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

Overview

Journal Int J Environ Res Public Health

Publisher MDPI

Specialties Environmental Health
Public Health

Date 2014 Sep 19

PMID 25233012

Citations 9

Authors

Svenja Rieke

Sophie Koehn

Karen Hirsch-Ernst

Rudolf Pfeil

Carsten Kneuer

Philip Marx-Stoelting

Affiliations

Soon will be listed here.

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.

Citing Articles

Understanding the impact of triazoles on female fertility and embryo development: Mechanisms and implications.

Sharma S, Pandey G Toxicol Rep. 2025; 14:101948.

PMID: 39996041 PMC: 11848504. DOI: 10.1016/j.toxrep.2025.101948.

The epoxiconazole and tebuconazole fungicides impair granulosa cells functions partly through the aryl hydrocarbon receptor (AHR) signalling with contrasted effects in obese, normo-weight and polycystic ovarian syndrome (PCOS) patients.

Serra L, Estienne A, Bongrani A, Rame C, Caria G, Froger C Toxicol Rep. 2024; 12:65-81.

PMID: 38259722 PMC: 10801249. DOI: 10.1016/j.toxrep.2023.12.009.

Triazole pesticides exposure impaired steroidogenesis associated to an increase in AHR and CAR expression in testis and altered sperm parameters in chicken.

Serra L, Bourdon G, Estienne A, Freville M, Rame C, Chevaleyre C Toxicol Rep. 2023; 10:409-427.

PMID: 37025555 PMC: 10070196. DOI: 10.1016/j.toxrep.2023.03.005.

Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection.

Gridan I, Ciorsac A, Isvoran A ADMET DMPK. 2022; 7(3):161-173.

PMID: 35350663 PMC: 8957235. DOI: 10.5599/admet.668.

The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity.

Marx-Stoelting P, Knebel C, Braeuning A Cells. 2020; 9(5).

PMID: 32403288 PMC: 7290820. DOI: 10.3390/cells9051192.

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