Biotransformation in the zebrafish embryo –temporal gene transcription changes of cytochrome P450 enzymes and internal exposure dynamics of the AhR binding xenobiotic benz[a]anthracene

Kühnert, Agnes; Vogs, Carolina; Seiwert, Bettina; Aulhorn, Silke; Altenburger, Rolf; Hollert, Henner; Küster, Eberhard; Busch, Wibke

doi:10.1016/j.envpol.2017.04.083

Cited by 29 publications

(12 citation statements)

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“…Compared to the size of the "hotspots" detected for PAS-B domains of HIF-1α and HIF-2α (which were consistent with experimental structures), the binding site of AhR was predicted to be able to accommodate larger and chemically diverse ligands. This is consistent with the information on the chemical structure of known AhR ligands, which include large, rigid, and highly hydrophobic polyaromatic hydrocarbons, 48 endogenous metabolites such as kynurenine, 49 polyphenols, 50 and a lot of chemically diverse approved drug molecules 51 and natural products. 52 Predicting the binding affinity for these compounds using virtual screening methods is nontrivial, but doable.…”

Section: Resultssupporting

confidence: 88%

Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

et al. 2019

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Section: Resultssupporting

confidence: 88%

Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

et al. 2019

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“…A delayed expression of cyp1b and cyp1c underscore the differences in capability for fish embryos to metabolize xenobiotics depending on their embryonic developmental window. Our results coincide with the findings of (Kuhnert et al, 2017) where the expression of cyp1b and cyp1c is also delayed in zebrafish exposed to benzo(a)pyrene.…”

Section: Pah Uptake Cyp Induction and Metabolismsupporting

confidence: 91%

Untangling mechanisms of crude oil toxicity: linking gene expression, morphology and PAHs at two developmental stages in a cold-water fish

Sørhus¹,

Donald²,

Dasilva

et al. 2020

Preprint

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Early life stages of fish are highly sensitive to crude oil exposure and thus, short term exposures during critical developmental periods could have detrimental consequences for juvenile survival. To obtain a broader understanding of the mechanisms behind crude oil toxicity, we administered crude oil to Atlantic haddock (Melanogrammus aeglefinus) in short term (3-day) exposures at two developmental time-points, before and after onset of heartbeat. A frequent sampling regime enabled us to determine and link immediate PAH uptake, metabolite formation and gene expression changes (cyp1a,b,c,d, bmp10, abcb1 and rhag). In general, the embryotoxic consequences were more severe in the earliest exposure, and oil droplet fouling enhanced the toxicity. This study detected circulation-independent, oil-induced gene expression changes and separated phenotypes linked to proliferation, growth and disruption of formation events at early and late developmental stages. A greater understanding of crude oil toxicity is essential for predicting the consequences of oil spills.Graphic abstractHighlightsOil droplet fouling occurred in the whole water column and increased the oil toxicity.Early exposure resulted in higher PAH uptake due to lower metabolism resulting in more severe abnormalities.A rapid and circulation-indepenent regulation of bmp10 suggested a direct oil-induced effect on calcium homeostasis.Expression of rhag indicated a direct oil-induced effect on osmoregulatory cells and osmoregulation.Severe eye abnormalities especially in the late exposure was linked to inappropriate overexpression of cyp1b in the eyes.

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“…Since the same whole zebrafish body samples were used as in a study of Vergauwen et al [54], the time window for the mRNA expression analysis was extended to 32 dpf to make the results comparable between both studies. As in literature, data on the ontogeny of CYP1 , CYP3 and, to a lesser extent, CYP2 mRNA expression in zebrafish are limited to approximately 6 dpf [22,26,31,32,55,56,57,58,59,60,61,62,63], we decided to also include the constitutive mRNA expression of zebrafish CYP1 , CYP2 , and CYP3 families at different time points between 1.5 hpf and 32 dpf in our assessment. Similar to the in vivo CYP activity study with BOMR, the mRNA expression of most CYP enzymes, phase II enzymes and P-glycoprotein reached maximum expression levels by the end of zebrafish organogenesis and remained stable throughout larval development.…”

Section: Introductionmentioning

confidence: 99%

From mRNA Expression of Drug Disposition Genes to In Vivo Assessment of CYP-Mediated Biotransformation during Zebrafish Embryonic and Larval Development

Verbueken

Bars

Ball

et al. 2018

IJMS

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The zebrafish (Danio rerio) embryo is currently explored as an alternative for developmental toxicity testing. As maternal metabolism is lacking in this model, knowledge of the disposition of xenobiotics during zebrafish organogenesis is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this study was to assess cytochrome P450 (CYP) activity in zebrafish embryos and larvae until 14 d post-fertilization (dpf) by using a non-specific CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR) and a CYP1-specific substrate, i.e., 7-ethoxyresorufin (ER). Moreover, the constitutive mRNA expression of CYP1A, CYP1B1, CYP1C1, CYP1C2, CYP2K6, CYP3A65, CYP3C1, phase II enzymes uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and sulfotransferase 1st1 (SULT1ST1), and an ATP-binding cassette (ABC) drug transporter, i.e., abcb4, was assessed during zebrafish development until 32 dpf by means of quantitative PCR (qPCR). The present study showed that trancripts and/or the activity of these proteins involved in disposition of xenobiotics are generally low to undetectable before 72 h post-fertilization (hpf), which has to be taken into account in teratogenicity testing. Full capacity appears to be reached by the end of organogenesis (i.e., 120 hpf), although CYP1—except CYP1A—and SULT1ST1 were shown to be already mature in early embryonic development.

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Biotransformation in the zebrafish embryo –temporal gene transcription changes of cytochrome P450 enzymes and internal exposure dynamics of the AhR binding xenobiotic benz[a]anthracene

Cited by 29 publications

References 50 publications

Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

Untangling mechanisms of crude oil toxicity: linking gene expression, morphology and PAHs at two developmental stages in a cold-water fish

From mRNA Expression of Drug Disposition Genes to In Vivo Assessment of CYP-Mediated Biotransformation during Zebrafish Embryonic and Larval Development

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