Dataset Information

Carbamazepine Ozonation Byproducts: Toxicity in Zebrafish (Danio rerio) Embryos and Chemical Stability.

ABSTRACT: Carbamazepine (CBZ) is an anticonvulsant medication with highly persistent properties in the aquatic environment, where it has the potential to affect nontarget biota. Because CBZ and many other pharmaceuticals are not readily removed in conventional sewage treatment plants (STP), additional STP effluent treatment technologies are being evaluated and implemented. Whole effluent ozonation is a prospective method to remove pharmaceuticals such as CBZ, yet knowledge on the toxicity of CBZ ozonation byproducts (OBPs) is lacking. This study presents, for the first time, in vivo individual and mixture toxicity of four putative OBPs, that is, carbamazepine 10,11-epoxide, 10,11-Dihydrocarbamazepine, 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one (BQM), and 1-(2-benzaldehyde)-(1H,3H)-quinazoline-2,4-dione (BQD) in developing zebrafish (Danio rerio) embryos. BQM and BQD were isolated from the ozonated solution as they were not commercially available. The study confirmed that the OBP mixture caused embryotoxic responses comparable to that of ozonated CBZ. Individual compound embryotoxicity assessment further revealed that BQM and BQD were the drivers of embryotoxicity. OBP chemical stability in ozonated CBZ water solution during 2 week dark storage at 22 °C was also assessed. The OBP concentrations remained over time, except for BQD which decreased by 94%. Meanwhile, ozonated CBZ persistently induced embryotoxicity over 2 week storage, potentially illustrating environmental concern.

SUBMITTER: Pohl J

PROVIDER: S-EPMC7307904 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Carbamazepine Ozonation Byproducts: Toxicity in Zebrafish (<i>Danio rerio</i>) Embryos and Chemical Stability.

Pohl Johannes J Golovko Oksana O Carlsson Gunnar G Eriksson Johan J Glynn Anders A Örn Stefan S Weiss Jana J

Environmental science & technology 20200211 5

Carbamazepine (CBZ) is an anticonvulsant medication with highly persistent properties in the aquatic environment, where it has the potential to affect nontarget biota. Because CBZ and many other pharmaceuticals are not readily removed in conventional sewage treatment plants (STP), additional STP effluent treatment technologies are being evaluated and implemented. Whole effluent ozonation is a prospective method to remove pharmaceuticals such as CBZ, yet knowledge on the toxicity of CBZ ozonation ...[more]

PMID: 31990190

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Project description:BACKGROUND:In mammals, ABCB1 constitutes a cellular "first line of defense" against a wide array of chemicals and drugs conferring cellular multidrug or multixenobiotic resistance (MDR/MXR). We tested the hypothesis that an ABCB1 ortholog serves as protection for the sensitive developmental processes in zebrafish embryos against adverse compounds dissolved in the water. RESULTS:Indication for ABCB1-type efflux counteracting the accumulation of chemicals in zebrafish embryos comes from experiments with fluorescent and toxic transporter substrates and inhibitors. With inhibitors present, levels of fluorescent dyes in embryo tissue and sensitivity of embryos to toxic substrates were generally elevated. We verified two predicted sequences from zebrafish, previously annotated as abcb1, by cloning; our synteny analyses, however, identified them as abcb4 and abcb5, respectively. The abcb1 gene is absent in the zebrafish genome and we explored whether instead Abcb4 and/or Abcb5 show toxicant defense properties. Quantitative real-time polymerase chain reaction (qPCR) analyses showed the presence of transcripts of both genes throughout the first 48 hours of zebrafish development. Similar to transporter inhibitors, morpholino knock-down of Abcb4 increased accumulation of fluorescent substrates in embryo tissue and sensitivity of embryos toward toxic compounds. In contrast, morpholino knock-down of Abcb5 did not exert this effect. ATPase assays with recombinant protein obtained with the baculovirus expression system confirmed that dye and toxic compounds act as substrates of zebrafish Abcb4 and inhibitors block its function. The compounds tested comprised model substrates of human ABCB1, namely the fluorescent dyes rhodamine B and calcein-am and the toxic compounds vinblastine, vincristine and doxorubicin; cyclosporin A, PSC833, MK571 and verapamil were applied as inhibitors. Additionally, tests were performed with ecotoxicologically relevant compounds: phenanthrene (a polycyclic aromatic hydrocarbon) and galaxolide and tonalide (two polycyclic musks). CONCLUSIONS:We show that zebrafish Abcb4 is a cellular toxicant transporter and provides protection of embryos against toxic chemicals dissolved in the water. Zebrafish Abcb4 thus is functionally similar to mammalian ABCB1, but differs from mammalian ABCB4, which is not involved in cellular resistance to chemicals but specifically transports phospholipids in the liver. Our data have important implications: Abcb4 could affect bioavailability - and thus toxicologic and pharmacologic potency - of chemicals to zebrafish embryos and inhibition of Abcb4 therefore causes chemosensitization, that is, enhanced sensitivity of embryos to toxicants. These aspects should be considered in (eco)toxicologic and pharmacologic chemical screens with the zebrafish embryo, a major vertebrate model.

Dataset Information

Carbamazepine Ozonation Byproducts: Toxicity in Zebrafish (Danio rerio) Embryos and Chemical Stability.

Publications

Carbamazepine Ozonation Byproducts: Toxicity in Zebrafish (<i>Danio rerio</i>) Embryos and Chemical Stability.

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