Abstract
Polychlorinated biphenyls (PCBs) are ubiquitously occurring pollutants with different chemical and toxicological properties. In this study we evaluated blood plasma samples of two PCB-exposed cohorts for their ability to alter telomerase (hTERT) gene expression. Blood plasma from PCB-exposed individuals inhibited hTERT expression depending solely on the concentration of lower chlorinated PCBs, with the lowest observed adverse effect level (LOAEL) at a plasma concentration between 0.5 and 2 µg/L of LC PCBs. Individual OH-metabolites derived from the WHO indicator congeners PCB 28 and PCB 101 mimicked these effects on hTERT expression in vitro with high toxicity, including DNA damage. However, by the combination of different OH-metabolites, the bio effective PCB concentration was reduced and the respective effects on hTERT expression could be increased. At a concentration which showed no toxic activity in MTT assay, hTERT inhibition reflected the interference of OH-PCBs with the mitochondrial respiratory chain, which could lead to the production of reactive oxygen species (ROS). As individual OH-metabolites already showed a much stronger inhibition of hTERT gene expression at a lower concentration than their parental compounds, the hTERT gene expression bioassay described in this study seems to indicate metabolic activation of LC PCBs rather than the mere effect of LC PCBs on their own. In summary, this study provides dose-response linkages between effects of lower chlorinated PCBs and their concentrations in human plasma.
Highlights
Polychlorinated biphenyls (PCBs) are abundantly present organochlorine pollutants eliciting adverse biological effects
When incubated with longitudinally collected blood plasma samples from individuals with a high PCB body burden due to occupational exposure (HELPcB-cohort)[21], the capability of plasma to inhibit hTERT gene expression in tert+ B6B5.1 cells was reduced over time, whereas plasma samples collected in 2011 inhibited hTERT expression by a factor of 7 as compared to untreated controls, the suppressive effect of plasma was less pronounced in 2015 (Fig. 1A)
Similar results were obtained when tetanus toxoid stimulated peripheral blood mononuclear cells (PBMCs) were incubated with blood plasma from the HELPcB-cohort and hTERT mRNA levels were assessed by quantitative RT-PCR
Summary
Polychlorinated biphenyls (PCBs) are abundantly present organochlorine pollutants eliciting adverse biological effects. Through autoxidation (autocatalytic oxidation in the presence of oxygen), peroxidases (POX) or the prostaglandin-H synthase (PHS), catechols and hydroquinones can be further modified to ortho- or para-quinones These reactive arene oxides can covalently bind to biological macromolecules and form protein-, RNA- and DNA-adducts[14]. Leukocyte telomere length were prolonged in individuals after long-term exposure to low doses of non orthochlorinated PCBs and DL PCBs16–18. In contrast to these observations, in vitro studies with individual airborne PCB congeners showed a reduced TL and hTERT enzyme activity in liver and keratinocyte cell lines[13,19]. We extended findings from blood plasma samples in a model cell culture system using hydroxylated metabolites of PCB 28 and PCB 101
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