Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

Abstract

PCBs are persistent organic pollutants with carcinogenic, immune- and developmental toxicity. This suggests that they may interfere with normal cell maturation. Cancer and stem/progenitor cells have telomerase activity to maintain and protect the chromosome ends, but lose this activity during differentiation. We hypothesized that PCBs interfere with telomerase activity and the telomere complex thereby disturbing cell differentiation and stem/progenitor cell function. HL-60 cells are cancer cells that can differentiate to granulocytes and monocytes. We exposed HL-60 cells to the PCB126 (dioxin-like) and PCB153 (non-dioxin-like) 6 days before and during 3 days of differentiation. The differentiated cells showed G0/G1 phase arrest and very low telomerase activity. hTERT and hTR, two telomerase-related genes, were down-regulated. The telomere shelterins TRF1, TRF2, and POT were upregulated in granulocytes, TRF2 was up- and POT1 downregulated in monocytes. Both PCBs reduced telomerase activity in undifferentiated cells and further reduced telomerase activity in differentiated cells, but had only small effects on the differentiation and telomere-related genes. Long term treatment of undifferentiated HL-60 cells with PCB126 produced a downregulation of telomerase activity and decrease of hTERT, hTR, TRF1, and POT1 gene expression. With PCB153 the effects were less pronounced and some shelterin genes were increased after 30 days exposure. With each PCB no differentiation of cells was observed and cells continued to proliferate despite reduced telomerase activity, resulting in shortened telomeres after 30 days of exposure. These results indicate cell type and PCB congener specific effects on telomeres/telomerase-related genes and, although PCBs do not seem to strongly affect differentiation, they could influence the longevity of stem or progenitor cells through telomere attrition with potential long-term consequences for health.

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).…”

“…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).…”

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

“…In addition PCB126 (dioxin-like) and PCB153 (non-dioxin-like) reduced telomerase activity in HL-60 cells and shortened telomeres after 30 days of exposure (Xin et al 2016). Our finding that blood plasma of PCB-exposed individuals inhibits telomerase expression in lymphoproliferation assays is well in line with these previous reports.…”

“…Several studies investigating telomere dynamics in PCB-exposed individuals or PCB-treated telomerase positive tumor cell lines have been published (Xin et al 2016; Jacobus et al 2008; Shin et al 2010; Senthilkumar et al 2011, 2012; Mitro et al 2015). Whereas in two population-based studies low dose exposure to non-ortho PCBs was associated with longer TL in leukocytes (Shin et al 2010; Mitro et al 2015), long-term treatment of cell lines with PCBs resulted in cell-type and PCB congener-specific adverse effects on TL, htert activity and expression of telomere-associated shelterin genes (Xin et al 2016; Jacobus et al 2008; Senthilkumar et al 2011, 2012). Based on these recent findings, we selectively analyzed TL of granulocytes and lymphocytes in peripheral blood from individuals occupationally exposed to very high levels of PCBs.…”

Effects of polychlorinated biphenyls (PCBs) on telomere maintenance in hematopoietic stem cells and progenitor cells

“…Telomere attrition and telomerase dysfunction, which are reported to be involved in stem cell dysfunction (failure to self-renew and differentiate) (Zhang and Ju 2010) and immune function injury (Eisenberg 2011), can also be induced by PCBs in HaCaT cells (Jacobus et al 2008;Senthilkumar et al 2011;Senthilkumar et al 2012) and HL-60 cells (Xin et al 2015). However, no study so far has investigated if PCB126 affects telomeres and telomerase of stem cells and impacts their differentiation capacity.…”