Endpoints as human biomarkers in exposure assessment of triazoles fungicides

https://doi.org/10.1016/j.etap.2021.103703Get rights and content

Highlights

  • Plasmatic androstenedione can be a biomarker in the assessment of triazoles exposure.

  • Glycine-conjugated bile acids can be biomarkers to triazoles exposure assessment.

  • Oxidative stress didn’t present significant differences in triazoles exposed group.

  • Testosterone levels didn’t present differences between groups of rural residents.

  • Unconjugated and taurine conjugated bile acids weren’t efficient effect biomarkers.

Abstract

Potential endpoint biomarkers were evaluated in the assessment of exposure to triazoles, in the southern region of Minas Gerais, Brazil. Volunteers were divided into three groups: occupationally exposed and rural residents (n = 21), non-occupationally exposed and rural residents (n = 35) and non-occupationally exposed and urban residents (n = 30). Of all endpoints evaluated, plasma concentration of androstenedione (p < 0.001) and glycine-conjugated bile acids presented statistical differences in the three studied groups (p < 0.05). However, our findings concerning oxidative stress and testosterone levels, plus that related to unconjugated and taurine conjugated bile acids, suggested that more studies are necessary to evaluate their potential as biomarkers for triazole exposure, as statistical significance was not attained between the groups. Our human population data contributes to the development of triazole exposure risk assessment with respect to these potential effect biomarkers, in potentially vulnerable groups and individuals.

Introduction

The harmful effects that pesticides have on human health have been widely studied, focusing mainly on the lack of selectivity of action of these compounds, which represents a risk to humans and other life forms present in the environment. Among the most used pesticides in the world are fungicides, and triazoles as a class of these agents, are widely used. This partly because of their antifungal effectiveness, but also due to their lower environmental persistence, as their short half-lives reduce bioaccumulation; these features compare favourably with other heavily used pesticides, such as the organochlorine/organophosphate agents (Huang et al., 2016; Rieke et al., 2017; Silvério et al., 2017). That said, the assessment of exposure to triazoles should establish priorities and effective forms of intervention to protect the population from potential risks related to these compounds.

Triazoles have endocrine disrupting effects, mainly due to their mechanism of action. They are potent inhibitors of the CYP51 (lanosterol-14α-demethylase) family, their main antifungal mechanism of action. However, studies show that there is no specificity in the enzyme inhibition mechanism and inhibitions of various cytochrome P450 isoenzymes such as CYP3A4, CYP2C9 and CYPC19 have been documented, which may cause toxic effects on non-target organisms (Heise et al., 2018; Rieke et al., 2017; Tully et al., 2006). In humans, a product derived from CYP51 demethylation is cholesterol, which is required for the synthesis of bile acids, mineralocorticoids, glucocorticoids and sex steroids (Strushkevich et al., 2010; Trösken et al., 2006).

In order to avoid the appearance of toxic adverse effects during the use of these chemicals, occupational exposure monitoring should be carried out by assessing biomarkers, which expresses correlation with exposure and are previously determined by animal studies using surrogate endpoints, which are markers intended to replace a clinical endpoint, with the ability to predict damage short of irreversibility (Berns et al., 2007; Silins and Högberg, 2011; Machado and Martins, 2018). Hence, surrogate endpoints are potential parameters that can be applied to estimate the risk of the exposure and could help to prevent toxic sequalae in human populations.

Therefore, the objective of this study was to evaluate potential surrogate endpoints candidates for effect biomarkers in the assessment of exposure to triazoles, based on animal studies or other biological matrices, noting possible clinical effects that could reproduce in humans, mainly related to its mechanism of action, such as the endocrine disrupting effect, oxidative stress and liver damage assessment. These fungicides were selected for this study due to their high frequency of use, as well as their toxicity shown in animal studies. Unfortunately, human data is scarce, which encouraged our mission to evaluate tools that can be applied in the prevention of poisoning and contribute to the assessment of occupational exposure to such substances.

Section snippets

Study design

For the study of potential biomarkers to assess the exposure to triazoles, a random sampling was carried out from people exposed in the last 30 days, based on the period of application of fungicides in coffee plantations, in Alfenas and region (southern region of Minas Gerais, Brazil (21°36′37″ S; 45°34′8″ W)). Volunteers were divided into three groups: occupationally exposed and rural residents (n = 21), non-occupationally exposed and rural residents (n = 35) and non-occupationally exposed and

Results and discussion

This innovative work was developed to evaluate animal endpoints as potential biomarkers of exposure to triazoles in humans. For this purpose, a study with workers occupationally exposed to these fungicides was performed to analyse potential surrogate endpoints that can be applied to estimate the risk of the exposure and to prevent toxic effects. The mean age of the rural residents was 42.6 ± 11.98 years (occupationally exposed group) and 42.2 ± 12.76 years (non-occupationally exposed group). In

Conclusions

Of all endpoints evaluated for the application in the biomonitoring of the exposure to triazoles, only plasma concentrations of androstenedione and glycine-conjugated bile acids presented statistical difference in the three studied groups (occupationally exposed and rural residents, non-occupationally exposed and rural residents and non-occupationally exposed and urban residents). Thus, based on the data, these biomarkers should be considered in the biomonitoring of exposure to these

Funding

This work was supported in part by the CAPES (Higher Level Personnel Improvement Commission) [Finance Code 001] and FAPEMIG (Foundation to support the research of Minas Gerais) [grant number APQ-02281-16].

Conflict of Interest

The authors declare no conflict of interest.

CRediT authorship contribution statement

Simone Caetani Machado: Methodology, Validation, Formal analysis, Investigation, Writing - original draft, Writing - review & editing. Bruna Maciel Souza: Validation, Investigation. Luiz Paulo de Aguiar Marciano: Validation, Investigation. Ana Flávia Souza Pereira: Validation, Investigation. Maisa Ribeiro Pereira Lima Brigagão: Conceptualization, Methodology, Resources. André Luiz Machado Viana: Validation, Investigation. Maria Rita Rodrigues: Conceptualization, Methodology. Isarita Martins:

Declaration of Competing Interest

The authors report no declarations of interest.

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