Accelerated telomere shortening in peripheral blood lymphocytes after occupational polychlorinated biphenyls exposure

Abstract

Polychlorinated biphenyls (PCBs) are organochlorine pollutants with a worldwide dissemination. We examined telomere length (TL) in peripheral blood cells of 207 individuals with a high body burden of PCBs due to occupational exposure in a transformer recycling company. Whereas TL in granulocytes was not affected, the age-adjusted TL in lymphocytes (∆TLLymph) of exposed individuals was significantly shorter than expected [−0.77 kb; 95 % confidence interval (CI) −0.9316; −0.6052; p = 0.0001]. PCB exposure did not affect lymphocyte numbers or T cell receptor excision circle (TREC) levels in T cells, suggesting that PCBs cause loss of telomeric DNA in T cells due to their metabolic activation and antigen-stimulated proliferation. In support of this hypothesis, blood plasma levels of PCB-exposed individuals inhibited expression of telomerase, the telomere elongating enzyme in vitro in antigen-specific T cell proliferation assays. 3-OH-CB28, a downstream metabolite of the lower chlorinated PCB-28 in PCB-exposed individuals (mean blood plasma concentration: 0.185 ± 0.68 ng/mL), inhibited telomerase gene expression within 48 h of incubation in lymphoproliferative assays starting at a concentration of 0.27–6.75 µg/mL and accelerated telomere shortening in long-term cell culture experiments. Accelerated telomere shortening due to PCB exposure may lead to limitations of cell renewal and clonal expansion of lymphocyte populations. As PCB-related immune dysfunctions have been linked to increased susceptibility to infectious diseases and increased risk of cancer, our data provide a possible explanation, for how PCBs could promote infections and cancer through limiting immune surveillance.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1725-8) contains supplementary material, which is available to authorized users.

Serum polychlorinated biphenyls and leukocyte telomere length in a highly-exposed population: The Anniston Community Health Survey

“…Our results are inconsistent with the findings of prior in vitro studies that observed telomere shortening because of exposure to PCB 153, PCB 126, PCB 52, PCB 28, or 2-(4′-chlorophenyl)-1, 4-benzoquinone (PCB3pQ) (Jacobus et al, 2008; Senthilkumar et al, 2011; Senthilkumar et al, 2012; Xin et al, 2016; Ziegler et al, 2016). Alternative mechanisms by which PCBs may induce telomere lengthening have been proposed (Scinicariello and Buser, 2015).…”

“…Conversely, serum PCBs were associated with shorter LTL in lymphocytes in a study of 207 German individuals occupationally exposed to PCBs via employment for a transformer recycling company. When compared with 104 healthy non-exposed controls, those occupationally exposed had a LTL of lymphocytes 0.77 kb shorter than expected (95 % CI −0.93; −0.61) (Ziegler et al, 2016). In the only longitudinal study to date, serum levels of PCB 153 at baseline were associated with shorter LTL ten years later (r= −0.071, p-value 0.02) (Guzzardi et al, 2016).…”

“…In the largest NHANES analysis, comprising 2,175 participants, those in the highest quartile of sum PCBs (>142.80 ng/g) had 11.63% longer telomeres (95% CI:6.18; 17.35) than those in the lowest quartile (Scinicariello and Buser, 2015) . Conversely, in a study of 207 participants occupationally exposed to PCBs and 104 non-occupationally exposed controls, LTL in lymphocytes, but not granulocytes, was shorter among those exposed to PCBs (Ziegler et al, 2016). In the only longitudinal study to date, serum levels of PCB 153 were associated with shorter LTL after ten years of follow-up (Guzzardi et al, 2016).…”

“…In vitro , immortalized human skin keratinocytes, hamster lung fibroblasts, immortalized lymphocytes, or human promyelocytic leukemia cells exposed to PCB 153, PCB 126, PCB 52, PCB 28, or 2-(4′-chlorophenyl)-1, 4-benzoquinone (PCB3pQ), have shortened telomeres (Jacobus et al, 2008; Senthilkumar et al, 2011; Senthilkumar et al, 2012; Xin et al, 2016; Ziegler et al, 2016). Conversely, PCB 138 and PCB 153 upregulate c- myc in vitro (Ghosh et al, 2007; Gribaldo et al, 1998).…”

Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

“…TL analysis was done by a modified protocol of immunoquantitative fluorescence in situ hybridization (Q-FISH) as previously described [31][32][33][34][35]. FFPE sections of the cohort were deparaffinized and rehydrated before antigen retrieval in 10 mM citrate buffer (pH 6.0).…”