Identification and Quantification of Metabolites of the Fungicide Tebuconazole in Human Urine

Mercadante, Rosa; Polledri, Elisa; Scurati, Silvia; Moretto, Angelo; Fustinoni, Silvia

doi:10.1021/tx500291t

Cited by 43 publications

(30 citation statements)

References 10 publications

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“…52 In human urine, hydroxyl and carboxyl products of tebuconazole were identified as major BTPs, both free and as glucuronide conjugates. 60 For propiconazole, the large majority of BTPs identified in mammals contained the unchanged triazole ring which is in line with our results. 52 Little data is available for epoxiconazole.…”

Section: Comparison With Literature Data For Other Speciessupporting

confidence: 92%

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

Rösch

Anliker

Hollender

2016

Environ. Sci. Technol.

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Biotransformation is a key process that can greatly influence the bioaccumulation potential and toxicity of organic compounds. In this study, biotransformation of seven frequently used azole fungicides (triazoles: cyproconazole, epoxiconazole, fluconazole, propiconazole, tebuconazole and imidazoles: ketoconazole, prochloraz) was investigated in the aquatic invertebrate Gammarus pulex in a 24 h exposure experiment. Additionally, temporal trends of the whole body internal concentrations of epoxiconazole, prochloraz, and their respective biotransformation products (BTPs) were studied to gain insight into toxicokinetic processes such as uptake, elimination and biotransformation. By the use of high resolution tandem mass spectrometry in total 37 BTPs were identified. Between one (ketoconazole) and six (epoxiconazole) BTPs were identified per parent compound except for prochloraz, which showed extensive biotransformation reactions with 18 BTPs detected that were mainly formed through ring cleavage or ring loss. In general, most BTPs were formed by oxidation and conjugation reactions. Ring loss or ring cleavage was only observed for the imidazoles as expected from the general mechanism of oxidative ring openings of imidazoles, likely affecting the bioactivity of these BTPs. Overall, internal concentrations of BTPs were up to 3 orders of magnitude lower than that of the corresponding parent compound. Thus, biotransformation did not dominate toxicokinetics and only played a minor role in elimination of the respective parent compound, with the exception of prochloraz.

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Section: Comparison With Literature Data For Other Speciessupporting

confidence: 92%

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

Rösch

Anliker

Hollender

2016

Environ. Sci. Technol.

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“…As a triazole fungicide, TEB has been widely used in agriculture, leading to adverse effects on humans and wildlife (Sivikova, Dianovsky, Holeckova, Galdikova, & Kolesarova, ; Renzo et al, 2011; Castro et al, ; Bernardes, Andrade‐Vieira, Aragao, Ferreira, & Ferreira, ; Mercadante et al, ). The persistence in the environment and long half‐life mean that transgenerational investigation by parental exposure becomes very significant.…”

Section: Discussionmentioning

confidence: 99%

“…A survey conducted by Lefrancq et al assessed 20 runoff events from 2009 to 2012 at the outlet of a vineyard catchment in the Layon catchment in France and the results showed that the concentration of TEB could reach 357 μg/L (Lefrancq, Jadas‐Hecart, La Jeunesse, Landry, & Payraudeau, ). Evidence showed that the metabolites of TEB in agricultural workers ranged from 3 to 473 μg/L in urine (Mercadante, Polledri, Scurati, Moretto, & Fustinoni, ). Additionally, an increase in TEB levels in agricultural workers ranging from 15.5 to141.3 pg/mg hairs, which indicated that TEB could accumulate in hair during the agricultural season (Mercadante, Polledri, Moretto, & Fustinoni, ).…”

Section: Introductionmentioning

confidence: 99%

Transgenerational reproductive and developmental toxicity of tebuconazole in Caenorhabditis elegans

Liu

2020

J of Applied Toxicology

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The transgenerational reproductive and developmental toxicity of tebuconazole (TEB) in Caenorhabditis elegans was investigated over five generations (P0 − F4). Only parental C.elegans (P0) were exposed to TEB (0, 0.01, 0.1, 1, and 10 μg/L) for 24 h and the subsequent offspring (F1-F4) were grown under TEB-free conditions. TEB exposure caused dose-dependent reproductive defects and developmental impairments in C.elegans. In the P0 generation reproductive defects were observed such as:reduced brood size and embryo hatchability, prolonged generation time, retarded gonadal development, and slower germline proliferation, even at 0.01 μg/L, together with developmental toxicity with significant reduced body length and narrowed body width at 10 μg/L. Additionally, the brood size significantly reduced in F2, which began to recover from F3, but was still lower than the control in F4. The proportion of abnormalities increased significantly in F2 and reduced from F3, but was still higher than the control, suggesting that TEB could have cumulative potential and be passed to offspring through parental exposure. Furthermore, exposure to TEB (10 μg/L) in P0 significantly reduced the body length in F1, which began to recover from F2, and was the same level as the control in F4. There was a concentrationdependent increase in body width in F1-F4, with a significant increase only observed in F1 at 10 μg/L. Thus, parental exposure to TEB induced transgenerational defects in both reproduction and development, emphasizing the significance of considering bio-toxicity over multiple generations to conduct accurate assessment of environmental risks of toxicants. K E Y W O R D SCaenorhabditis elegans, parental exposure, reproductive and developmental toxicity, Tebuconazole, trans-generation

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“…7 The aim of this work was to identify the major metabolites of PEN in human urine; this was achieved analyzing samples of agricultural workers exposed to PEN by LC-QqLIT MS; the second aim was to estimate the abundance of these metabolites to orientate the choice of a molecular marker for biomonitoring human exposure.…”

Section: ■ Introductionmentioning

confidence: 99%

Identification of Metabolites of the Fungicide Penconazole in Human Urine

Mercadante

Polledri

Scurati³

et al. 2016

Chem. Res. Toxicol.

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Penconazole (PEN) is a fungicide used in agriculture that has been classified as hazardous to humans and the environment. The objective of this work was to identify PEN urinary metabolites in humans and propose a biomarker for PEN exposure. Five urine samples were collected from agricultural workers who worked with and were exposed to PEN. Samples were analyzed by liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry, with the source operating in the electrospray ionization mode. Metabolites previously identified in animal studies were searched as possible metabolites in humans. Candidate metabolites were first identified by multiple reaction monitoring following the protonated molecular ions that generated the protonated triazole moiety, which is expected to be present in all PEN metabolites; second, the isotopic patterns of the molecular ions were checked for consistency with the presence of two chlorine atoms; third, the full mass spectra were evaluated for consistency with the molecular structure. Seven different oxidized metabolites were found, both in the free and glucuronide conjugate forms. The major metabolite was the monohydroxyl-derivative PEN-OH (median molar fraction approximately 0.92 as a sum of free and glucuronide conjugated form). The product of further oxidation was the carboxyl-derivate PEN-COOH (median molar fraction approximately 0.03). After hydrolysis with β-glucuronidase, the free compounds were quantified in the presence of deuterated PEN as an internal standard; PEN-OH levels ranged from 230 to 460 μg/L, and PEN-COOH levels ranged from 5.2 to 16.7 μg/L. We propose a pathway for PEN metabolism in humans and suggest PEN-OH, after hydrolysis of glucuronide conjugates, as a biomarker for monitoring human exposure to PEN.

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Identification and Quantification of Metabolites of the Fungicide Tebuconazole in Human Urine

Cited by 43 publications

References 10 publications

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

How Biotransformation Influences Toxicokinetics of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex

Transgenerational reproductive and developmental toxicity of tebuconazole in Caenorhabditis elegans

Identification of Metabolites of the Fungicide Penconazole in Human Urine

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