Mixture effects of two plant protection products in liver cell lines

Zahn, Elisabeth; Wolfrum, J.; Knebel, Constanze; Heise, T.; Weiss, F. T.; Poetz, Oliver; Marx‐Stoelting, Philip; Rieke, S.

doi:10.1016/j.fct.2017.12.067

Cited by 13 publications

(9 citation statements)

References 45 publications

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“…CYPs are the major enzymes involved in xenobiotic metabolism. Nuclear receptors play vital roles in the regulation of CYPs expressions . CYPs are heavily investigated for chemical compounds‐induced toxicity in many animal models such as mice, rats, or rabbits.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear receptors play vital roles in the regulation of CYPs expressions. [14][15][16][17][18] CYPs are heavily investigated for chemical compounds-induced toxicity in many animal models such as mice, rats, or rabbits. Changes in expression levels or enzyme function of CYPs after certain chemical compound exposure are often used to analyze the mechanism for chemical compound-induced toxicity.…”

Section: Effects Of Pyrene Exposure On the Function Of Kidneys In Ratsmentioning

confidence: 99%

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Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Zhu

Zhao

Wang

et al. 2018

Environmental Toxicology

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Polycyclic aromatic hydrocarbons (PAHs) are a group of persistent organic pollutants primarily formed from the incomplete combustion of carbonaceous materials, and have adverse effects on human health. In this study, we investigated whether pyrene, a PAH consisting of 4 fused benzene rings, has adverse effects on rat. Adult male Sprague‐Dawly rats were treated daily by oral gavage with vehicle (corn oil) or pyrene at doses of 375, 750, 1500, or 2200 mg/kg/day for 4 days. The results showed that pyrene caused hepatotoxicity in rats. When compared with the control group, relative liver weights, plasma alanine aminotransferase, and direct bilirubin levels significantly increased after pyrene exposure. Hepatocyte swelling and degeneration and decreased hepatic total glutathione (GSH) levels were also found in pyrene‐exposed rats. We further observed that mRNA levels of several hepatic metabolizing enzymes regulated by constitutive androstane receptor (CAR) such as CYP2B1 and CYP2B2 significantly increased in pyrene‐exposed rats. These results suggest that decreased GSH levels, elevated hepatic metabolizing enzyme gene expression, and CAR activation are important contributors for pyrene‐induced hepatotoxicity in rats. Additionally, we found pyrene significantly induced plasma inflammatory indices including white blood cell and lymphocyte counts. We also observed that pyrene exposure increased relative weight of kidneys and disrupted kidney function with elevated urea and creatinine levels in rats.

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Pyrene Exposure On the Function Of Kidneys In Ratsmentioning

confidence: 99%

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Zhu

Zhao

Wang

et al. 2018

Environmental Toxicology

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“…For this purpose, we propose to investigate the applicability of liver cell cytotoxicity testing and the zebrafish early-life stage test. 5,6,32 The test systems were selected based on regulatory acceptance, the relevance of target sites, and sensitivity. On the one hand, they allow for the investigation of the kinetic influence of co-formulants on AS bioavailability.…”

Section: Tiered Toxicity Testingmentioning

confidence: 99%

“…[2][3][4] Nevertheless, non-active co-formulants may affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction, as demonstrated in studies comparing AS and PPPs. [5][6][7] Even though co-formulants need not be toxic themselves, their properties can influence the toxicity of the PPP. This influence is not likely to be limited to the generally tested acute endpoints.…”

Section: Introductionmentioning

confidence: 99%

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Bloch

Marx‐Stoelting

Martin

2020

Pest Management Science

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Plant protection products (PPPs) consist of pesticide active substances and co‐formulants. Generally, active substance effects are assumed to dominate in PPP toxicity. Nevertheless, co‐formulants may well affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction. To account for potential mixture effects and improve PPP data requirements for application in risk assessment, a tiered test strategy is proposed. The strategy is based on a comparison of PPP and active substance toxicity, which enables the prioritisation of PPPs for further testing, adaptation of the toxicological threshold value or removal of toxic co‐formulants from the PPP. Moreover, it focuses on the integrative assessment of existing information and newly generated data using alternative test methods. The proposed strategy will improve PPP toxicological assessment by accounting for mixture toxicity, providing a set of regulatory options for risk assessment and the necessary data for hazard assessment. The predictivity of alternative methods for PPPs will improve by evaluation of their reliability and uncertainty. © 2020 The Authors. Pest Management Science published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.

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“…Quantitative real-time PCR was performed of 40 ng cDNA on an ABI 7900HT instrument (Applied Biosystems) using Maxima SYBR Green/ROX qPCR Mastermix (Thermo Fisher Scientific) and primers (0.25 µM, synthesized at Eurofins Genomics, see Table 2). (Zahn et al, 2017). Afterwards, each sample was prepared and measured as described previously (Marx-Stoelting et al, 2017;Wegler et al, 2017).…”

Section: Gene Expression Analysismentioning

confidence: 99%

Propiconazole is an activator of AHR and causes concentration additive effects with an established AHR ligand

et al. 2018

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Pesticides can exert adverse effects on different target organs via the activation of nuclear receptor pathways. Hepatotoxic effects of the widely used triazole fungicide propiconazole (Pi) are generally attributed to the activation of the ligand-activated transcription factor constitutive androstane receptor (CAR) or the pregnane X receptor (PXR). We now investigated the effects of Pi on the ligand-activated transcription factor aryl hydrocarbon receptor AHR. Therefore, the effects of Pi on AHR-dependent reporter gene transactivation, AHR target gene mRNA and protein expression as well as enzyme activities were examined in HepG2 or HepaRG human hepatoma cells using dual luciferase assays, RT-PCR, mass spectrometry or the ethoxyresorufin-O-deethylase assay, respectively. Additionally mRNA expression and enzyme activity was analyzed in rat liver ex vivo. Furthermore, AHR target gene expression was measured in AHR-, CAR-, and PXR-knockout HepaRG cells. Subsequently, we investigated combination effects of Pi and the model AHR ligand benzo[b]fluoranthene (BbF) in vitro. Our results show that Pi activates the AHR in reporter gene assays in human HepG2 cells. This dose-dependent activation of the AHR was subsequently confirmed by real-time RT-PCR analyses of the model AHR target genes CYP1A1 and CYP1A2 in human HepaRG cells and in livers of rats treated with Pi for 28 days via the diet. In addition, results of CYP1A1 protein level quantification showed Pi-dependent induction of the enzyme. CYP1A1 enzyme activity measurements demonstrate that higher concentrations of Pi significantly induce CYP1A1-dependent reactions in human HepaRG cells and in rat liver. Gene expression analysis in AHR-knockout HepaRG cells showed no induction of CYP1A1 and CYP1A2, whereas gene expression in CAR-, and PXR-knockout cells was induced. Furthermore, mixture effects of Pi and BbF were observed in human cell lines. Modeling of dose-response curves revealed that these cellular effects can be explained by concentration additivity. In conclusion, our results demonstrate that the triazole Pi is an activator of AHR.

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Mixture effects of two plant protection products in liver cell lines

Cited by 13 publications

References 45 publications

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Propiconazole is an activator of AHR and causes concentration additive effects with an established AHR ligand

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