Toxicity Profiles in Rats Treated with Tumorigenic and Nontumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

Abstract

Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for triadimefon-induced thyroid gland tumors was not supported by the data.

Transcriptional Profiles in Liver from Rats Treated with Tumorigenic and Non-tumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

“…The triadimefon-induced rat thyroid tumors were proposed to arise secondary to hepatic metabolism of T4 with an associated persistent increase in TSH. However, the data from Wolf et al (2006) suggested that although there was induction of UGT enzyme activity and a mild decrease in serum T3 and T4 levels, there were no associated increases in TSH levels. Thus triadimefon-induced thyroid tumors are likely due to another mode of action.…”

“…Inflammation responses and damaged proteins could be a source of toxicity in and of itself or could certainly amplify any initial hepatic toxicity. Combining the evidence presented in Wolf et al (2006) with the present systematic analysis of transcription after conazole exposure provides a differential response by triadimefon, associated with dysregulation of cell-regulating processes whereas propiconazole appeared to have a unique toxicity profile of acute inflammation and protein metabolism. Both of these profiles certainly could underlie the observed hepatic toxicity of hypertrophy and increased liver weight, and could serve as key events to characterize and distinguish the rat tumorigen, triadimefon, from nonthyroid tumorigen propiconazole.…”

“…The complete details of the in life experiments are described in Wolf et al (2006). All studies mentioned in that report were approved by an Institutional Animal Care and Use Committee and conform to the Guide for the Care and Use of Laboratory Animals.…”

Analysis of Hexaconazole in Agricultural Products using Multi Class Pesticide Multiresidue Method

“…Triazole계 농약은 ergosterol biosynthesis inhibitor (EBI)계 농약의 한 종류로 침투 이행성, 내우성 농약으로 예방 및 치료효과가 좋아 사용량이 많 다 2) . EBI계 농약은 isoprenoid 생합성 경로에 관여하여 병 원성 미생물의 세포막 ergosterol 생합성을 저해하여 병원 균 증식을 저해한다 3) . Triazole계 잔류농약 분석에 흔히 이 용되는 방법은 ECD (electron capture detector) 4,5) 나 NPD (nitrogen phosphorous detector) 6,7) 를 이용한 GC 분석과 SIM (selective ion monitoring)이나 Full scan mode에서의 GC-MS .…”

A Review on Microextraction Techniques for Selected Triazole Fungicides Determination in Water and Food Samples

“…Many studies have been carried out concerning these pesticides effects in animals. Tumorigenic effects [4], endocrine disrupting effects [5] and disturbances in reproductive systems have been shown in rats [6]. Those fungicides can also induce some tumors in mice livers [7].…”