Influence of pH on the uptake and toxicity of β-blockers in embryos of zebrafish, Danio rerio

Bittner, Lisa; Teixidó, Elisabet; Seiwert, Bettina; Escher, Beate I.; Klüver, Nils

doi:10.1016/j.aquatox.2018.05.020

Cited by 48 publications

(49 citation statements)

References 62 publications

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“…The pH dependency of toxicity originates from pH-dependent uptake of the antihistamines, consistent with previous findings for β-blockers (Bittner et al 2018). An increase in neutral fraction led to higher BCF apparent values and higher internal concentrations for ketotifen, doxylamine, and dimethindene.…”

Section: Resultssupporting

confidence: 91%

“…Data on body length, eye area, head size, yolk and pericardium size, and inflation of the swim bladder were extracted for each embryo; and dimensions were calculated within the open source software KNIME (Ver 3.5.3) using analytical workflows developed in-house as described inTeixido et al (2018a). Videos of 15 s and a frame rate of 30 frames/s were analyzed for heart rate analogously with a different workflow (according toTeixido et al 2018). For each exposure scenario and pH a control group was chosen, representing conditions in the treatment in the absence of the test compound, taking into account pH, test vessel, and solvent concentration.…”

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confidence: 99%

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pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

Bittner

Teixidó

Keddi

et al. 2019

Enviro Toxic and Chemistry

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Reported off‐target effects of antihistamines in humans draw interest in ecotoxicity testing of first‐ and second‐generation antihistamines, the latter of which have fewer reported side effects in humans. Because antihistamines are ionizable compounds, the pH influences uptake and toxicity and thus is highly relevant when conducting toxicity experiments. Zebrafish embryo toxicity tests were performed with the 3 first‐generation antihistamines ketotifen, doxylamine, and dimethindene and the 2 second‐generation antihistamines cetirizine and levocabastine at pH 5.5, 7.0, and 8.0. We detected effects on survival, phenotype, swimming activity, and heart rate for 4 antihistamines with the exception of levocabastine, which did not show any lethal or sublethal effects. When compared to lethal concentrations, effect concentrations neither of phenotype malformation nor of swimming activity or heart rate deviated by more than a factor of 10 from lethal concentrations, indicating that all sublethal effects were fairly nonspecific. First‐generation antihistamines are weak bases and showed decreasing external effect concentrations with increasing neutral fraction, accompanied by increased uptake in the fish embryo. As a result, internal effect concentrations were independent from external pH. The pH‐dependent toxicity originates from speciation‐dependent uptake, with neutral species taken up in higher amounts than the corresponding ionic species. Cetirizine, which shifts from a zwitterionic to an anionic state in the measured pH range, did not show any pH‐dependent uptake or toxicity. Environ Toxicol Chem 2019;00:1–11. © 2019 SETAC

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Section: Resultssupporting

confidence: 91%

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confidence: 99%

pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

Bittner

Teixidó

Keddi

et al. 2019

Enviro Toxic and Chemistry

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“…Zebrafish embryos can tolerate pH values between 5 and 10 (Andrade et al ), so a large shift in pH may go unnoticed in controls but may affect IOC speciation and resulting effects in test treatments. Bittner et al () demonstrated that Good’s buffers are suitable to adjust the pH within the range that is tolerable for zebrafish embryos.…”

Section: Ph Dependence Of Aquatic Toxicity Of Iocsmentioning

confidence: 99%

Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Escher

Abagyan

Embry

et al. 2020

Enviro Toxic and Chemistry

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Ionizable organic chemicals (IOCs) such as organic acids and bases are an important substance class requiring aquatic hazard evaluation. Although the aquatic toxicity of IOCs is highly dependent on the water pH, many toxicity studies in the literature cannot be interpreted because pH was not reported or not kept constant during the experiment, calling for an adaptation and improvement of testing guidelines. The modulating influence of pH on toxicity is mainly caused by pHdependent uptake and bioaccumulation of IOCs, which can be described by ion-trapping and toxicokinetic models. The internal effect concentrations of IOCs were found to be independent of the external pH because of organisms' and cells' ability to maintain a stable internal pH milieu. If the external pH is close to the internal pH, existing quantitative structure-activity relationships (QSARs) for neutral organics can be adapted by substituting the octanol-water partition coefficient by the ionization-corrected liposome-water distribution ratio as the hydrophobicity descriptor, demonstrated by modification of the target lipid model. Charged, zwitterionic and neutral species of an IOC can all contribute to observed toxicity, either through concentration-additive mixture effects or by interaction of different species, as is the case for uncoupling of mitochondrial respiration. For specifically acting IOCs, we recommend a 2-step screening procedure with ion-trapping/QSAR models used to predict the baseline toxicity, followed by adjustment using the toxic ratio derived from in vitro systems. Receptor-or plasmabinding models also show promise for elucidating IOC toxicity. The present review is intended to help demystify the ecotoxicity of IOCs and provide recommendations for their hazard and risk assessment. Environ Toxicol Chem 2020;39:269-286. /ETC FIGURE 1: Speciation in relation to the pH and acid dissociation constant, pK a , for (A) monoprotic acids and (B) monoprotic bases. The experimentally accessible pH range is marked by blue (fish) and green (daphnia, algae) boxes. Further discussion on the experimentally accessible pH range is provided in the section Testing guidelines.

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“…Developmental stages were identified according to Kimmel (1995). The fish embryo acute toxicity test was conducted as described in the OECD TG 236 and in Bittner et al [36], but additional endpoints were included.…”

Section: Fish Culture Fish Embryo Production and Selectionmentioning

confidence: 99%

Toxicity and neurotoxicity profiling of contaminated sediments from Gulf of Bothnia (Sweden): a multi-endpoint assay with Zebrafish embryos

et al. 2019

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Background: The toxicological characterization of sediments is an essential task to monitor the quality of aquatic environments. Many hazardous pollutants may accumulate in sediments and pose a risk to the aquatic community. The present study provides an attempt to integrate a diagnostic whole mixture assessment workflow based on a slightly modified Danio rerio embryo acute toxicity test with chemical characterization. Danio rerio embryos were directly exposed to sieved sediment (≤ 63 μm) for 96 h. Sediment samples were collected from three polluted sites (Kramfors, Sundsvall and Örnsköldsvik) in the Gulf of Bothnia (Sweden) which are characterized by a long history of pulp and paper industry impact. Effect data were supported by chemical analyses of 237 organic pollutants and 30 trace elements. Results: The results show that malformations and neurotoxic compounds are the main drivers of differentiation in chemical and effects analyses, respectively. Specific spinal cord malformations and delayed hatching were observed only in sediments from Kramfors while light hyperactivity was seen only after exposure to sediments from Sundsvall. Conclusions: Our experiments demonstrate that specific chemical profiles lead to specific effect patterns in Danio rerio embryos. In fact, behavioral endpoints could help detect the exposure to neurotoxins, and the observation of body malformations seems to be a potential tool for the identification of site-specific pollutants as polychlorinated biphenyl (PCBs), brominated flame retardants (BFRs) and several pesticides. Overall, results show the suitability of Danio rerio embryos for the fast screening of sediment samples.

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Influence of pH on the uptake and toxicity of β-blockers in embryos of zebrafish, Danio rerio

Cited by 48 publications

References 62 publications

pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

Recommendations for Improving Methods and Models for Aquatic Hazard Assessment of Ionizable Organic Chemicals

Toxicity and neurotoxicity profiling of contaminated sediments from Gulf of Bothnia (Sweden): a multi-endpoint assay with Zebrafish embryos

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