Andrea Baccarelli

Massachusetts Department of Public Health, Boston, Massachusetts, United States

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Publications (293)1423.76 Total impact

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    Andrea A Baccarelli · Hyang-Min Byun
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    ABSTRACT: Platelets are critical in the etiology of cardiovascular disease (CVD), and the mitochondria in these cells serve as an energy source for platelet function. Epigenetic factors, especially DNA methylation, have been employed as markers of CVD. Unlike nuclear DNA methylation, mitochondrial DNA (mtDNA) methylation has not been widely studied, in part, due to debate about its existence and role. In this study, we examined platelet mtDNA methylation in relation to CVD. We measured mtDNA methylation in platelets by bisulfite-PCR pyrosequencing and examined associations of CVD with methylation in mitochondrial genes; cytochrome c oxidase (MT-CO1, MT-CO2, and MT-CO3); tRNA leucine 1 (MT-TL1); ATP synthase (MT-ATP6 and MT-ATP8); and NADH dehydrogenase (MT-MD5). We report that CVD patients have significantly higher mtDNA methylation than healthy controls in MT-CO1 (18.53%, P < 0.0001), MT-CO2 (3.33%, P = 0.0001), MT-CO3 (0.92%, P < 0.0001), and MT-TL1 (1.67%, P = 0.0001), which are involved in ATP synthesis. Platelet mtDNA methylation was not related with age, BMI, and race in this study. Our results suggest that platelet mtDNA methylation, which could serve as non-invasive and easy-to-obtain markers, may be implicated in the etiology of CVD.
    Clinical Epigenetics 12/2015; 7(1). DOI:10.1186/s13148-015-0078-0 · 6.22 Impact Factor
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    ABSTRACT: Chronic inflammation plays a key role in cancer etiology. DNA methylation modification, one of the epigenetic mechanisms regulating gene expression, is considered a hallmark of cancer. Human and animal models have identified numerous links between DNA methylation and inflammatory biomarkers. Our objective was to prospectively and longitudinally examine associations between methylation of four inflammatory genes and cancer risk. We included 795 Normative Aging Study participants with blood drawn 1-4 times from 1999-2012 (median follow up 10.6 years). Promoter DNA methylation of IL-6, ICAM-1, IFN, and TLR2 in blood leukocytes was measured using pyrosequencing at multiple CpG sites and averaged by gene for data analysis. We used Cox regression models to examine prospective associations of baseline and time-dependent methylation with cancer risk, and compared mean methylation differences over time between cancer cases and cancer-free participants. Baseline IFN hypermethylation was associated with all-cancer (HR=1.49, p=0.04) and prostate cancer incidence (HR=1.69, p=0.02). Baseline ICAM-1 and IL-6 hypermethylation were associated with prostate cancer incidence (HR=1.43, p=0.02; HR=0.70, p=0.03 respectively). In our time-dependent analyses, IFN hypermethylation was associated with all-cancer (HR=1.79, p=0.007) and prostate cancer (HR=1.57, p=0.03) incidence; and ICAM-1 and IL-6 hypermethylation were associated with prostate cancer incidence (HR=1.39, p=0.02; HR=0.69, p=0.03 respectively). We detected significant ICAM-1 hypermethylation in cancer cases (p=0.0003) 10-13 years pre-diagnosis. Hypermethylation of IFN and ICAM-1 may play important roles in early carcinogenesis, particularly that of prostate cancer. These methylation changes could inform the development of early detection biomarkers and potential treatments of inflammation-related carcinogenesis. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 08/2015; DOI:10.1158/1055-9965.EPI-15-0198 · 4.32 Impact Factor
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    ABSTRACT: Prenatal smoke exposure, maternal obesity, aberrant fetal growth, and preterm birth are all risk factors for offspring metabolic syndrome. Cord blood aryl-hydrocarbon receptor repressor (AHRR) DNA methylation is responsive to maternal smoking during pregnancy. AHRR serves not only to inhibit aryl-hydrocarbon receptor (AHR) transcription, which is involved in mediating xenobiotic metabolism, but it is also involved in cell growth and differentiation. Other than maternal smoking, other predictors of offspring AHRR DNA methylation status remain unknown; we sought to identify them among newborns. We enrolled pregnant women in the PROGRESS birth cohort in Mexico City. Using pyrosequencing, we analyzed DNA methylation of three CpG sites within the AHRR gene promoter from the umbilical cord blood of 531 infants. We used generalized estimating equations to account for the correlation of DNA methylation between CpG sites. Multivariable models were used to adjust for maternal age, BMI, education, parity, smoke-exposure, infant sex, gestational age, and birth weight-for-gestational age. AHRR DNA methylation was positively associated with maternal BMI (P=0.0009) and negatively associated with the length of gestation (P<0.0001) and birth weight-for-gestational age (P<0.0001). AHRR DNA methylation was 2.1% higher in offspring of obese vs. normal weight mothers and 3.1 higher in preterm vs. term infants, representing a third and a half standard deviation differences in methylation. In conclusion, offspring AHRR DNA methylation was associated with maternal obesity during pregnancy as well as infant gestational age and birth weight-for-gestational age. Further work to discover the health impacts of altered AHRR DNA methylation is warranted.
    Epigenetics: official journal of the DNA Methylation Society 08/2015; DOI:10.1080/15592294.2015.1078963 · 5.11 Impact Factor
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    ABSTRACT: Short-term exposure to particulate matter (PM) is associated with increased blood pressure (BP) in epidemiological studies. Understanding the impact of specific PM components on BP is essential in developing effective risk-reduction strategies. We investigated the association between endotoxin and β-1,3-d-Glucan-two major biological PM components-and BP. We also examined whether vascular endothelial growth factor, a vasodilatory inflammatory marker, modified these associations. We conducted a single-blind, randomized, crossover trial of controlled human exposure to concentrated ambient particles with 50 healthy adults. Particle-associated-endotoxin and β-1,3-d-Glucan were sampled using polycarbonate-membrane-filters. Supine resting systolic BP and diastolic BP were measured pre-, 0.5-hour post-, and 20-hour postexposure. Urine vascular endothelial growth factor concentration was determined using enzyme-linked immunosorbant assay and creatinine-corrected. Exposures to endotoxin and β-1,3-d-Glucan for 130 minutes were associated with increases in BPs: at 0.5-hour postexposure, every doubling in endotoxin concentration was associated with 1.73 mm Hg higher systolic BP (95% confidence interval, 0.28, 3.18; P=0.02) and 2.07 mm Hg higher diastolic BP (95% confidence interval, 0.74, 3.39; P=0.003); every doubling in β-1,3-d-Glucan concentration was associated with 0.80 mm Hg higher systolic BP (95% confidence interval, -0.07, 1.67; P=0.07) and 0.88 mm Hg higher diastolic BP (95% confidence interval, 0.09, 1.66; P=0.03). Vascular endothelial growth factor rose after concentrated ambient particle endotoxin exposure and attenuated the association between endotoxin and 0.5-hour postexposure diastolic BP (Pinteraction=0.02). In healthy adults, short-term endotoxin and β-1,3-d-Glucan exposures were associated with increased BP. Our findings suggest that the biological PM components contribute to PM-related cardiovascular outcomes, and postexposure vascular endothelial growth factor elevation might be an adaptive response that attenuates these effects. © 2015 American Heart Association, Inc.
    Hypertension 06/2015; DOI:10.1161/HYPERTENSIONAHA.115.05342 · 7.63 Impact Factor
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    ABSTRACT: To examine the association of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anthropometry in the offspring of mothers with gestational diabetes mellitus (GDM). We performed a retrospective cohort study in 1263 GDM mother-child pairs. General linear models and Logistic regression models were used to assess the single and joint associations of maternal pre-pregnancy BMI (normal weight, overweight, and obesity) and GWG (inadequate, adequate and excessive GWG) with anthropometry and overweight status in the offspring from birth to 1-5 years old. Maternal pre-pregnancy BMI and GWG were positively associated with birth weight for gestational age Z score and birth weight for length for gestational age Z score at birth, and weight for age Z score, length/height for age Z score, and weight for length/height Z score at of 1-5 years old offspring. Maternal pre-pregnancy overweight, obesity, and excessive GWG were associated with increased risks of large for gestational age [ORs 95% CIs = 1.87 (1.37-2.55), 2.98 (1.89-4.69), and 2.93 (2.07-4.13), respectively] and macrosomia [ORs 95% CIs = 2.06 (1.50-2.84), 2.89 (1.78-4.70), and 2.84 (1.98-4.06), respectively] at birth and childhood overweight at 1-5 years old [ORs 95% CIs = 1.26 (0.92-1.73), 1.96 (1.24-3.09), and 1.59 (1.15-2.21), respectively]. Offspring born to GDM mothers with pre-pregnancy overweight/obesity or excessive GWG were associated with increased risks of large for gestational age and macrosomia at birth, and childhood overweight at 1-5 years old, compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG.
    PLoS ONE 06/2015; 10(6):e0129536. DOI:10.1371/journal.pone.0129536 · 3.23 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are post-transcriptional gene suppressors and potential mediators of environmental effects. In addition to human miRNAs, viral miRNAs expressed from latent viral sequences are detectable in human cells. In a highly exposed population in Beijing, China, we evaluated the associations of particulate air pollution exposure on blood miRNA profiles. The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers. We investigated associations of short-term air pollution exposure, using measures of personal PM2.5 and (Elemental Carbon) EC, and ambient PM10, with blood NanoString-nCounter miRNA profiles at two exams separated by one to two weeks. No miRNA was significantly associated with personal PM2.5 at a false discovery rate (FDR) of 20%. Short-term ambient PM10 was associated with the expression of 12 miRNAs in office workers only (FDR <20%). Short-term EC was associated with differential expression of 46 human and seven viral miRNAs, the latter including three and four viral miRNAs in office workers and truck drivers, respectively. EC-associated miRNAs differed between office workers and truck drivers with significant effect modification by occupational group. Functional interaction network analysis suggested enriched cellular proliferation/differentiation pathways in truck drivers and pro-inflammation pathways in office workers. Short-term EC exposure was associated with the expression of human and viral miRNAs that may influence immune responses and other biological pathways. Associations between EC exposure and viral miRNA expression suggest that latent viral miRNAs are potential mediators of air pollution-associated health effects. PM2.5/PM10 exposures showed no consistent relationships with miRNA expression.
    Environmental Health Perspectives 06/2015; DOI:10.1289/ehp.1408519 · 7.98 Impact Factor
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    ABSTRACT: Recent advances in estimating fine particle (PM2.5) ambient concentrations use daily satellite measurements of aerosol optical depth (AOD) for spatially and temporally resolved exposure estimates. Mexico City is a dense megacity that differs from other previously modeled regions in several ways: it has bright land surfaces, a distinctive climatological cycle, and an elevated semi-enclosed air basin with a unique planetary boundary layer dynamic. We extend our previous satellite methodology to the Mexico City area, a region with higher PM2.5 than most US and European urban areas. Using a novel 1 km resolution AOD product from the MODIS instrument, we constructed daily predictions across the greater Mexico City area for 2004-2014. We calibrated the association of AOD to PM2.5 daily using municipal ground monitors, land use, and meteorological features. Predictions used spatial and temporal smoothing to estimate AOD when satellite data were missing. Our model performed well, resulting in an out-of-sample cross validation R2 of 0.724. Cross-validated root mean squared prediction error (RMSPE) of the model was 5.55 μg/m3. This novel model reconstructs long- and short-term spatially resolved exposure to PM2.5 for epidemiological studies in Mexico City.
    Environmental Science & Technology 06/2015; 49(14). DOI:10.1021/acs.est.5b00859 · 5.48 Impact Factor
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    ABSTRACT: Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), though the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E Prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of AERD subjects resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P<0.0001 at 1µM) compared with nasal fibroblasts from aspirin tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from AERD subjects than in fibroblasts from healthy controls and aspirin-tolerant subjects (P<0.01 for both). Treatment of the fibroblasts with trichostatin A (TSA), a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects, but had no effect on COX-2, EP4 and mPGES1 mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r=0.80, P<0.01). These studies suggest that the EP2 promotor is under epigenetic control and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression which could contribute to the refractory nasal polyposis typically observed in this syndrome.
    American Journal of Respiratory Cell and Molecular Biology 06/2015; DOI:10.1165/rcmb.2014-0486OC · 4.11 Impact Factor
  • Kelly J Brunst · Andrea A Baccarelli · Rosalind J Wright
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    ABSTRACT: The amount of scientific research linking environmental exposures and childhood health outcomes continues to grow; yet few studies have teased out the mechanisms involved in environmentally-induced diseases. Cells can respond to environmental stressors in many ways: inducing oxidative stress/inflammation, changes in energy production and epigenetic alterations. Mitochondria, tiny organelles that each retains their own DNA, are exquisitely sensitive to environmental insults and are thought to be central players in these pathways. While it is intuitive that mitochondria play an important role in disease processes, given that every cell of our body is dependent on energy metabolism, it is less clear how environmental exposures impact mitochondrial mechanisms that may lead to enhanced risk of disease. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in children's environmental health, (ii) why environmental mitochondriomics is well suited to biomarker development in this context, and (iii) how molecular and epigenetic changes in mitochondria and mitochondrial DNA (mtDNA) may reflect exposures linked to childhood health outcomes. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 06/2015; DOI:10.1002/jat.3182 · 3.17 Impact Factor
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    ABSTRACT: Prenatal exposure to neurotoxicants such as Lead (Pb) may cause stable changes in the DNA methylation (5mC) profile of the fetal genome. However few studies have examined its effect on the DNA de-methylation pathway, specifically the dynamic changes of the 5-hydroxymethylcytosine (5hmC) profile. Therefore, in this study, we investigate the relationship between Pb exposure and 5mC and 5hmC modifications during early development. To study the changes in the 5hmC profile, we use a novel modification of the Infinium™ Human methylation 450K assay (Illumina, Inc.), which we named HMeDIP-450K assay, in an in vitro human embryonic stem cell model of Pb-exposure. We model Pb-exposure associated 5hmC changes as clusters of correlated, adjacent CpG sites, which are co-responding to Pb. We further extend our study to look at Pb-dependent changes in high density 5hmC regions in umbilical cord blood DNA from 48 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort. For our study, we randomly selected UCB from 24 male and 24 female children from the 1st and 4th quartiles of Pb levels. Our data show that Pb-associated changes in the 5hmC and 5mC profiles can be divided into sex-dependent and sex-independent categories. Interestingly, differential 5mC sites are better markers of Pb-associated sex-dependent changes compared to differential 5hmC sites. In this study we identified several 5hmC and 5mC genomic loci, which we believe might have some potential as early biomarkers of prenatal Pb-exposure.
    Epigenetics: official journal of the DNA Methylation Society 06/2015; 10(7). DOI:10.1080/15592294.2015.1050172 · 5.11 Impact Factor
  • The Journal of allergy and clinical immunology 05/2015; DOI:10.1016/j.jaci.2015.04.032 · 11.25 Impact Factor
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    ABSTRACT: Most research to date has focused on epigenetic modifications in the nuclear genome, with little attention devoted to mitochondrial DNA (mtDNA). Placental mtDNA content has been shown to respond to environmental exposures that induce oxidative stress, including airborne particulate matter (PM). Damaged or non-functioning mitochondria are specifically degraded through mitophagy, exemplified by lower mtDNA content, and could be primed by epigenetic modifications in the mtDNA. We studied placental mtDNA methylation in the context of the early life exposome. We investigated placental tissue from 381 mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. We determined mtDNA methylation by bisulfite-pyrosequencing in two regions, i.e., the D-loop control region and 12S ribosomal RNA (MT-RNR1), and measured mtDNA content by qPCR. PM2.5 exposure was calculated for each participant's home address using a dispersion model. An interquartile range (IQR) increment in PM2.5 exposure over the entire pregnancy was positively associated with mtDNA methylation (MT-RNR1: +0.91%, P = 0.01 and D-loop: +0.21%, P = 0.05) and inversely associated with mtDNA content (relative change of -15.60%, P = 0.001) in placental tissue. mtDNA methylation was estimated to mediate 54% [P = 0.01 (MT-RNR1)] and 27% [P = 0.06 (D-loop)] of the inverse association between PM2.5 exposure and mtDNA content. This study provides new insight into the mechanisms of altered mitochondrial function in the early life environment. Epigenetic modifications in the mitochondrial genome, especially in the MT-RNR1 region, substantially mediate the association between PM2.5 exposure during gestation and placental mtDNA content, which could reflect signs of mitophagy and mitochondrial death.
    Epigenetics: official journal of the DNA Methylation Society 05/2015; 10(6). DOI:10.1080/15592294.2015.1048412 · 5.11 Impact Factor
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    ABSTRACT: Previous studies have reported epigenetic changes induced by environmental exposures. However, previous investigations did not distinguish 5-methylcytosine (5mC) from a similar oxidative form with opposite functions, 5-hydroxymethylcytosine (5hmC). Here, we measured blood DNA global 5mC and 5hmC by ELISA and used adjusted mixed-effects regression models to evaluate the effects of ambient PM10 and personal PM2.5 and its elemental components-black carbon (BC), aluminum (Al), calcium (Ca), potassium (K), iron (Fe), sulfur (S), silicon (Si), titanium (Ti), and zinc (Zn)-on blood global 5mC and 5hmC levels. The study was conducted in 60 truck drivers and 60 office workers in Beijing, China from The Beijing Truck Driver Air Pollution Study at two exams separated by one to two weeks. Blood 5hmC level (0.08%) was ˜83-fold lower than 5mC (6.61%). An inter-quartile range (IQR) increase in same-day PM10 was associated with increases in 5hmC of 26.1% in office workers (P=0.004), 20.2% in truck drivers (P=0.014), and 21.9% in all participants combined (P<0.001). PM10 effects on 5hmC were increasingly stronger when averaged over 4, 7, and 14 days preceding assessment (up to 132.6% for the 14-day average in all participants, P<0.001). PM10 effects were also significant after controlling for multiple testing (family-wise error rate; FWER<0.05). 5hmC was not correlated with personal measures of PM2.5 and elemental components (FWER>0.05). 5mC showed no correlations with PM10, PM2.5, and elemental components measures (FWER>0.05). Our study suggests that exposure to ambient PM10 affects 5hmC over time, but not 5mC. This finding demonstrates the need to differentiate 5hmC and 5mC in environmental studies of DNA methylation.
    Epigenetics: official journal of the DNA Methylation Society 05/2015; 10(7). DOI:10.1080/15592294.2015.1050174 · 5.11 Impact Factor
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    ABSTRACT: Pulmonary embolism (PE) is the most serious manifestation of venous thromboembolism and a leading cause of sudden death. Several studies have suggested associations of venous thromboembolism with short-term particulate matter (PM) exposure; evidence on long-term PM and traffic exposure is mixed. We examined the association of long-term exposure to PM2.5, PM2.5-10 and PM10, and distance to roadways with overall incident PE and with PE subtypes in a cohort of US women. The study included 115,745 women from the Nurses' Health Study, followed from 1992-2008. Incident PE cases were self-reported biennially. Nonidiopathic PE were cases for which the medical record revealed an underlying health condition related to PE (i.e., surgery, trauma or malignancy); idiopathic PE were cases with no such history. We used spatiotemporal models combining spatial smoothing and geographic covariates to quantify exposure at residential addresses, and Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI). PM2.5 averaged over 1 month (HR=1.22, 95% CI: 1.04, 1.44) or 12 months (HR=1.17, 95% CI: 0.93, 1.48) was associated with incident PE, after adjusting for known risk factors and PM2.5-10. Equivalent analyses restricted to PE subtypes showed a positive association for PM2.5 with nonidiopathic PE, but not with idiopathic PE. We did not find evidence of an association between distance to roadways and PE risk. We provide evidence that PM in the prior 1 and 12 months is associated with PE risk. Our results also suggest that women with underlying health conditions may be more susceptible to PE after PM exposure.
    Environmental Health Perspectives 05/2015; DOI:10.1289/ehp.1408927 · 7.98 Impact Factor
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    ABSTRACT: CYP2E1 is a versatile phase I drug-metabolizing enzyme responsible for the biotransformation of most volatile organic compounds, including toluene. Human toluene exposure increase CYP2E1 mRNA and modifies its activity in leucocytes; however, epigenetic implications of this interaction have not been investigated. To determine promoter methylation of CYP2E1 and other genes known to be affected by toluene exposure. We obtained venous blood from 24 tannery workers exposed to toluene (mean levels: 10.86 +/- 7mg/m(3)) and 24 administrative workers (reference group, mean levels 0.21 +/- 0.02mg/m(3)) all of them from the city of León, Guanajuato, México. After DNA extraction and bisulfite treatment, we performed PCR-Pyrosequencing in order to measure methylation levels at promoter region of 13 genes. In exposed group we found significant correlations between toluene airborne levels and CYP2E1 promoter methylation (r=-.36, p<0.05), as well as for IL6 promoter methylation levels (r=.44, p<0.05). Moreover, CYP2E1 promoter methylation levels where higher in toluene-exposed smokers compared to non smokers (p=0.009). We also observed significant correlations for CYP2E1 promoter methylation with GSTP1 and SOD1 promoter methylation levels (r=-.37, p<0.05 and r=-.34, p<0.05 respectively). These results highlight the importance of considering CYP2E1 epigenetic modifications, as well as its interactions with other genes, as key factors for unraveling the sub cellular mechanisms of toxicity exerted by oxidative stress, which can initiate disease process in chronic, low-level toluene exposure. People co-exposed to toluene and tobacco smoke are in higher risk due to a possible CYP2E1 repression. Copyright © 2015. Published by Elsevier Inc.
    Toxicology and Applied Pharmacology 05/2015; 286(3). DOI:10.1016/j.taap.2015.04.016 · 3.63 Impact Factor
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    ABSTRACT: Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence. We included 792 Normative Aging Study participants with 1-4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis. Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (pdifference = 0.017); all participants had similar age-adjusted BTL 8-14 years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p = 0.003) and four (p = 0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR = 1.79, p = 0.03), and longer BTL measured ≤ 4 years pre-diagnosis with any (OR = 3.27, p < 0.001) and prostate cancers (OR = 6.87, p < 0.001). Age-related BTL attrition was faster in cancer cases but their age-adjusted BTL attrition began decelerating as diagnosis approached. This may explain prior inconsistencies and help develop BTL as a cancer detection biomarker.
    04/2015; 63(6). DOI:10.1016/j.ebiom.2015.04.008
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    2015 New England Science Symposium, Joseph B. Martin Conference Center, Harvard Medical School; 04/2015
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    ABSTRACT: Air pollution has been related to mean changes in outcomes, including DNA methylation. However, mean regression analyses may not capture associations that occur primarily in the tails of the outcome distribution. This study examined whether the association between particulate air pollution and DNA methylation differs across quantiles of the methylation distribution. We focused on methylation of candidate genes related to coagulation and inflammation: coagulation factor III (F3), intercellular adhesion molecule 1 (ICAM-1), interferon gamma (IFN-γ), interleukin-6 (IL-6), and toll-like receptor 2 (TRL-2). We measured gene-specific blood DNA methylation repeatedly in 777 elderly men participating in the Normative Aging Study (1999-2010). We fit quantile regressions for longitudinal data to investigate whether the associations of particle number, PM2.5 black carbon, and PM2.5 mass concentrations (4-weeks moving average) with DNA methylation [expressed as the percentage of methylated cytosines over the sum of methylated and unmethylated cytosines at position 5 (%5mC)] varied across deciles of the methylation distribution. We reported the quantile regression coefficients which corresponded to absolute differences in DNA methylation (expressed in %5mC) associated with an interquartile range increase in air pollution concentration. Interquartile range increases in particle number, PM2.5 black carbon, and PM2.5 mass concentrations were associated with significantly lower methylation in the lower tails of the IFN-γ and ICAM-1 methylation distributions. For instance, a 3.4 µg/m(3) increase in PM2.5 mass concentration was associated with a 0.18%5mC (95% CI: -0.30, -0.06) decrease on the 20th percentile of ICAM-1 methylation, but was not significantly related to the 80th percentile (Estimate: 0.07%5mC, 95% CI: -0.09, 0.24). In our study population of older men, air pollution exposures were associated with a left shift in the lower tails of the IFN-γ and ICAM-1 methylation distributions.
    Environmental Health Perspectives 03/2015; DOI:10.1289/ehp.1307824 · 7.98 Impact Factor
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    ABSTRACT: BACKGROUND Single-nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism, and skin cancer genes might influence susceptibility to arsenic-induced skin lesions.METHODSA case-control study was conducted in Pabna, Bangladesh (2001-2003), and the drinking-water arsenic concentration was measured for each participant. A panel of 25 candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in the skin lesion risk, with adjustments for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls.RESULTSIn the discovery population, genetic variants in the one-carbon metabolism genes phosphatidylethanolamine N-methyltransferase (rs2278952, P for interaction = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene interleukin 10 (rs3024496, P for interaction = .04), and the skin cancer genes inositol polyphosphate-5-phosphatase (INPP5A; rs1133400, P for interaction = .03) and xeroderma pigmentosum complementation group C (rs2228000, P for interaction = .01) significantly modified the association between arsenic and skin lesions after adjustments for multiple comparisons. The significant gene-environment interaction between a SNP in the INPP5A gene (rs1133400) and water arsenic with respect to the skin lesion risk was successfully replicated in an independent population (P for interaction = .03).CONCLUSIONS Minor allele carriers of the skin cancer gene INPP5A modified the odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity. Cancer 2015. © 2015 American Cancer Society.
    Cancer 03/2015; 121(13). DOI:10.1002/cncr.29291 · 4.90 Impact Factor
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    ABSTRACT: Recently the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also the approach used to perform these evaluations. Some critics have claimed that IARC Working Groups' failures to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. The authors of this paper are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We have examined here criticisms of the IARC classification process to determine the validity of these concerns. We review the history of IARC evaluations and describe how the IARC evaluations are performed. We conclude that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various discipline and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.
    Environmental Health Perspectives 02/2015; DOI:10.1289/ehp.1409149 · 7.98 Impact Factor

Publication Stats

7k Citations
1,423.76 Total Impact Points

Institutions

  • 2011–2015
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 2007–2015
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Harvard University
      • Department of Environmental Health
      Cambridge, Massachusetts, United States
  • 2000–2014
    • University of Milan
      • • Department of Occupational and Environmental Health
      • • Department of Medical Sciences
      Milano, Lombardy, Italy
  • 2013
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2012
    • Università degli Studi di Sassari
      Sassari, Sardinia, Italy
    • Boston College, USA
      Boston, Massachusetts, United States
  • 2009–2012
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      • Occupational Medicine 1
      Milano, Lombardy, Italy
  • 2008
    • Ospedale Maggiore Carlo Alberto Pizzardi di Bologna
      Bolonia, Emilia-Romagna, Italy
  • 2002–2008
    • National Institutes of Health
      • • Division of Cancer Epidemiology and Genetics
      • • Branch of Genetic Epidemiology
      Maryland, United States
  • 2004–2006
    • National Cancer Institute (USA)
      • • Division of Cancer Epidemiology and Genetics
      • • Genetic Epidemiology
      Bethesda, MD, United States
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy
  • 2001–2004
    • NCI-Frederick
      Maryland, United States