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Combination Effects of (Tri)Azole Fungicides on Hormone Production and Xenobiotic Metabolism in a Human Placental Cell Line

Author

Listed:
  • Svenja Rieke

    (Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany)

  • Sophie Koehn

    (Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany)

  • Karen Hirsch-Ernst

    (Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany)

  • Rudolf Pfeil

    (Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany)

  • Carsten Kneuer

    (Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany)

  • Philip Marx-Stoelting

    (Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany)

Abstract

Consumers are exposed to multiple residues of different pesticides via the diet. Therefore, EU legislation for pesticides requires the evaluation of single active substances as well as the consideration of combination effects. Hence the analysis of combined effects of substances in a broad dose range represents a key challenge to current experimental and regulatory toxicology. Here we report evidence for additive effects for (tri)azole fungicides, a widely used group of antifungal agents, in the human placental cell line Jeg-3. In addition to the triazoles cyproconazole, epoxiconazole, flusilazole and tebuconazole and the azole fungicide prochloraz also pesticides from other chemical classes assumed to act via different modes of action ( i.e. , the organophosphate chlorpyrifos and the triazinylsulfonylurea herbicide triflusulfuron-methyl) were investigated. Endpoints analysed include synthesis of steroid hormone production (progesterone and estradiol) and gene expression of steroidogenic and non-steroidogenic cytochrome-P-450 (CYP) enzymes. For the triazoles and prochloraz, a dose dependent inhibition of progesterone production was observed and additive effects could be confirmed for several combinations of these substances in vitro . The non-triazoles chlorpyrifos and triflusulfuron-methyl did not affect this endpoint and, in line with this finding, no additivity was observed when these substances were applied in mixtures with prochloraz. While prochloraz slightly increased aromatase expression and estradiol production and triflusulfuron-methyl decreased estradiol production, none of the other substances had effects on the expression levels of steroidogenic CYP-enzymes in Jeg-3 cells. For some triazoles, prochloraz and chlorpyrifos a significant induction of CYP1A1 mRNA expression and potential combination effects for this endpoint were observed. Inhibition of CYP1A1 mRNA induction by the AhR inhibitor CH223191 indicated AhR receptor dependence this effect.

Suggested Citation

  • Svenja Rieke & Sophie Koehn & Karen Hirsch-Ernst & Rudolf Pfeil & Carsten Kneuer & Philip Marx-Stoelting, 2014. "Combination Effects of (Tri)Azole Fungicides on Hormone Production and Xenobiotic Metabolism in a Human Placental Cell Line," IJERPH, MDPI, vol. 11(9), pages 1-20, September.
    • Handle: RePEc:gam:jijerp:v:11:y:2014:i:9:p:9660-9679:d:40317
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    References listed on IDEAS

    as
    1. Niels Hadrup & Camilla Taxvig & Mikael Pedersen & Christine Nellemann & Ulla Hass & Anne Marie Vinggaard, 2013. "Concentration Addition, Independent Action and Generalized Concentration Addition Models for Mixture Effect Prediction of Sex Hormone Synthesis In Vitro," PLOS ONE, Public Library of Science, vol. 8(8), pages 1-13, August.
    2. Yanming Wu & Xiao Chen & Qian Zhou & Qizhi He & Jiuhong Kang & Jing Zheng & Kai Wang & Tao Duan, 2014. "ITE and TCDD Differentially Regulate the Vascular Remodeling of Rat Placenta via the Activation of AhR," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-9, January.
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    Cited by:

    1. Suhui Zhang & Xiaoqin Cheng & Yu Wang & Junpei Fan & Rui Li & Su Zhou & Shihong Liu & Jingmin Shi & Jie Sun & Yue Hu & Chaojin Xu & Chunhua Wu & Xiuli Chang & Liming Tang & Zhijun Zhou, 2015. "Ninety Day Toxicity and Toxicokinetics of Fluorochloridone after Oral Administration in Rats," IJERPH, MDPI, vol. 12(5), pages 1-25, May.

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