Rieke Svenja, Koehn Sophie, Hirsch-Ernst Karen, Pfeil Rudolf, Kneuer Carsten, Marx-Stoelting Philip
Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str 8-10, 10589 Berlin, Germany.
Int J Environ Res Public Health. 2014 Sep 17;11(9):9660-79. doi: 10.3390/ijerph110909660.
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.
消费者通过饮食接触到多种不同农药的残留。因此，欧盟的农药立法要求对单一活性物质进行评估，并考虑联合效应。因此，分析物质在广泛剂量范围内的联合效应是当前实验和监管毒理学面临的关键挑战。在此，我们报告了在人胎盘细胞系Jeg-3中，（三）唑类杀菌剂（一类广泛使用的抗真菌剂）存在相加效应的证据。除了环丙唑醇、环氧唑菌唑、氟硅唑和戊唑醇这几种三唑类杀菌剂以及咪鲜胺外，还研究了其他化学类别的农药，这些农药被认为通过不同的作用模式起作用（即有机磷毒死蜱和三嗪基磺酰脲类除草剂甲基三氟磺隆）。分析的终点包括类固醇激素生成（孕酮和雌二醇）的合成以及类固醇生成和非类固醇生成细胞色素P-450（CYP）酶的基因表达。对于三唑类杀菌剂和咪鲜胺，观察到孕酮生成呈剂量依赖性抑制，并且在体外可以确认这些物质的几种组合存在相加效应。非三唑类的毒死蜱和甲基三氟磺隆不影响该终点，与此发现一致，当这些物质与咪鲜胺混合使用时未观察到相加性。虽然咪鲜胺略微增加了芳香化酶的表达和雌二醇的生成，而甲基三氟磺隆降低了雌二醇的生成，但其他物质均未对Jeg-3细胞中类固醇生成CYP酶的表达水平产生影响。对于某些三唑类杀菌剂、咪鲜胺和毒死蜱，观察到CYP1A1 mRNA表达有显著诱导以及该终点存在潜在的联合效应。AhR抑制剂CH223191对CYP1A1 mRNA诱导的抑制表明该效应依赖于AhR受体。
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