Telomeres as targets for persistent organic pollutants: The Anniston community health survey
Callahan, Catherine Lee
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Background: Telomeres are tandem nucleotide repeats on the ends of chromosomes that maintain genomic stability. Telomere length (TL), measured in DNA extracted from peripheral blood, has been posited as a potentially useful biomarker of early effect with regards to exogenous exposures that have been implicated in carcinogenesis. There are plausible mechanisms by which either aberrantly short or long telomere length may contribute to malignant transformation. Several previous studies have identified demographic and behavioral characteristics that are associated with TL including, age, race, cigarette smoking, alcohol use, sex, body mass index, education, and physical activity. However, these reports have been inconsistent, and likely depend on the distribution of component causes within an individual study population. Persistent organic pollutants (POPs) are a heterogeneous class of chemicals that are characterized by their lengthy half-lives and persistence in the environment. POPs include polychlorinated biphenyls (PCBs), a class of 209 organic synthetic chemicals with one to ten chlorine atoms attached to the biphenyl ring, that were previously used in a variety of commercial applications and organochlorine (OC) insecticides, a class of pesticides that were heavily used in agriculture and pest control from the 1940s until the 1960s. Although manufacture of PCBs and most OCs has been banned they remain ubiquitous in the environment. POPs have been demonstrated to induce oxidative stress and inflammation, which can shorten telomeres. However, PCB 138 and 153 have also been demonstrated to upregulate the proto-oncogene c-myc, which can lead to telomere lengthening. Most, but not all, prior studies of PCBs and TL have reported an association between exposure to PCBs and longer TL; however these studies were limited by racially homogenous samples and narrow exposure gradients. There is a lacuna of studies of exposure to OCs and TL. Aims: The three aims of this project were to investigate 1) the association between demographic and behavioral characteristics and relative TL among Anniston Community Health Survey (ACHS) participants; 2) the association between serum levels of PCBs and relative TL among ACHS participants; 3) the association between serum levels of OC insecticides and relative TL among ACHS participants. Methods: The ACHS is a cross-sectional study of residents of Anniston, Alabama, one of the two places where PCBs were produced in the United States. Participants completed a structured interview that queried demographic information, personal and family medical history, and health behaviors. Serum levels of 35 PCB congeners and nine OC insecticides were quantified by the Center for Disease Control National Center for Environmental Health laboratory using high-resolution gas chromatography/isotope dilution high-resolution mass spectrometry. DNA was extracted from stored blood clot samples donated by ACHS participants and relative TL was measured using monochrome multiplex quantitative polymerase chain reaction. Multivariate linear regression was utilized to estimate the association between participant characteristics and telomere length. Relative TL was log-transformed and then exponentiated to present results as percent differences. Models were adjusted for age in years, age in years squared, PCR plate, and pertinent covariates. Serum POPs were parameterized continuously and as quartiles. We used multiple imputation to impute values for serum POPs that were below the limit of detection as well as for participants missing information on pertinent covariates. All analyses were stratified by race. Results: Relative TL was successfully measured for 556 ACHS participants (329 whites and 227 African Americans). Race was not statistically significantly associated with relative TL. African American race was associated with 1.71% longer relative TL when compared with white participants [95% confidence interval (CI): -0.68; 4.16]. Age was inversely associated with relative TL, a one year increase in age among white participants was associated with 0.08% shorter relative TL among whites (95% CI: -0.17; 0.01) and 0.10% shorter TL among African Americans (95% CI: -0.20; 0.01). African American females had 5.26% longer relative TL than African American males (95% CI: 1.26; 9.01). We did not observe a difference in relative TL by sex among white participants. Among both whites and African Americans, higher educational obtainment was associated with longer telomeres, compared with those who had less than 12 years of education white participants with greater than 12 years of education had 3.50% longer telomeres (95% CI: -0.69; 7.87), and African American participants with greater than 12 years of education had 4.68% longer telomeres than those with less than 12 years of education (95%CI: 0.12; 9.45). Among white participants current smokers had 3.89% shorter telomeres than never smokers (95% CI: -7.55; -0.08). Among African American participants, former smokers had the shortest telomeres, 4.42% shorter than never smokers (95% CI: -8.80; -0.16). Body mass index, leisure time physical activity, and alcohol consumption were not associated with TL among either race. Prevalent self-reported diseases of cancer, diabetes, or hypertension were not associated with TL. Serum PCBs were associated with longer relative TL among white, but not African American participants. Among white participants, compared with those in the first quartile of sum PCBs those in the third quartile of sum PCBs had 8.20% longer relative TL (95% CI: 1.93; 14.85) and those in the fourth had 7.08% longer relative TL (95%CI: -0.67; 15.44) (p-quadratic = 0.05). The association was strongest when congeners that induce cytochrome-P450 enzyme IIB were considered. We observed limited evidence that OC insecticides were associated with relative TL. The only OC associated with TL was p,p'-dichlorodiphenyldichloroethylene (p,p’-DDE), among white participants, those in the third quartile of serum p,p’-DDE had 5.59% longer telomeres than the first quartile (95% CI: 0.25; 11.22). Those in the fourth quartile of p,p’-DDE had 2.39% longer telomeres than those in the first quartile and this measure was imprecise (95% CI: -3.54; 8.69). Conclusions: We corroborated the results of previous studies that age is inversely associated with TL and that African American women have longer TL than African American men. We did not observe an association between race and TL. Our results provide further evidence that individual characteristics are associated with TL. We observed a positive association between serum PCBs and TL among white participants only. The positive association between serum PCBs and TL is in accord with previous reports. We are the first study to report effect measure modification by race. This potentially important interaction warrants further research. Serum levels of OC insecticides were generally not associated with relative TL. Further studies regarding exposure to POPs using a longitudinal study design that assesses cancer incidence in a racially diverse setting are warranted.