Faculty Bibliography

Growing evidence suggests that environmental exposures can influence blood pressure over the course of a lifetime. Exposure to toxic metals, such as lead (Pb) and arsenic (As), has been associated with increased blood pressure in adults, but few studies have examined the impacts of in utero and early life toxic metals exposure on blood pressure in childhood. As subclinical vascular changes are thought to begin early in life, it is possible that in utero toxic metals exposure may play a role in blood pressure homeostasis. In the ongoing New Hampshire Birth Cohort Study, we investigated whether in utero exposure to Pb and As was associated with measures of blood pressure in a total of 323 young children (mean age 5.5 years, SD 0.4). Pb and As were measured in maternal toenail samples collected at ~28 weeks gestation (n = 257) and/or 6 weeks postpartum (n = 285), which represent exposures ~6 to 12 months prior to collection and therefore reflect the early prenatal and late prenatal exposures, respectively. Five measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were averaged for each child using a standardized technique. In linear regression analyses, where log₂-transformed prenatal toenail Pb and As were modeled jointly and adjusted for child age, sex, height, weight and maternal smoking during pregnancy, we observed that a doubling of maternal prenatal toenail Pb was associated with statistically significant increases in child SBP (β: 0.58 mm Hg, 95% CI: 0.05, 1.11). We did not observe any association of prenatal or postpartum As, or postpartum Pb, with SBP or DBP. Exploratory sex-stratified analyses suggest that associations of prenatal Pb with BP may be stronger among boys (SBP β: 0.72 mm Hg: 95% CI: -0.01, 1.44; DBP β: 0.37; 95% CI: -0.09, 0.84), compared to girls (SBP β: 0.48 mm Hg: 95% CI: -0.31, 1.26; DBP β: -0.05; 95% CI: -0.52, 0.41), though tests for interaction did not reach statistical significance (p-interaction SBP = 0.059; DBP = 0.057). Our preliminary results suggest that in utero toxic metals exposures may be associated with early life increases in blood pressure in children, which could have consequences for long-term health.

Importance/UNASSIGNED:The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation. Objective/UNASSIGNED:To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics. Design, Setting, and Participants/UNASSIGNED:This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017. Exposures/UNASSIGNED:Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years. Main Outcomes and Measures/UNASSIGNED:Invasive or in situ premenopausal breast cancer. Results/UNASSIGNED:Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall. Conclusions and Relevance/UNASSIGNED:The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.

PURPOSE/OBJECTIVE:The soluble receptor for advanced glycation end-products (sRAGE) and endogenous secretory RAGE (esRAGE) have been considered as biomarkers of several chronic diseases. However, the temporal reliability of their concentrations in the circulation is yet to be demonstrated. We evaluated whether a single measurement of serum sRAGE and esRAGE could serve as an estimate for usual serum levels in epidemiologic studies. METHODS:Serum sRAGE and esRAGE were measured using ELISAs in three yearly samples from 36 participants in the New York University Women's Health Study. The intraclass correlation coefficient (ICC) was used to evaluate temporal reliability. RESULTS:-transformed data. CONCLUSION/CONCLUSIONS:Our results indicate that a single measurement of serum sRAGE and esRAGE is a sufficiently reliable measure of their usual levels that can be used in epidemiologic studies.

Background: Antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG) proteins, especially pilus protein Gallo2178, have been consistently associated with colorectal cancer risk. Previous case-control studies and prospective studies with up to 8 years of follow-up, however, were unable to decipher the temporality of antibody responses to SGG in the context of the long-term multistep development of colorectal cancer. In this study, we analyzed a large U.S. colorectal cancer cohort consortium with follow-up beyond 10 years for antibody responses to SGG.Methods: We applied multiplex serology to measure antibody responses to 9 SGG proteins in participants of 10 prospective U.S. cohorts (CLUE, CPSII, HPFS, MEC, NHS, NYUWHS, PHS, PLCO, SCCS, and WHI) including 4,063 incident colorectal cancer cases and 4,063 matched controls. Conditional logistic regression was used to assess whether antibody responses to SGG were associated with colorectal cancer risk, overall and by time between blood draw and diagnosis.Results: Colorectal cancer risk was increased among those with antibody responses to Gallo2178, albeit not statistically significant [OR, 1.23; 95% confidence interval (CI), 0.99-1.52]. This association was stronger for cases diagnosed <10 years after blood draw (OR, 1.40; 95% CI, 1.09-1.79), but was not found among cases diagnosed ≥10 years after blood draw (OR, 0.79; 95% CI, 0.50-1.24).Conclusions: In a large cohort consortium, we reproduced the association of antibody responses to SGG Gallo2178 with colorectal cancer risk for individuals diagnosed within 10 years after blood draw.Impact: This timing-specific finding suggests that antibody responses to SGG are associated with increased colorectal cancer risk only after tumorigenesis has begun. Cancer Epidemiol Biomarkers Prev; 27(10); 1186-94. ©2018 AACR.

BACKGROUND:Multiple myeloma (MM) patients with t(14;20) have a poor prognosis and their outcome has not improved following the introduction of bortezomib (Bzb). The mechanism underlying the resistance to proteasome inhibitors (PIs) for this subset of patients is unknown. METHODS:IC50 of Bzb and carfilzomib (CFZ) in human myeloma cell lines (HMCLs) were established by MTT assay. Gene Expression profile (GEP) analysis was used to determine gene expression in primary myeloma cells. Immunoblotting analysis was performed for MAFb and caspase family proteins. Immunofluorescence staining was used to detect the location of MAFb protein in MM cells. Lentiviral infections were used to knock-down MAFb expression in two lines. Apoptosis detection by flow cytometry and western blot analysis was performed to determine the molecular mechanism MAFb confers resistance to proteasome inhibitors. RESULTS:We found high levels of MAFb protein in cell lines with t(14;20), in one line with t(6;20), in one with Igλ insertion into MAFb locus, and in primary plasma cells from MM patients with t(14;20). High MAFb protein levels correlated with higher IC50s of PIs in MM cells. Inhibition of GSK3β activity or treatment with Bzb or CFZ prevented MAFb protein degradation without affecting the corresponding mRNA level indicating a role for GSK3 and proteasome inhibitors in regulation of MAFb stability. Silencing MAFb restored sensitivity to Bzb and CFZ, and enhanced PIs-induced apoptosis and activation of caspase-3, - 8, - 9, PARP and lamin A/C suggesting that high expression of MAFb protein leads to insensitivity to proteasome inhibitors. CONCLUSION/CONCLUSIONS:These results highlight the role of post-translational modification of MAFb in maintaining its protein level, and identify a mechanism by which proteasome inhibitors induced stabilization of MAFb confers resistance to proteasome inhibitors, and provide a rationale for the development of targeted therapeutic strategies for this subset of patients.

BACKGROUND:Chronic exposure to inorganic arsenic from drinking water has been associated with a host of cancer and noncancer diseases. The application of metabolomics in epidemiologic studies may allow researchers to identify biomarkers associated with arsenic exposure and its health effects. OBJECTIVE:Our goal was to evaluate the long-term reproducibility of urinary metabolites and associations between reproducible metabolites and arsenic exposure. METHODS:We studied samples and data from 112 nonsmoking participants (58 men and 54 women) who were free of any major chronic diseases and who were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS), a large prospective cohort study in Bangladesh. Using a global gas chromatography-mass spectrometry platform, we measured metabolites in their urine samples, which were collected at baseline and again 2 y apart, and estimated intraclass correlation coefficients (ICCs). Linear regression was used to assess the association between arsenic exposure at baseline and metabolite levels in baseline urine samples. RESULTS:We identified 2,519 molecular features that were present in all 224 urine samples from the 112 participants, of which 301 had an ICC of ≥0.60. Of the 301 molecular features, water arsenic was significantly related to 31 molecular features and urinary arsenic was significantly related to 74 molecular features after adjusting for multiple comparisons. Six metabolites with a confirmed identity were identified from the 82 molecular features that were significantly associated with either water arsenic or urinary arsenic after adjustment for multiple comparisons. CONCLUSIONS:Our study identified urinary metabolites with long-term reproducibility that were associated with arsenic exposure. The data established the feasibility of using metabolomics in future larger studies. https://doi.org/10.1289/EHP1992.

Previous studies on the association between number of children and carotid intima-media thickness (cIMT) were limited to Western populations. Pregnancy in women is associated with physiologic changes that may influence the risk of cardiovascular disease. Comparing the association between number of children and cIMT in men and women can provide insights on whether the association may be due to pregnancy. We investigated the association between number of children and cIMT among 718 female (mean age 37.5 years) and 417 male participants (mean age 41.3 years), randomly selected from the Health Effect of Arsenic Longitudinal Study (HEALS), a population-based cohort study in Bangladesh. Multivariate linear regression was used to assess the association and to control for education attainment, history of diabetes, age, smoking, betel use, BMI, systolic blood pressure, and diastolic blood pressure. The average number of children was 4.43 for women and 3.74 for men. There were no nulliparous women. We observed a positive association between number of children and cIMT in women. Mean cIMT increased by 4.5 μm (95% CI, 0.8-8.1) per increment of one birth (P = 0.02). Compared to women with two children, cIMT in women with 4 children and ≥5 children was 23.6μm (95%CI, 2.6-44.7; P = 0.03) and 25.1 μm (95%CI, 3.5-46.6; P = 0.02) greater, respectively. The association was not modified by BMI, SBP, betel use or age. Data in men showed no evidence of association (P = 0.4). The finding suggests a role of high parity in atherosclerosis in women of a low-income, high parity population.

BACKGROUND:Arsenic (As) exposure has been associated with increased risk for cardiovascular disease (CVD) and with biomarkers of potential CVD risk and inflammatory processes. However, few studies have evaluated the effects of As on such biomarkers in U.S. populations, which are typically exposed to low to moderate As concentrations. OBJECTIVES/OBJECTIVE:We investigated associations between As exposures and biomarkers relevant to inflammation, oxidative stress, and CVD risk in a subset of participants from the New Hampshire Health Study, a population with low to moderate As exposure (n=418). METHODS:Associations between toenail As, total urine As (uAs), and %uAs metabolites [monomethyl (%uMMAV), dimethyl (%uDMAV), and inorganic (%iAs) species] and plasma biomarkers, including soluble plasma vascular and cellular adhesion molecules (VCAM-1 and ICAM-1, respectively), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α, plasminogen activator inhibitor-1 (PAI-1), and urinary oxidative stress marker 15-F2t-isoprostane (15-F2t-IsoP), were evaluated using linear regression models. RESULTS:Covariate-adjusted estimates of associations with a doubling of urinary As suggested an 8.8% increase in 15-F2t-IsoP (95% CI: 3.2, 14.7), and a doubling of toenail As was associated with a 1.7% increase in VCAM-1 (95% CI: 0.2, 3.2). Additionally, a 5% increase in %uMMA was associated with a 7.9% increase in 15-F2t-IsoP (95% CI: 2.1, 14.1), and a 5% increase in %uDMA was associated with a 2.98% decrease in 15-F2t-IsoP [(95% CI: -6.1, 0.21); p=0.07]. However, in contrast with expectations, a doubling of toenail As was associated with a 2.3% decrease (95% CI: -4.3, -0.3) in MMP-9, and a 5% increase in %uMMA was associated with a 7.7% decrease (95% CI: -12.6, -2.5) in PAI-1. CONCLUSION/CONCLUSIONS:In a cross-sectional study of U.S. adults, we observed some positive associations of uAs and toenail As concentrations with biomarkers potentially relevant to CVD pathogenesis and inflammation, and evidence of a higher capacity to metabolize inorganic As was negatively associated with a marker of oxidative stress. https://doi.org/10.1289/EHP2062.