Altering cytochrome P4501A activity affects polycyclic aromatic hydrocarbon metabolism and toxicity in rainbow trout (<i>Oncorhynchus mykiss</i>)

Hawkins, Stephanie A.; Billiard, Sonya M.; Tabash, Samir; Brown, R. Stephen; Hodson, Peter V.

doi:10.1002/etc.5620210912

Cited by 108 publications

(41 citation statements)

References 36 publications

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“…The findings of enhanced PAH toxicity when in combination with a CYP1A inhibitor suggests that such inhibition may enhance the half-life of toxic PAHs [53]. However, less is known about exogenous inhibitors of CYP1A in combination with natural or endogenous ligands and AHR activators such as FICZ.…”

Section: Discussionmentioning

confidence: 99%

Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner

Wincent

Kubota

Timme‐Laragy

et al. 2016

Biochemical Pharmacology

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6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphtoflavone and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.

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Section: Discussionmentioning

confidence: 99%

Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner

Wincent

Kubota

Timme‐Laragy

et al. 2016

Biochemical Pharmacology

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“…Billiard (2002) found that the rank order for CYP1A induction in these fish did not predict the rank order for the induction of blue-sac-like symptoms; in fact, the only PAHs that caused blue-sac-like symptoms were retene and phenanthrene, the low- and non-inducing PAHs used in that study. Hawkins et al (2002) observed apparent additive toxicity in juvenile and larval rainbow trout coexposed to one of two PAHs, the alkylated AHR agonist retene or the non-AHR-agonist phenanthrene, with the P450 inhibitor PBO. In contrast, another study found that cotreatment with the partial AHR antagonist and CYP1A inhibitor ANF prevented the reduction of circulation in the dorsal midbrain of zebrafish caused by the PAH-type AHR agonist β-naphthoflavone (BNF; Dong et al 2002).…”

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confidence: 94%

“…Some PAHs have impacts on early life stages of fish, including reduced growth, cranial–facial malformations, yolk sac and pericardial edema, and subcutaneous hemorrhaging (Billiard et al 1999; Carls et al 1999; Hawkins et al 2002). These deformities closely resemble the “blue sac syndrome” that has been described in several fish species, including rainbow trout ( Oncorhynchus mykiss ), zebrafish ( Danio rerio ), medaka ( Oryzias latipes ), and killifish ( Fundulus heteroclitus ), exposed to certain halogenated aromatic compounds that are agonists for the aryl hydrocarbon receptor (AHR) (Chen and Cooper 1999; Elonen et al 1998; Helder 1981; Toomey et al 2001; Walker and Peterson 1991; Wannemacher et al 1992).…”

mentioning

confidence: 99%

Synergistic Embryotoxicity of Polycyclic Aromatic Hydrocarbon Aryl Hydrocarbon Receptor Agonists with Cytochrome P4501A Inhibitors inFundulus heteroclitus

Wassenberg¹,

Giulio²

2004

Environ Health Perspect

187

175

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Widespread contamination of aquatic systems with polycyclic aromatic hydrocarbons (PAHs) has led to concern about effects of PAHs on aquatic life. Some PAHs have been shown to cause deformities in early life stages of fish that resemble those elicited by planar halogenated aromatic hydrocarbons (pHAHs) that are agonists for the aryl hydrocarbon receptor (AHR). Previous studies have suggested that activity of cytochrome P4501A, a member of the AHR gene battery, is important to the toxicity of pHAHs, and inhibition of CYP1A can reduce the early-life-stage toxicity of pHAHs. In light of the effects of CYP1A inhibition on pHAH-derived toxicity, we explored the impact of both model and environmentally relevant CYP1A inhibitors on PAH-derived embryotoxicity. We exposed Fundulus heteroclitus embryos to two PAH-type AHR agonists, β-naphthoflavone and benzo(a)pyrene, and one pHAH-type AHR agonist, 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126), alone and in combination with several CYP1A inhibitors. In agreement with previous studies, coexposure of embryos to PCB-126 with the AHR antagonist and CYP1A inhibitor α-naphthoflavone decreased frequency and severity of deformities compared with embryos exposed to PCB-126 alone. In contrast, embryos coexposed to the PAHs with each of the CYP1A inhibitors tested were deformed with increased severity and frequency compared with embryos dosed with PAH alone. The mechanism by which inhibition of CYP1A increased embryotoxicity of the PAHs tested is not understood, but these results may be helpful in elucidating mechanisms by which PAHs are embryotoxic. Additionally, these results call into question additive models of PAH embryotoxicity for environmental PAH mixtures that contain both AHR agonists and CYP1A inhibitors.

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“…Waterborne PAH exposure caused toxicity and altered the rate of development in fish early life-stages (Barron et al, 2004; Hawkins et al, 2002; Incardona et al, 2004; Colavecchia et al, 2004). Fundulus heteroclitus , a model fish species used in ecotoxicological studies, had elevated deformity indices (heart elongation, pericardial edema, tail shortening, and hemorrhaging) after exposure to binary mixtures of PAHs including BaP, β-naphthoflavone (BNF), α-naphthoflavone (ANF), fluoranthene (FL), piperonyl butoxide (PBO), and 2-aminoanthracene (AA) (Wassenberg and Di Giulio, 2004).…”

Section: Introductionmentioning

confidence: 99%

Multigenerational effects of benzo[a]pyrene exposure on survival and developmental deformities in zebrafish larvae

et al. 2014

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In the aquatic environment, adverse outcomes from dietary polycyclic aromatic hydrocarbon (PAH) exposure are poorly understood, and multigenerational developmental effects following exposure to PAHs are in need of exploration. Benzo[a]pyrene (BaP), a model PAH, is a recognized carcinogen and endocrine disruptor. Here adult zebrafish (F0) were fed 0, 10, 114, or 1012 μg BaP/g diet at a feed rate of 1% body weight twice/day for 21 days. Eggs were collected and embryos (F1) were raised to assess mortality and time to hatch at 24, 32, 48, 56, 72, 80, and 96 hours post fertilization (hpf) before scoring developmental deformities at 96 hpf. F1 generation fish were raised to produce the F2 generation followed by the F3 and F4 generations. Mortality significantly increased in the higher dose groups of BaP (2.3 and 20 μg BaP/g fish) in the F1 generation while there were no differences in the F2, F3, or F4 generations. In addition, premature hatching was observed among the surviving fish in the higher dose of the F1 generation, but no differences were found in the F2 and F3 generations. While only the adult F0 generation was BaP-treated, this exposure resulted in multigenerational phenotypic impacts on at least two generations (F1 and F2). Body morphology deformities (shape of body, tail, and pectoral fins) were the most severe abnormality observed, and these were most extreme in the F1 generation but still present in the F2 but not F3 generations. Craniofacial structures (length of brain regions, size of optic and otic vesicles, and jaw deformities), although not significantly affected in the F1 generation, emerged as significant deformities in the F2 generation. Future work will attempt to molecularly anchor the persistent multigenerational phenotypic deformities noted in this study caused by BaP exposure.

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Altering cytochrome P4501A activity affects polycyclic aromatic hydrocarbon metabolism and toxicity in rainbow trout (Oncorhynchus mykiss)

Cited by 108 publications

References 36 publications

Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner

Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner

Synergistic Embryotoxicity of Polycyclic Aromatic Hydrocarbon Aryl Hydrocarbon Receptor Agonists with Cytochrome P4501A Inhibitors inFundulus heteroclitus

Multigenerational effects of benzo[a]pyrene exposure on survival and developmental deformities in zebrafish larvae

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