Abstract
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.
Highlights
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
After flies were fed for 24 h with PCB congeners, a human-like pattern of respective OH-metabolites was detected in Drosophila whole body lysates
As synthetic OH-metabolites of PCB 28-induced cytotoxicity in a model cell culture s ystem[3], we conclude that PCB 28 bioactivation by cytochrome p450 (Cyp) enzymes leads to toxicity in Drosophila
Summary
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. OH-PCBs can potentially reach any hydrophilic compartment in the body, where they are oxidized in peripheral tissues by enzymatic catalysis (e.g. myeloperoxidase, prostaglandin-H-synthase) or autoxidized to catechols or hydroquinones, which after further oxidation to quinones and semichinones can covalently bind to biological macromolecules such as purine bases or proteins (adduct formation)[6,7,8] Compared to their parental compounds OH-PCBs often show equal or higher toxicity, greater distribution in the human. An accumulation of hydrogen peroxide and an increased lipid peroxidation were demonstrated These results suggested that reactive intermediates of the PCB metabolism trigger neurodegenerative processes in the brain, which can eventually lead to the loss of neurons. We investigated the PCB 28-mediated lethality in Drosophila using the neuron-specific expression of an apoptosis-sensitive biosensor
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