolic complications of pregnancy, but no study has investigated metabolic outcomes beyond pregnancy.

Objectives: To examine associations of exposure to phthalates during pregnancy with post-delivery metabolic health.

Design: We quantified 15 urinary phthalate biomarker concentrations during the second and third trimesters among 618 pregnant women from Mexico City. Maternal metabolic health biomarkers included fasting blood measures of glycemia [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], % hemoglobin A1c (HbA1c%)] and lipids (total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides), at 4-5 and 6-8 years post-delivery. To estimate the influence of the phthalates mixture, we used Bayesian weighted quantile sum regression and Bayesian kernel machine regression; for individual biomarkers, we used linear mixed models.

Results: As a mixture, higher urinary phthalate biomarker concentrations during pregnancy were associated with post-delivery concentrations of plasma glucose (interquartile range [IQR] difference: 0.13 SD, 95%CrI: 0.05, 0.20), plasma insulin (IQR difference: 0.06 SD, 95%CrI: -0.02, 0.14), HOMA-IR (IQR difference: 0.08 SD, 95% CrI: 0.01, 0.16), and HbA1c% (IQR difference: 0.15 SD, 95%CrI: 0.05, 0.24). Associations were primarily driven by mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and the sum of dibutyl phthalate biomarkers (∑DBP). The phthalates mixture was associated with lower HDL (IQR difference: -0.08 SD, 95%CrI: -0.16, -0.01), driven by ∑DBP and monoethyl phthalate (MEP), and higher triglyceride levels (IQR difference: 0.15 SD, 95%CrI: 0.08, 0.22), driven by MECPTP and MEP. The overall mixture was not associated with total cholesterol and LDL. However, ∑DBP and MEP were associated with lower and higher total cholesterol, respectively, and MECPTP and ∑DBP were associated with lower LDL.

Conclusions: Phthalate exposure during pregnancy is associated with adverse long-term changes in maternal metabolic health. A better understanding of timing of the exact biological changes and their implications on metabolic disease risk is needed.
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http://dx.doi.org/10.1016/j.envint.2021.106612DOI Listing
May 2021

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Genome Med 2021 Apr 30;13(1):74. Epub 2021 Apr 30.

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.

Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.

Results: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.

Conclusions: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
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http://dx.doi.org/10.1186/s13073-021-00877-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088054PMC
April 2021

Epigenetically mediated electrocardiographic manifestations of sub-chronic exposures to ambient particulate matter air pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.

Environ Res 2021 Apr 22;198:111211. Epub 2021 Apr 22.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Background: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease.

Materials And Methods: We estimated associations between monthly mean concentrations of PM < 10 μm and 2.5-10 μm in diameter (PM PM) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (n = 82,107; n = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (n = 7,169; n = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm.

Results: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm.

Conclusions: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.
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http://dx.doi.org/10.1016/j.envres.2021.111211DOI Listing
April 2021

Association between follicular fluid phthalate concentrations and extracellular vesicle microRNAs expression.

Hum Reprod 2021 Apr 22. Epub 2021 Apr 22.

Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat-Gan and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Study Question: Are phthalate metabolite concentrations in follicular fluid (FF) associated with the expression of extracellular vesicle microRNAs (EV-miRNAs)?

Summary Answer: Phthalate metabolite concentrations are associated with the expression of EV-miRNA and their associated pathways in FFs.

What Is Known Already: Phthalate metabolites were recently detected in FF. Urinary phthalate metabolite concentrations alter the expression of EV-miRNAs in FF.

Study Design, Size, Duration: Prospective study including 105 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital.

Participants/materials, Setting, Methods: We assessed FF concentrations of 12 phthalate metabolites. EV-miRNAs were isolated from aliquots of the same FF, and their expression profiles were measured using a human miRNA panel. Associations between EV-miRNAs that were present in >50% of the samples and phthalate metabolites that were measured in >74% of the FF samples were tested. Genes regulated by EV-miRNAs that were found to be significantly (false discovery rate q-value < 0.1) correlated with FF-phthalates were analyzed for pathways linked with female fertility using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources and Kyoto Encyclopedia of Genes and Genomes (KEGG).

Main Results And The Role Of Chance: Of 12 phthalate metabolites, 11 were measured in at least one FF sample. Mono (6-COOH-2-methylheptyl) phthalate (MCOMHP), mono-2-ethyl-5-carboxypentyl phthalate (mECPP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono (7-COOH-2-methyloctyl) phthalate (MCOMOP) were detected in more than 74% of the samples. Of 754 EV-miRNAs tested, 39 were significantly associated either with MEP, MBzP, MCOMOP, MCOMHP and/or with mECPP, after adjusting for multiple testing (P < 0.05). KEGG-based pathway enrichment analysis of the genes regulated by these miRNAs showed that these EV-miRNAs may be involved in pathways related to ovary or oocyte development, maturation and fertilization.

Limitations, Reasons For Caution: The use of miRNA panel array limits the number of potential relevant miRNAs. Moreover, several of the phthalate metabolites examined may be biased due to internal (enzymatic activity) or external (contamination in medical interventions) causes.

Wider Implications Of The Findings: Phthalate metabolites may alter follicular EV-miRNAs profile and thus impair pathways that are involved with oocyte development, maturation and fertilization. Our results contribute to understanding of possible mechanism(s) in which endocrine disruptor chemicals interfere with female fertility.

Study Funding/competing Interests: This work was supported by the National Institutes of Environmental Health Sciences [Grant R21-ES024236]; and Environmental Health Fund, Israel [Grant 1301], no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab063DOI Listing
April 2021

Residential PM exposure and the nasal methylome in children.

Environ Int 2021 Apr 16;153:106505. Epub 2021 Apr 16.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Rationale: PMinduced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known.

Objectives: We aimed to study associations of fine particulate matter PM exposure with DNA methylation in nasal cells.

Methods: We conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina MethylationEPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA).

Results: In adjusted analyses, we found 362 CpGs associated with 1-year PM (FDR < 0.05), 20 CpGs passing Bonferroni correction (P < 7.0x10) and 10 Differentially Methylated Regions (DMRs). In 445 PIAMA participants (mean age 16.3 years) 11 of 203 available CpGs replicated at P < 0.05. We observed differential DNAm at/near genes implicated in cell cycle, immune and inflammatory responses. There were no CpGs or regions associated with PM levels at 1-day, 1-week, or 1-month prior to sample collection, although 2 CpGs were associated with past 3-month PM.

Conclusion: We observed wide-spread DNAm variability associated with average past year PM exposure but we did not detect associations with shorter-term exposure. Our results suggest that nasal DNAm marks reflect chronic air pollution exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106505DOI Listing
April 2021

Nanoparticle Tracking Analysis for the Quantification and Size Determination of Extracellular Vesicles.

J Vis Exp 2021 03 28(169). Epub 2021 Mar 28.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health;

The physiological and pathophysiological roles of extracellular vesicles (EVs) have become increasingly recognized, making the EV field a quickly evolving area of research. There are many different methods for EV isolation, each with distinct advantages and disadvantages that affect the downstream yield and purity of EVs. Thus, characterizing the EV prep isolated from a given source by a chosen method is important for interpretation of downstream results and comparison of results across laboratories. Various methods exist for determining the size and quantity of EVs, which can be altered by disease states or in response to external conditions. Nanoparticle tracking analysis (NTA) is one of the prominent technologies used for high-throughput analysis of individual EVs. Here, we present a detailed protocol for quantification and size determination of EVs isolated from mouse perigonadal adipose tissue and human plasma using a breakthrough technology for NTA representing major advances in the field. The results demonstrate that this method can deliver reproducible and valid total particle concentration and size distribution data for EVs isolated from different sources using different methods, as confirmed by transmission electron microscopy. The adaptation of this instrument for NTA will address the need for standardization in NTA methods to increase rigor and reproducibility in EV research.
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http://dx.doi.org/10.3791/62447DOI Listing
March 2021

Risks of Macrosomia Associated with Catechol--Methyltransferase Genotypes and Genetic-Epigenetic Interactions among Children with and without Gestational Diabetes Exposure.

Child Obes 2021 Apr 6. Epub 2021 Apr 6.

Department of Preventive Medicine, Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Gestational diabetes mellitus (GDM) is a major macrosomia risk factor. Variations in the catechol--methyltransferase (COMT; rs4680) genotypes are associated with heightened susceptibility to environmental exposures and nutritional conditions. However, macrosomia risks associated with COMT genetics, epigenetics, and the interaction between genetic and epigenetics among children with and without exposure to GDM are unknown. Data from women/children pairs ( = 1087) who participated in the Tianjin Gestational Diabetes Birth Cohort were used to examine the odds of being born with macrosomia associated with COMT-genotypes, 55 CpG sites located on the COMT gene, and genetic and epigenetic interactions. Odds of macrosomia associated with COMT genetic, epigenetic, genetic and epigenetic interactions, and moderations with GDM were tested using adjusted logistic regression models. Overall, 16.1% ( = 175) of children were born with macrosomia. Models showed that children with at least one copy of the minor allele (A) had higher odds of macrosomia (odds ratio, 1.82; 95% confidence interval 1.25-2.64) compared with children with the GG-genotype. After false discovery rate corrections, none of the 55 CpG sites located on the COMT gene was associated with odds of macrosomia. The genetic and epigenetic associations were not modified by exposure to GDM. Findings suggest carriers of the COMT GG-genotype had lower odds of macrosomia, and this association was not modified by epigenetics or exposure to GDM.
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http://dx.doi.org/10.1089/chi.2020.0327DOI Listing
April 2021

Metal exposure and bone remodeling during pregnancy: Results from the PROGRESS cohort study.

Environ Pollut 2021 Mar 17;282:116962. Epub 2021 Mar 17.

Occupational Research Unit, Mexican Social Security Institute (IMSS), Mexico City, Mexico.

Pregnancy is characterized by high bone remodeling and might be a window of susceptibility to the toxic effects of metals on bone tissue. The aim of this study was to assess associations between metals in blood [lead (Pb), cadmium (Cd)and arsenic (As)] and bone remodeling during pregnancy. We studied pregnant woman from the PROGRESS Cohort (Programming Research in Obesity, Growth, and Environment and Social Stress). We measured concentrations of metals in blood and obtained measures of bone remodeling by quantitative ultrasound (QUS) at the radius in the second and third trimester of pregnancy. To account for chronic lead exposure, we measured lead in tibia and patella one-month postpartum with K-shell X-ray fluorescence. We assessed cross-sectional and longitudinal associations between multiple-metal concentrations and QUS z-scores using linear regression models and linear mixed models adjusted for potential confounders. Third trimester blood Cd concentrations were marginal associated with lower QUS z-scores [-0.16 (95% CI: -0.33, 0.007); P-Value = 0.06]. Mixed models showed that blood Cd was longitudinally and marginally associated with an average of -0.10 z-score (95% CI: -0.21, 0.002; P-Value = 0.06) over the course of pregnancy. Associations for Pb and As were all inverse however none reached significance. Additionally, bone Pb concentrations in patella, an index of cumulative exposure, were significantly associated with -0.06 z-score at radius (95% CI: -0.10, -0.01; P-Value = 0.03) during pregnancy. Pb and Cd blood levels are associated with lower QUS distal radius z-scores in pregnant women. Bone Pb concentrations in patella were negatively associated with z-score at radius showing the long-term effects of Pb on bone tissue. However, we cannot exclude the possibility of reverse causality for patella Pb and radius z-score associations. Our results support the importance of reducing women's metal exposure during pregnancy, as metals exposure during pregnancy may have consequences for bone strength later in life. The main finding of our study is the association between Cd blood levels and radius z-score during pregnancy. Bone lead in patella was also negatively associated with radius z-scores.
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http://dx.doi.org/10.1016/j.envpol.2021.116962DOI Listing
March 2021

DNA methylation architecture of the ACE2 gene in nasal cells of children.

Sci Rep 2021 03 29;11(1):7107. Epub 2021 Mar 29.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity. The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean = 12.71%) and 3 sites greater DNAm (mean = 1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference = 3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference = 1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference = 7.86%) and females (mean absolute difference = 8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences. Findings need to be confirmed among adults and patients with risk factors for COVID-19 severity.
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http://dx.doi.org/10.1038/s41598-021-86494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007733PMC
March 2021

Epigenetic age in young African American adults with perinatally-acquired HIV.

J Acquir Immune Defic Syndr 2021 Mar 18. Epub 2021 Mar 18.

Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA Department of Pediatrics, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA ICAP at Columbia, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA.

Background: Prior studies have measured accelerated aging in people with HIV (PWH) using a DNA methylation (DNAm)-based biomarker of aging, "epigenetic age", but data are limited in African American (AA) young adults with perinatally-acquired HIV infection (PHIV).

Methods: We performed a cross-sectional study of AA young adults ages 20-35 years with PHIV (N=31) and seronegative controls (N=30) using DNAm measured in whole blood and cognitive function measured by the NIH Toolbox. Illumina EPIC Array was utilized to measure DNAm age, and accelerated aging markers including epigenetic age acceleration (EAA), as well as extrinsic (EEAA) and intrinsic (IEAA) epigenetic age acceleration.

Results: PHIV and controls did not differ by sex (45 vs. 43% male), chronological age (26.2 vs. 28.0 years), or ethnicity. Chronological age and DNAm age were correlated (r=0.56, p<0.01). PHIV had a higher mean EAA (2.86±6.5 vs. -2.96±3.9, p<0.01) and EEAA (4.57±13.0 vs. -4.72±6.0, p<0.01) than controls; however, IEAA was not different between groups. Among PHIV, EAA and EEAA were higher in those with HIV viral load ≥50 copies/ml than <50 copies/ml (EEA: 8.1±5.2 vs. 0.11±5.5, p=0<0.01; EEAA: 16.1±10.6 vs. -1.83±9.7, p<0.01). We observed negative correlations (r=-0.36 to -0.31) between EEAA and executive function, attention, and language scores.

Conclusion: In conclusion, epigenetic age acceleration in blood was observed in AA young adults with PHIV on ART using two measures, including EEAA which up-weights the contribution of immunosenescent cell types. However, there was no evidence of age acceleration with a measure independent of cell type composition.
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http://dx.doi.org/10.1097/QAI.0000000000002687DOI Listing
March 2021

Human milk extracellular vesicle miRNA expression and associations with maternal characteristics in a population-based cohort from the Faroe Islands.

Sci Rep 2021 Mar 12;11(1):5840. Epub 2021 Mar 12.

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, 10023, USA.

Human milk plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. Milk contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). We aimed to characterize milk EV-miRNA profiles in a human population cohort, assess potential pathways and ontology, and investigate associations with maternal characteristics. We conducted the first study to describe the EV miRNA profile of human milk in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1523 miRNAs with ≥ one read in 70% of samples. Using hierarchical clustering, we determined five EV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster human milk EV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. miRNA expression was associated with time to milk collection post-delivery, maternal body mass index, and maternal smoking, but not maternal parity. Future studies investigating determinants of human EV-miRNAs and associated health outcomes are needed to elucidate the role of human milk EV-miRNAs in health and disease.
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http://dx.doi.org/10.1038/s41598-021-84809-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970999PMC
March 2021

Long-term PM exposure before diagnosis is associated with worse outcome in breast cancer.

Breast Cancer Res Treat 2021 Mar 8. Epub 2021 Mar 8.

Unit for Breast Cancer Oncology, Instituto Nacional de Cancerología, San Fernando 22, Colonia Seccion XVI, Tlalpan, 14080, Mexico, Mexico.

Purpose: Increasingly epidemiological evidence supports that environmental factors are associated with breast cancer (BC) outcomes after a BC diagnosis. Although evidence suggests that air pollution exposure is associated with higher mortality in women with BC, studies investigating potential mechanisms have been lacking.

Methods: We evaluated women with BC (N = 151) attended at the National Cancer Institute-Mexico from 2012 to 2015. We calculated 1-year average exposures to particulate matter < 2.5 μm (PM) at home address before diagnosis. We used linear and logistic regression models to determine the associations between PM exposure and BC aggressiveness (tumor size, molecular phenotype).

Results: Average annual PM exposure of this population was 23.0 μg/m [standard deviation (SD)]: 1.90 μg/m]. PM levels were positively correlated with tumor size at diagnosis (r = 0.22; p = 0.007). Multivariable linear models had a similar inference [risk ratio (RR): 1.32; 95% confidence interval (95% CI): 1.04, 1.674]. We did not observe differences in this association by age or menopause status. Further, women with triple-negative BC (TNBC) had significantly higher PM levels compared with other phenotypes (p = 0.015). Multivariable-adjusted logistic regression models assessing the association between PM and tumor size had a similar inference (RR 1.41; 95% CI 1.05, 1.89) overall for all ages and also for women who were ≤ 50 years old at diagnosis (RR 1.63; 95% CI 1.036, 2.57).

Conclusions: Our findings suggest a significant association between long-term PM exposure and BC aggressiveness based on tumor size and phenotype, as well as a worse outcome.
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http://dx.doi.org/10.1007/s10549-021-06167-xDOI Listing
March 2021

Prenatal blood lead levels and reduced preadolescent glomerular filtration rate: Modification by body mass index.

Environ Int 2021 Feb 26:106414. Epub 2021 Feb 26.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Background: For the developing kidney, the prenatal period may represent a critical window of vulnerability to environmental insults resulting in permanent nephron loss. Given that the majority of nephron formation is complete in the 3rd trimester, we set out to test whether 1) prenatal lead exposure is associated with decreased preadolescent kidney function and 2) whether preadolescent obesity acts synergistically with early life lead exposure to reduce kidney function.

Methods: Our study included 453 mother-child pairs participating in the PROGRESS birth cohort. We assessed prenatal blood lead levels (BLLs) in samples collected in the 2nd and 3rd trimesters and at delivery, as well as tibial and patellar bone lead measures assessed one-month postpartum. Preadolescent estimated glomerular filtration rate (eGFR) was derived from serum levels of creatinine and/or cystatin C measured at age 8-12 years. We applied linear regression to assess the relationship between prenatal bone and BLL with preadolescent eGFR, and adjusted for covariates including age, sex, BMI z-score, indoor tobacco smoke exposure, and socioeconomic status. We also examined sex-specific associations and tested for effect modification by BMI status.

Results: We observed null associations between prenatal lead exposure and eGFR. However, in interaction analyses we found that among overweight children, there was an inverse association between BLL (assessed at 2nd and 3rd trimester and at delivery) and preadolescent eGFR. For example, among overweight participants, a one ln-unit increase in 2nd trimester BLL was associated with a 10.5 unit decrease in cystatin C-based eGFR (95% CI: -18.1, -2.8; p = 0.008). Regardless of lead exposure, we also observed null relationships between BMI z-score and eGFR overall, as well as among overweight participants. However, among participants with preadolescent obesity, we observed a significant 5.9-unit decrease in eGFR We observed no evidence of sex-specific effects.

Conclusions: Our findings, if confirmed in other studies, suggest a complex interplay between the combined adverse effects of adiposity and perinatal lead exposure as they relate to adolescent kidney function. Future studies will assess kidney function and adiposity trajectories through adolescence to better understand environmental risk factors for kidney function decline.
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http://dx.doi.org/10.1016/j.envint.2021.106414DOI Listing
February 2021

Hallmarks of environmental insults.

Cell 2021 Mar 2;184(6):1455-1468. Epub 2021 Mar 2.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.

Environmental insults impair human health around the world. Contaminated air, water, soil, food, and occupational and household settings expose humans of all ages to a plethora of chemicals and environmental stressors. We propose eight hallmarks of environmental insults that jointly underpin the damaging impact of environmental exposures during the lifespan. Specifically, they include oxidative stress and inflammation, genomic alterations and mutations, epigenetic alterations, mitochondrial dysfunction, endocrine disruption, altered intercellular communication, altered microbiome communities, and impaired nervous system function. They provide a framework to understand why complex mixtures of environmental exposures induce severe health effects even at relatively modest concentrations.
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http://dx.doi.org/10.1016/j.cell.2021.01.043DOI Listing
March 2021

Is your environment making you older? Molecular biomarkers and new approaches to investigate the influences of environmental chemicals through aging.

Med Lav 2021 Feb 23;112(1):8-14. Epub 2021 Feb 23.

Columbia University Mailman School of Public Health .

Aging is characterized by a gradual and progressive decline in system integrity that occurs with advancing chronological age. Although it is a physiological process, aging is associated with a myriad of age-related diseases (ARDs), including frailty, sarcopenia, chronic obstructive pulmonary disease, cardiovascular disease, cancer, and neurodegenerative diseases. While not exclusively ARDs, many of these diseases lead to death, a lesser quality of life, and increased healthcare costs for individuals and systems. ARDs share several underlying molecular mechanisms, such as cellular damage, inflammation, DNA methylation changes, stem cells exhaustion, and DNA mutations, which have been outlined as hallmarks of aging. Evidence suggests that environmental exposures, including but not limited to metals, air pollution, endocrine-disrupting chemicals, and noise, may accelerate biological aging. Over the past few years, aging research has identified new molecular biomarkers of the aging process. When applied to investigate environmental influences, these biomarkers can help identify individuals who are particularly susceptible to the influences of environmental exposures on aging processes and therefore guide in implementing possible preventive measures.
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http://dx.doi.org/10.23749/mdl.v112i1.10826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023055PMC
February 2021

Exosomal miRNAs in urine associated with children's cardiorenal parameters: a cross-sectional study.

Epigenomics 2021 Apr 26;13(7):499-512. Epub 2021 Feb 26.

Department of Environmental Medicine & Public Health, Icahn School of Medicine at Mount Sinai, 10029 New York, USA.

The authors sought to examine associations between urinary exosomal miRNAs (exo-miRs), emerging biomarkers of renal health, and cardiorenal outcomes in early childhood. The authors extracted exo-miRs in urine from 88 healthy Mexican children aged 4-6 years. The authors measured associations between 193 exo-miRs and cardiorenal outcomes: systolic/diastolic blood pressure, estimated glomerular filtration rate and urinary sodium and potassium levels. The authors adjusted for age, sex, BMI, socioeconomic status, indoor tobacco smoke exposure and urine specific gravity. Multiple exo-miRs were identified meeting a false discovery rate threshold of q < 0.1. Specifically, three exo-miRs had increased expression with urinary sodium, 17 with urinary sodium-to-potassium ratio and one with decreased estimated glomerular filtration rate. These results highlight urinary exo-miRs as early-life biomarkers of children's cardiorenal health.
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http://dx.doi.org/10.2217/epi-2020-0342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033423PMC
April 2021

Association of cardiovascular health and epigenetic age acceleration.

Clin Epigenetics 2021 Feb 25;13(1):42. Epub 2021 Feb 25.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the "Life's Simple 7" ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age.

Methods And Results: We performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p < 0.0001), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score, p < 0.028).

Conclusions: These cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity.
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http://dx.doi.org/10.1186/s13148-021-01028-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905851PMC
February 2021

Extracellular vesicles and female reproduction.

J Assist Reprod Genet 2021 Mar 20;38(3):549-557. Epub 2021 Jan 20.

Environmental Precision Biosciences Laboratory, Columbia University, Mailman School of Public Health, New York, NY, USA.

Extracellular vesicles (EVs) are nano-sized membrane bound complexes that have been identified as a mean for intercellular communication between cells and tissues both in physiological and pathological conditions. These vesicles contain numerous molecules involved in signal transduction including microRNAs, mRNAs, DNA, proteins, lipids, and cytokines and can affect the behavior of recipient cells. Female reproduction is dependent on extremely fine-tuned endocrine regulation, and EVs may represent an added layer that contributes to this regulation. This narrative review article provides an update on the research of the role of EVs in female reproduction including folliculogenesis, fertilization, embryo quality, and implantation. We also highlight potential pitfalls in typical EV studies and discuss gaps in the current literature.
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http://dx.doi.org/10.1007/s10815-020-02048-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910356PMC
March 2021

A methodological pipeline to generate an epigenetic marker of prenatal exposure to air pollution indicators.

Epigenetics 2021 Jan 19:1-9. Epub 2021 Jan 19.

Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, New York.

A barrier in the children's environmental health field has been the lack of early-warning systems to identify risks of childhood illness and developmental disorders. We aimed to develop a methodology to identify an accessible biomarker measured in a small amount of blood to distinguish newborns at elevated risk from a toxic prenatal exposure, using air pollutants as a case study. Because air pollutants are associated with altered DNA methylation, we developed a pipeline using DNA methylation signatures measured in umbilical cord blood, which could be used as predictors of prenatal exposure. We used air pollution indicators, including modelled trimester-specific and pregnancy average NO and PM, and DNA methylation signatures from Illumina arrays measured in two New York City-based longitudinal birth cohorts from the Columbia Centre for Children's Environmental Health. We developed a screening plus three-part pipeline that incorporates selection, testing, and validation to identify whether DNA methylation can be used to predict exposure to prenatal air pollution indicators, NO and PM. Applying this pipeline, we found that cord blood DNA methylation could be used to predict high vs. low average pregnancy NO (AUC = 0.60, 95% CI: 0.52-0.68, with validation AUC = 0.60). Similar results were found for high vs. low third trimester NO. In this proof of concept study using air pollutants as an example, we provide an approach (with a generalizable analytic pipeline) that can be used for prediction of prenatal exposure to contaminants. This approach has potential to identify children at risk of developmental disorders and illness resulting from prenatal exposure.
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http://dx.doi.org/10.1080/15592294.2021.1872926DOI Listing
January 2021

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Erasmus MC, University Medical Center Rotterdam, Generation R Study Group, Rotterdam, The Netherlands.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.
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http://dx.doi.org/10.1038/s41380-020-00976-0DOI Listing
January 2021

Prenatal lead exposure and cord blood DNA methylation in PROGRESS: an epigenome-wide association study.

Environ Epigenet 2020 8;6(1):dvaa014. Epub 2020 Dec 8.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New York, NY 10029, USA.

The effects of prenatal lead exposure on child development include impaired growth and cognitive function. DNA methylation might be involved in the underlying mechanisms and previous epigenome-wide association studies reported associations between lead exposure during pregnancy and cord blood methylation levels. However, it is unclear during which developmental stage lead exposure is most harmful. Cord blood methylation levels were assayed in 420 children from a Mexican pre-birth cohort using the Illumina Infinium MethylationEPIC microarray. Lead concentrations were measured in umbilical cord blood as well as in blood samples from the mothers collected at 2nd and 3rd trimester and delivery using inductively coupled plasma-mass spectrometry. In addition, maternal bone lead levels were measured in tibia and patella using X-ray fluorescence. Comprehensive quality control and preprocessing of microarray data was followed by an unbiased restriction to methylation sites with substantial variance. Methylation levels at 202 111 cytosine-phosphate-guanine sites were regressed on each exposure adjusting for child sex, leukocyte composition, batch variables, gestational age, birthweight-for-gestational-age, maternal age, maternal education and mode of delivery. We find no association between prenatal lead exposure and cord blood methylation. This null result is strengthened by a sensitivity analysis showing that in the same dataset known biomarkers for birthweight-for-gestational-age can be recovered and the fact that phenotypic associations with lead exposure have been described in the same cohort.
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http://dx.doi.org/10.1093/eep/dvaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722799PMC
December 2020

DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4.

EBioMedicine 2021 Jan 3;63:103151. Epub 2020 Dec 3.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, 401 Park Drive, West of Landmark Center, Boston, MA 02215, United States.

Background: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints.

Methods: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing.

Findings: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer.

Interpretation: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions.

Funding: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.
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http://dx.doi.org/10.1016/j.ebiom.2020.103151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724153PMC
January 2021

DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.

Genome Med 2020 11 25;12(1):105. Epub 2020 Nov 25.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.

Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.

Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.

Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P = 1; childhood P = 2.00 × 10; adolescence P = 2.10 × 10).

Conclusions: There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
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http://dx.doi.org/10.1186/s13073-020-00810-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687793PMC
November 2020

Associations Between Maternal Lifetime Stress and Placental Mitochondrial DNA Mutations in an Urban Multiethnic Cohort.

Biol Psychiatry 2021 03 18;89(6):570-578. Epub 2020 Sep 18.

Department of Pediatrics and Department of Environmental Medicine & Public Health, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Disrupted placental functioning due to stress can have lifelong implications. Cumulative stress and trauma are likely to have lasting impacts on maternal physiological functioning and offspring development, resulting in increased risk for later-life complex disorders for which racial disparities exist.

Methods: This study examined the association between maternal lifetime stress and placental mitochondrial DNA mutational load in an urban multiethnic cohort. Maternal lifetime exposure to stressful events was assessed using the validated Life Stressor Checklist-Revised. Whole mitochondrial DNA sequencing was performed and mutations were determined for 365 placenta samples with complete exposure and covariate data. Multivariable regression was used to model maternal lifetime stress in relation to placental mitochondrial DNA mutational load. Racial/ethnic differences were examined by cross-product terms and contrast statements. Gene-wise analyses were conducted.

Results: We identified 13,189 heteroplasmies (Phred score > 10,000, minor allele frequency < 0.5, number of mutant reads > 1). Women experiencing increased psychosocial stress over their lifetime exhibited a higher number of total placental mitochondrial mutations (β = .23, 95% confidence interval = .03 to .42) and heteroplasmic mutations (β = .18, 95% confidence interval = .05 to .31) but not homoplasmic mutations (β = -.008, 95% confidence interval = -.03 to .01); the strongest associations were observed among Black women and genes coding for NADH dehydrogenase and cytochrome c oxidase subunits.

Conclusions: Cumulative maternal lifetime stress is associated with a greater mitochondrial mutational load, particularly among Black women. The impact of racial/ethnic differences in mutational load on placental function directly affecting offspring development and/or leading to chronic disease disparities warrants further investigation.
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http://dx.doi.org/10.1016/j.biopsych.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889635PMC
March 2021

Maternal anxiety and depression in pregnancy and DNA methylation of the glucocorticoid receptor gene.

Epigenomics 2020 Nov 20. Epub 2020 Nov 20.

Division of Neonatology, Children's Hospital of Pennsylvania, Philadelphia, PA 19104, USA.

To quantify associations of anxiety and depression during pregnancy with differential cord blood DNA methylation of the glucorticoid receptor (). Pregnancy anxiety, trait anxiety and depressive symptoms were collected using the Pregnancy Related Anxiety Scale, State-Trait Anxiety Index and Edinburgh Postnatal Depression Scale, respectively. methylation was determined at four methylation sites. DNA methylation of CpG 1 in the CpG island shore was higher in infants born to women with high pregnancy anxiety (β 2.54, 95% CI: 0.49-4.58) and trait anxiety (β 1.68, 95% CI: 0.14-3.22). No significant association was found between depressive symptoms and methylation. We found that maternal anxiety was associated with increased CpG island shore methylation.
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http://dx.doi.org/10.2217/epi-2020-0022DOI Listing
November 2020

Association of ambient PM exposure with maternal bone strength in pregnant women from Mexico City: a longitudinal cohort study.

Lancet Planet Health 2020 11;4(11):e530-e537

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.

Background: Pregnancy is associated with deteriorations in maternal bone strength and heightened susceptibility to bone fractures. We aimed to investigate whether ambient particulate matter (PM) concentrations were associated with bone strength during pregnancy.

Methods: In this longitudinal cohort study, we analysed longitudinal data from women participating in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort in Mexico City, Mexico. Eligible women were aged 18 years or older, at less than 20 weeks' gestation at the time of recruitment, planning to stay in Mexico City for the next 3 years, without heart or kidney disease, did not use steroids or anti-epileptic drugs, were not daily consumers of alcohol, and had access to a telephone. Daily ambient PM concentrations were estimated from a spatio-temporal model that was based on the individual's address. Trabecular bone strength was measured using quantitative ultrasound from the radius of the middle finger and cortical bone strength from the proximal phalanx of the middle finger, during the second trimester, third trimester, and 1 and 6 months post partum. Bone strength T scores were modelled with PM concentrations using linear mixed models and distributed lag models.

Findings: Adjusting for multiple exposure windows, each 10 ug/m increase in PM exposure concentrations in the first trimester was associated with a 0·18 SD decrease (95% CI -0·35 to -0·01; p=0·033) in ultrasound speed-of-sound (SOS) T score of trabecular bone strength from the second trimester until 6 months post partum. Similarly, each 10 μg/m increase in third trimester PM exposure was associated with a 0·18 SD decrease (-0·36 to -0·01; p=0·044) in the SOS T score of trabecular bone strength from the third trimester until 6 months post partum. PM exposure in the first month post partum was associated with a 0·20 SD decline (-0·39 to -0·01; p=0·043) in cortical bone strength until 6 months post partum.

Interpretation: Ambient PM exposure during and after pregnancy was associated with diminished trabecular and cortical bone strength. Early pregnancy PM exposure was associated with a greater decline in bone strength later during pregnancy. Late pregnancy and early post-partum exposures adversely affected the post-partum bone strength recovery. Technological and policy solutions to reduce PM pollution could improve public health by reducing bone fracture risk.

Funding: US National Institute of Environmental Health Sciences.
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http://dx.doi.org/10.1016/S2542-5196(20)30220-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664993PMC
November 2020

Associations between daily ambient temperature and sedentary time among children 4-6 years old in Mexico City.

PLoS One 2020 30;15(10):e0241446. Epub 2020 Oct 30.

Department of Environmental Medicine & Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Background: Sedentary behavior is a worldwide public health concern. There is consistent and growing evidence linking sedentary behavior to mortality and morbidity. Early monitoring and assessment of environmental factors associated with sedentary behaviors at a young age are important initial steps for understanding children's sedentary time and identifying pertinent interventions.

Objective: This study examines the association between daily temperature (maximum, mean, minimum, and diurnal variation) and all-day sedentary time among 4-6 year old children in Mexico City (n = 559) from the year 2013 to 2015.

Methods: We developed a spatiotemporally resolved hybrid satellite-based land use regression temperature model and calculated percent daily sedentary time from aggregating 10-second epoch vertical counts captured by accelerometers that participants wore for one week. We modeled generalized additive models (GAMs), one for each temperature type as a covariate (maximum, mean, minimum, and diurnal variation). All GAMs included percent all-day sedentary time as the outcome and participant-level random intercepts to account for repeated measures of sedentary time. Our models were adjusted for demographic factors and environmental exposures.

Results: Daily maximum temperature, mean temperature, and diurnal variation have significant negative linear relationships with all-day sedentary time (p<0.01). There is no significant association between daily minimum temperature and all-day sedentary time. Children have on average 0.26% less daily sedentary time (approximately 2.2 minutes) for each 1°C increase in ambient maximum temperature (range 7.1-30.2°C), 0.27% less daily sedentary time (approximately 2.3 minutes) for each 1°C increase in ambient mean temperature (range 4.3-22.2°C), and 0.23% less daily sedentary time (approximately 2.0 minutes) for each 1°C increase in diurnal variation (range 3.0-21.6°C).

Conclusions: These results are contrary to our hypothesis in which we expected a curvilinear relationship between temperature (maximum, mean, minimum, and diurnal variation) and sedentary time. Our findings suggest that temperature is an important environmental factor that influences children's sedentary behavior.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598506PMC
January 2021

Prenatal maternal phthalate exposures and child lipid and adipokine levels at age six: A study from the PROGRESS cohort of Mexico City.

Environ Res 2021 01 14;192:110341. Epub 2020 Oct 14.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Prenatal phthalate exposures may affect processes that underlie offspring cardiometabolic health, but findings from studies examining these associations are conflicting. We examined associations between biomarkers of phthalate exposures during pregnancy with child lipid and adipokine levels.

Methods: Data were from 463 mother-child pairs in the PROGRESS cohort of Mexico City. We quantified 15 phthalate metabolites in 2nd and 3rd trimester maternal urine samples and created an average pregnancy measure using the geometric mean. We evaluated the 15 metabolites as nine biomarkers, including four metabolite molar sums. We measured fasting serum triglycerides, non-HDL cholesterol, leptin, and adiponectin in children at the six-year follow-up visit (mean = 6.8 years). We estimated associations using linear regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) and assessed effect modification by sex.

Results: In BKMR and WQS models, higher concentrations of the total mixture of phthalate biomarkers were associated with lower triglycerides (β = -3.7% [-6.5, -0.78] per 1 unit increase in WQS biomarker index) and non-HDL cholesterol (β = -2.0 [-3.7, -0.25] ng/ml per increase in WQS biomarker index). Associations between individual biomarkers and child outcomes were largely null. We observed some evidence of effect modification by child sex for mono-3-carboxypropyl phthalate (β = 19.4% [1.26, 40.7] per doubling of phthalate) and monobenzyl phthalate (β = -7.6% [-14.4, -0.23]) in girls for adiponectin.

Conclusions: Individual prenatal phthalate biomarkers were not associated with child lipid or adipokine levels. Contrary to our hypothesis, the total phthalate mixture was associated with lower child triglycerides and non-HDL cholesterol.
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http://dx.doi.org/10.1016/j.envres.2020.110341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736226PMC
January 2021

Associations of Plasma Folate and Vitamin B6 With Blood DNA Methylation Age: An Analysis of One-Carbon Metabolites in the VA Normative Aging Study.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):760-769

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

One-carbon metabolism is an important contributor to aging-related diseases; nevertheless, relationships of one-carbon metabolites with novel DNA methylation-based measures of biological aging remain poorly characterized. We examined relationships of one-carbon metabolites with 3 DNA methylation-based measures of biological aging: DNAmAge, GrimAge, and PhenoAge. We measured plasma levels of 4 common one-carbon metabolites (vitamin B6, vitamin B12, folate, and homocysteine) in 715 VA Normative Aging Study participants with at least 1 visit between 1999 and 2008 (observations = 1153). DNA methylation age metrics were calculated using the HumanMethylation450 BeadChip. We utilized Bayesian Kernel Machine Regression models adjusted for chronological age, lifestyle factors, age-related diseases, and study visits to determine metabolites important to the aging outcomes. Bayesian Kernel Machine Regression models allowed for the estimation of the relationships of single metabolites and the cumulative metabolite mixture with methylation age. Log vitamin B6 was selected as important to PhenoAge (β = -1.62 years, 95% CI: -2.28, -0.96). Log folate was selected as important to GrimAge (β = 0.75 years, 95% CI: 0.41, 1.09) and PhenoAge (β = 1.62 years, 95% CI: 0.95, 2.29). Compared to a model where each metabolite in the mixture is set to its 50th percentile, the log cumulative mixture with each metabolite at its 30th (β = -0.13 years, 95% CI: -0.26, -0.005) and 40th percentile (β = -0.06 years, 95% CI: -0.11, -0.005) was associated with decreased GrimAge. Our results provide novel characterizations of the relationships between one-carbon metabolites and DNA methylation age in a human population study. Further research is required to confirm these findings and establish their generalizability.
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http://dx.doi.org/10.1093/gerona/glaa257DOI Listing
April 2021

Anti-tumor necrosis factor drug responses and skin-blood DNA methylation age: Relationships in moderate-to-severe psoriasis.

Exp Dermatol 2020 Oct 4. Epub 2020 Oct 4.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Studies have examined the utility of DNA methylation as a biomarker of psoriasis treatment responses, but investigations of treatment responses with Skin-Blood DNA methylation age (SkinBloodAge)-a methylation-based measure of health designed using skin tissues-are lacking. Using a HumanMethylation450 BeadChip blood DNA methylation data set from 70 white patients who presented with moderate-to-severe plaque psoriasis and were treated with anti-tumor necrosis factor (TNF) agents in Madrid, Spain, we examined the cross-sectional relationships of SkinBloodAge with anti-TNF treatment responses. Partial responders had a 7.2-year higher mean SkinBloodAge than excellent responders (P = .03). In linear regression models adjusted for chronological age, sex and anti-TNF agents - on average - partial responders had a 2.65-year higher SkinBloodAge than excellent responders (95%CI: 0.44, 4.86, P = .02). This relationship was attenuated in a sensitivity analysis adjusting for white blood cells including known T-cell mediators of psoriasis pathophysiology (β = 1.91-years, 95%CI: -0.50, 4.32, P = .12). Overall, our study suggests that partial responders to anti-TNF therapy have higher SkinBloodAges when compared to excellent responders. Although these findings still need to be confirmed more broadly, they further suggest that SkinBloodAge may be a useful treatment response biomarker that can be incorporated with other blood tests before anti-TNF therapy initiation in moderate-to-severe psoriasis patients.
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http://dx.doi.org/10.1111/exd.14207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058824PMC
October 2020