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Polychlorinated biphenyl exposure and DNA methylation in the Anniston Community Health Survey.

ABSTRACT: Anniston, Alabama was home to a major polychlorinated biphenyl (PCB) production facility from 1929 until 1971. The Anniston Community Health Survey I and II (ACHS-I 2005-2007, ACHS-II 2013-2014) were conducted to explore the effects of PCB exposures. In this report we examined associations between PCB exposure and DNA methylation in whole blood using EPIC arrays (ACHS-I, n = 518; ACHS-II, n = 299). For both cohorts, 35 PCBs were measured in serum. We modelled methylation versus PCB wet-weight concentrations for: the sum of 35 PCBs, mono-ortho substituted PCBs, di-ortho substituted PCBs, tri/tetra-ortho substituted PCBs, oestrogenic PCBs, and antiestrogenic PCBs. Using robust multivariable linear regression, we adjusted for age, race, sex, smoking, total lipids, and six blood cell-type percentages. We carried out a two-stage analysis; discovery in ACHS-I followed by replication in ACHS-II. In ACHS-I, we identified 28 associations (17 unique CpGs) at p ≤ 6.70E-08 and 369 associations (286 unique CpGs) at FDR p ≤ 5.00E-02. A large proportion of the genes have been observed to interact with PCBs or dioxins in model studies. Among the 28 genome-wide significant CpG/PCB associations, 14 displayed replicated directional effects in ACHS-II; however, only one in ACHS-II was statistically significant at p ≤ 1.70E-04. While we identified many novel CpGs significantly associated with PCB exposures in ACHS-I, the differential methylation was modest and the effect was attenuated seven years later in ACHS-II, suggesting a lack of persistence of the associations between PCB exposures and altered DNA methylation in blood cells.

SUBMITTER: Pittman GS

PROVIDER: S-EPMC7153539 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPolychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress.ObjectivesWe tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort.MethodsSixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed.ResultsThe necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor α were well integrated within the top identified networks.DiscussionThese results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467.

Project description:Serum concentrations of 35 ortho-substituted polychlorinated biphenyl congeners (PCBs) were measured in 765 adults from Anniston, Alabama, where PCBs were manufactured between 1929 and 1971. As part of the Anniston Community Health Survey (ACHS), demographic data, questionnaire information, and blood samples were collected from participants in 2005-2007. Forty-six percent of study participants were African-American, 70% were female, and the median age was 56 years. The median concentration of the sum of 35 PCB congeners (ΣPCBs) was 528 ng/g lipid, with a 90th percentile of 2,600 ng/g lipid, minimum of 17.0 ng/g lipid, and maximum of 27,337 ng/g lipid. The least square geometric mean ΣPCBs was more than 2.5 times higher for African-American participants than for White participants (866 ng/g lipid vs. 331 ng/g lipid); this difference did not change materially after adjustment for age, sex, body mass index (BMI) and current smoking. In spite of large differences in absolute PCB levels, relative contributions of individual congeners to ΣPCBs were quite similar between race groups. Nevertheless, while percent contributions to ΣPCBs for most of the most abundant penta- to heptachlorobiphenyls were higher among African-Americans, the percentages were higher in Whites for the lower-chlorinated PCBs 28 and 74 and for octa- to decachlorinated PCBs. No major differences were observed in geometric mean ΣPCBs between women and men when adjusted for age, race, BMI and current smoking (516 ng/g lipid vs. 526 ng/g lipid). Principal component analysis revealed groups of co-varying congeners that appear to be determined by chlorine substitution patterns. These congener groupings were similar between ACHS participants and the National Health and Nutrition Examination Survey (NHANES) 2003-04 sample of the general United States population, despite ACHS participants having serum concentrations of ΣPCBs two to three times higher than those in comparable age and race groups from NHANES.

Project description:BackgroundIn 2014, we conducted a longitudinal study [Anniston Community Health Survey (ACHS II)] 8 y after the baseline (ACHS I).ObjectivesWe investigated the relationship between persistent chlorinated compounds and hypertension in residents living around the former polychlorinated biphenyl (PCB) production plant in Anniston, Alabama. We also examined the potential role of inflammatory cytokines in those with hypertension.MethodsA total of 338 participants had their blood pressure measured and medications recorded, gave a blood sample, and completed a questionnaire. Prevalent hypertension was defined as taking antihypertensive medication or having systolic blood pressure >140?mmHg and/or diastolic pressure >90?mmHg; incident hypertension used similar criteria in those who developed hypertension since the baseline in 2005-2007. PCB congeners were categorized into structure-activity groups, and toxic equivalencies (TEQs) were calculated for dioxin-like compounds. Descriptive statistics, logistic and linear regressions, as well as Cox proportional hazard models, were used to analyze the associations between exposures and hypertension.ResultsPrevalent hypertension (78%) in ACHS II showed statistically significant adjusted odds ratios (ORs) for PCBs 74, 99, 138, 153, 167, 177, 183, and 187, ranging from 2.18 [95% confidence interval (CI): 1.10, 4.33] to 2.76 (95% CI: 1.14, 6.73), as well as for two estrogenic-like PCB groups, and the thyroid-like group [ORs ranging from 2.25 (95% CI: 1.07, 4.75) to 2.54 (95% CI: 1.13, 5.74)]. Furthermore, analysis of quartiles demonstrated a monotonic relationship for dioxin-like non-ortho (non-o)-PCB TEQs [fourth vs. first quartile: 3.66 (95% CI: 1.40, 9.56)]. Longitudinal analyses of incident hypertension supported those positive associations. The results were strongest for the di-o-PCBs [hazard?ratio?(HR)=1.93 (95% CI: 0.93, 4.00)] and estrogenic II PCB group [HR=1.90 (95% CI: 0.96, 3.78)] but were weaker for the dioxin TEQs.DiscussionFindings supportive of positive associations were reported for dioxin-like mono-o- and non-o-PCBs as well as for nondioxin-like estrogenic and thyroid-like congeners with prevalent and incident hypertension, suggesting that multiple pathways may be involved in hypertension development. https://doi.org/10.1289/EHP5272.

Project description:The 2014 follow-up of the Anniston Community Health Survey (ACHS II) consisted of 338 surviving participants from the 2005-2007 baseline study (ACHS) who had previous polychlorinated biphenyl (PCB) measurements, were not pregnant, and were not institutionalized. Questionnaires and blood samples provided the demographic, personal history, and chemical concentration data of the Anniston residents. Approximately 51% of participants were African American, 72% were female, and the mean age was 63 years old. The objectives of this study were to provide an exposure assessment of dioxin-like chemicals in the ACHS II participants and compare the measurements with the general United States (U.S.) population via the National Health and Nutrition Examination Survey (NHANES). Stratified analyses revealed significantly higher average total dioxin toxic equivalencies (TEQs) among African Americans compared to Whites (33.1 vs. 19.2 pg/g lipid), and in females compared to males (29.8 vs. 17.0 pg/g lipid). When adjusting for age, sex, and race in linear regression, we found ACHS II participants to have significantly higher total dioxin TEQ than the general 2014 U.S. population that we estimated for using half-life and NHANES 2003/04 data (most recent NHANES individual samples data), by 16.7 pg/g lipid. Principal component analyses showed that non-ortho and mono-ortho PCBs were separated from the other dioxin-like chemicals among the Anniston residents, whereas the chemicals were all clustered together for estimated NHANES 2014. The concentrations of dioxin-like chemicals, especially non-ortho and mono-ortho PCBs, in Anniston residents who resided near the former PCB production plant were higher than those in the general U.S.PopulationAlthough data strongly supported this difference, these inferences are limited because NHANES 2013/14 data were unavailable and we used estimated NHANES 2014 levels that we imputed from NHANES 2003/04 data in conjunction with half-life values estimated from Milbrath et al., 2009.

Project description:In 1973-74, a polybrominated biphenyl (PBB) flame retardant mixture was shipped to Michigan livestock feed mills in place of a nutritional supplement and contaminated the food supply. Following the accident, the Michigan PBB Registry was established to study the long-term health effects of halogenated compounds and is now led by a community-academic partnership. PBB exposure is associated with altered DNA methylation in sperm, which may lead to adverse birth outcomes in children whose fathers have increased levels of serum PBB or polychlorinated biphenyl (PCB). Paternal PBB and PCB levels of men enrolled in the Michigan PBB Registry (n = 155) were analyzed against matched offspring birthweight and gestational age (n = 336). Birthweight and gestational age were dichotomized at the 25th percentile and 37 weeks, respectively, and paternal PBB and PCB levels were examined as continuous measures and divided into tertiles. Associations of offspring birthweight and gestational age with paternal PBB and PCB serum concentrations were modeled using multivariable linear spline and log-risk regression, adjusting for family clustering, paternal health and lifestyle factors, maternal PBB, and PCB serum concentrations, sex, and offspring gestational age (for birthweight). Fathers in the middle and upper PBB and PCB tertiles had increased risks for lowest quartile birthweight compared to the first tertile, with adjusted risk ratios (aRR) = 1.67 (95% CI: 0.93, 2.99) and aRR = 2.06 (95% CI: 1.12, 3.79) for PBB, and aRR = 1.47 (95% CI: 0.79, 2.75) and aRR = 1.34 (95% CI: 0.70, 2.54) for PCB, respectively. Elevated paternal PBB levels were not associated with an increased risk for preterm birth, while PCB levels were associated with a small, but not significant, decrease in gestational age, β = -0.37 (95% CI: -0.76, 0.03) weeks per log unit increase PCB. The findings suggest that increased paternal PBB and PCB levels negatively impact offspring birthweight, and paternal PCB levels may negatively impact gestational age.

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Polychlorinated biphenyl exposure and DNA methylation in the Anniston Community Health Survey.

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