Telomerase gene expression bioassays indicate metabolic activation of genotoxic lower chlorinated polychlorinated biphenyls

Vasko, Theresa; Hoffmann, Jenny; Gostek, Sonja; Schettgen, Thomas; Quinete, Natalia; Preisinger, Christian; Kraus, Thomas; Ziegler, Patrick

doi:10.1038/s41598-018-35043-w

Cited by 20 publications

(13 citation statements)

References 45 publications

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“…1C). As synthetic OH-metabolites of PCB 28-induced cytotoxicity in a model cell culture system 3 , we conclude that PCB 28 bioactivation by cytochrome p450 (Cyp) enzymes leads to toxicity in Drosophila. These Table 1).…”

Section: Bioactivation Of Pcb 28 Pcb 101 and Pcb 52 In Drosophila Mementioning

confidence: 85%

Metabolic activation and toxicological evaluation of polychlorinated biphenyls in Drosophila melanogaster

Idda

Bonas

Hoffmann

et al. 2020

Sci Rep

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Degradation of polychlorinated biphenyls (PCBs) is initiated by cytochrome P450 (CYP) enzymes and includes PCB oxidation to OH-metabolites, which often display a higher toxicity than their parental compounds. In search of an animal model reflecting PCB metabolism and toxicity, we tested Drosophila melanogaster, a well-known model system for genetics and human disease. Feeding Drosophila with lower chlorinated (LC) PCB congeners 28, 52 or 101 resulted in the detection of a human-like pattern of respective OH-metabolites in fly lysates. Feeding flies high PCB 28 concentrations caused lethality. Thus we silenced selected CYPs via RNA interference and analyzed the effect on PCB 28-derived metabolite formation by assaying 3-OH-2′,4,4′-trichlorobiphenyl (3-OHCB 28) and 3′-OH-4′,4,6′-trichlorobiphenyl (3′-OHCB 28) in fly lysates. We identified several drosophila CYPs (dCYPs) whose knockdown reduced PCB 28-derived OH-metabolites and suppressed PCB 28 induced lethality including dCYP1A2. Following in vitro analysis using a liver-like CYP-cocktail, containing human orthologues of dCYP1A2, we confirm human CYP1A2 as a PCB 28 metabolizing enzyme. PCB 28-induced mortality in flies was accompanied by locomotor impairment, a common phenotype of neurodegenerative disorders. Along this line, we show PCB 28-initiated caspase activation in differentiated fly neurons. This suggested the loss of neurons through apoptosis. Our findings in flies are congruent with observation in human exposed to high PCB levels. In plasma samples of PCB exposed humans, levels of the neurofilament light chain increase after LC-PCB exposure, indicating neuronal damage. In summary our findings demonstrate parallels between Drosophila and the human systems with respect to CYP mediated metabolism and PCB mediated neurotoxicity.

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Section: Bioactivation Of Pcb 28 Pcb 101 and Pcb 52 In Drosophila Mementioning

confidence: 85%

Metabolic activation and toxicological evaluation of polychlorinated biphenyls in Drosophila melanogaster

Idda

Bonas

Hoffmann

et al. 2020

Sci Rep

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“…Telomeres are considered to be a biological clock, playing a major role in aging and genome stability [7]. It is now well-documented that telomere dysfunction is a potential biomarker for age-related diseases and can contribute to the prognosis of several diseases [8][9][10][11][12]. Telomere sensitivity to inflammation and oxidative stress such as ionizing radiation has been previously demonstrated [13].…”

Section: Introductionmentioning

confidence: 99%

The Use of Natural Agents to Counteract Telomere Shortening: Effects of a Multi-Component Extract of Astragalus mongholicus Bunge and Danazol

et al. 2020

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A link between telomere shortening and oxidative stress was found in aging people and patients with cancer or inflammatory diseases. Extracts of Astragalus spp. are known to stimulate telomerase activity, thereby compensating telomere shortening. We characterized a multi-component hydroethanolic root extract (HRE) of Astragalus mongholicus Bunge and assessed its effects on telomeres compared to those of danazol. Astragalosides I to IV, flavonoids, amino acids and sugars were detected in the HRE. Samples of peripheral blood lymphocytes with short telomeres from 18 healthy donors (mean age 63.5 years; range 32–86 years) were exposed to a single dose of 1 µg/mL HRE or danazol for three days. Telomere length and telomerase expression were then measured. Significant elongation of telomeres associated to a less toxicity was observed in lymphocytes from 13/18 donors following HRE treatment (0.54 kb (0.15–2.06 kb)) and in those from 9/18 donors after danazol treatment (0.95 kb (0.06–2.06 kb)). The rate of cells with short telomeres (<3 kb) decreased in lymphocytes from all donors after exposure to either HRE or danazol, telomere elongation being telomerase-dependent. These findings suggest that the HRE could be used for the management of age-related diseases.

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“…The use and production of PCBs were banned in Germany in 1989, in the USA in the early 1970s and finally worldwide in 2004 (Stockholm convention on persistent organic pollutants (POPs) 2004). The basis for this ban was attributed to the toxicological effects of PCBs, which (Lehmann et al 2007;Ludewig and Robertson 2013) and are responsible for shortened telomere lengths in lymphocytes (Vasko et al 2018;Ziegler et al 2017). Finally, in 2013 the IARC classified PCBs as human carcinogens in category 1 (Lauby-Secretan et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Assessment of a potential PCB exposure among (former) underground miners by hydraulic fluids

Esser

Schettgen

Kraus

2020

Journal of Toxicology and Environmental Health, Part A

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Polychlorinated biphenyls (PCBs) were used in technical mixtures of different PCB congeners as hydraulic fluids in underground mining in Germany in North Rhine-Westphalia, Ibbenbueren, and Saarland from the mid-1960s to 1986. Mine workers who were involved in maintenance and repair or operation of hydraulically driven machines in underground mines were potentially exposed to liquids containing PCBs. The aim of the present study was to investigate whether this potential exposure which occurred more than 30 years ago was still detectable. Biomonitoring and a structured work anamnesis were conducted on a representative sample of 210 miners. PCBs in plasma were measured by gas chromatography coupled to mass spectrometry with an LOQ of 0.01 µg/L plasma for all congeners. The primary aim was comparison of the number of exceedances of the underlying comparative values for PCB congeners with those of the general population. Secondary endpoint was the question whether there were regional differences in potential PCB exposure. The biomonitoring showed a significant difference for PCB 74 with N= 94 (45%); for PCB 114 with N = 64 (31%) and for PCB 99 and PCB 105 with N = 23 (11%) and N = 19 (9%) of 210 measurements above the reference value compared to the general population (5%). The all over detection frequencies (µg/L plasma median | SD | min |max) of these congeners were as follows:

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Telomerase gene expression bioassays indicate metabolic activation of genotoxic lower chlorinated polychlorinated biphenyls

Cited by 20 publications

References 45 publications

Metabolic activation and toxicological evaluation of polychlorinated biphenyls in Drosophila melanogaster

Metabolic activation and toxicological evaluation of polychlorinated biphenyls in Drosophila melanogaster

The Use of Natural Agents to Counteract Telomere Shortening: Effects of a Multi-Component Extract of Astragalus mongholicus Bunge and Danazol

Assessment of a potential PCB exposure among (former) underground miners by hydraulic fluids

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