School of Environment and Sustainability
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Browsing School of Environment and Sustainability by Author "Brinkmann, Markus"
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Item Bioactivation of Quinolines in a Recombinant Estrogen Receptor Transactivation Assay Is Catalyzed by N-Methyltransferases(ACS Publications, 2019) Brinkmann, Markus; Barz, Bogdan; Carrière, Danielle; Velki, Mirna; Smith, Kilian; Meyer-Alert, Henriette; Müller, Yvonne; Thalmann, Beat; Bluhm, Kersti; Schiwy, Sabrina; Hotz, Simone; Salowsky, Helena; Tiehm, Andreas; Hecker, Markus; Hollert, HennerHydroxylation of polyaromatic compounds through cytochromes P450 (CYPs) is known to result in potentially estrogenic transformation products. Recently, there has been an increasing awareness of the importance of alternative pathways such as aldehyde oxidases (AOX) or N-methyltransferases (NMT) in bioactivation of small molecules, particularly N-heterocycles. Therefore, this study investigated the biotransformation and activity of methylated quinolines, a class of environmentally relevant N-heterocycles that are no native ligands of the estrogen receptor (ER), in the estrogen-responsive cell line ERα CALUX. We found that this widely used cell line overexpresses AOXs and NMTs while having low expression of CYP enzymes. Exposure of ERα CALUX cells to quinolines resulted in estrogenic effects, which could be mitigated using an inhibitor of AOX/NMTs. No such mitigation occurred after coexposure to a CYP1A inhibitor. A number of N-methylated but no hydroxylated transformation products were detected using liquid chromatography–mass spectrometry, which indicated that biotransformations to estrogenic metabolites were likely catalyzed by NMTs. Compared to the natural ER ligand 17β-estradiol, the products formed during the metabolization of quinolines were weak to moderate agonists of the human ERα. Our findings have potential implications for the risk assessment of these compounds and indicate that care must be taken when using in vitro estrogenicity assays, for example, ERα CALUX, for the characterization of N-heterocycles or environmental samples that may contain them.Item Ecotoxicity of NSO-heterocycles (NSO-HET) and short-chained alkyl phenols (SCAP) commonly detected in contaminated groundwater(Society of Environmental Toxicology and Chemistry, 2019) Brinkmann, Markus; Schneider, Anna-Lena; Bluhm, Kerstin; Schiwy, Sabrina; Lehmann, Gunnar; Deutschmann, Björn; Müller, Axel; Tiehm, Andreas; Hollert, HennerNitrogen, sulfur, or oxygen heterocyclic aromatic hydrocarbons (NSO-HETs) and short-chained alkyl phenols (SCAPs) are commonly detected in groundwater at contaminated sites and in the surrounding environment. It is now scientific consensus that these chemicals pose a risk to human and ecosystem health. However, toxicity data are comparably fragmentary, and only few studies have addressed the ecotoxicity of NSO-HETs and SCAPs in a systematic and comparative fashion. To overcome this shortcoming, we tested 18 SCAPs, 16 NSO-HETs, as well as the homocyclic hydrocarbons indane and indene in the Microtox® assay with Aliivibrio fischeri, the growth inhibition test with Desmodesmus subspicatus, the acute immobilization assay with Daphnia magna, as well as the fish embryo toxicity test with embryos of the zebrafish (Danio rerio). Because of the physicochemical properties of the tested chemicals (limited water solubility, volatility, and sorption to test vessels), actual exposure concentrations in test media and their dissipation over time were analytically quantified by means of gas chromatography with mass spectrometry. Analytically corrected effect levels (median effect and lethal concentrations) ranged from 0.017 to 180 mg L–1, underlining the environmental relevance of some NSO-HETs and SCAPs. Para-substituted phenols showed the overall greatest toxicities in all 4 toxicity tests. We provide, for the first time, a complete high-quality data set in support of better environmental risk assessments of these chemicals.