New Approach Methods for Hazard Identification: A Case Study with Azole Fungicides Affecting Molecular Targets Associated with the Adverse Outcome Pathway for Cholestasis.

Triazole fungicides such as propiconazole (Pi) or tebuconazole (Te) show hepatotoxicity in vivo, e.g., hypertrophy and vacuolization of liver cells following interaction with nuclear receptors such as PXR (pregnane-X-receptor) and CAR (constitutive androstane receptor).

Induction and repression effects on CYP and transporter protein abundance by azole mixture uptake in rat liver.

Detection of mixture effects is a major challenge in current experimental and regulatory toxicology. Robust markers are needed that are easy to quantify and responsive to chemical stressors in a broad dose range. Several hepatic enzymes and proteins related to drug metabolism like cytochrome-P-450 (CYP) enzymes and transporters have been shown to be responsive to pesticide active substances in a broad dose range and are therefore good candidates to be used as markers for mixture toxicity.

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

Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds.

The Acceptability and Effectiveness of Web-Based Developmental Surveillance Programs: Rapid Review.

Background: Web-based developmental surveillance programs may be an innovative solution to improving the early detection of childhood developmental difficulties, especially within disadvantaged populations.

Objective: This review aimed to identify the acceptability and effectiveness of web-based developmental surveillance programs for children aged 0 to 6 years.

Methods: A total of 6 databases and gray literature were searched using a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-informed protocol.

Assessment of mixture toxicity of (tri)azoles and their hepatotoxic effects in vitro by means of omics technologies.

Consumers are constantly exposed to chemical mixtures such as multiple residues of different pesticides via the diet. This raises questions concerning potential combination effects, especially because these substances are tested for regulatory purposes on an individual basis. With approximately 500 active substances approved as pesticides, there are too many possible combinations to be tested in standard animal experiments generally requested for regulatory purposes.

Pregnane X receptor mediates steatotic effects of propiconazole and tebuconazole in human liver cell lines.

Triazoles are commonly used fungicides which show liver toxicity in rodent studies. While hepatocellular hypertrophy is the most prominent finding, some triazoles have also been reported to cause hepatocellular steatosis. The aim of our study was to elucidate molecular mechanisms of triazole-mediated steatosis.

The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptor-dependent pathway.

Tebuconazole, a member of the triazole group of fungicides, exerts hepatotoxicity in rodent studies. Knowledge on the molecular mechanisms underlying tebuconazole toxicity is limited. Previous studies suggest that activation of xenobiotic-sensing nuclear receptors plays a role in triazole fungicide-mediated hepatotoxicity.

Propiconazole is an activator of AHR and causes concentration additive effects with an established AHR ligand.

Consumers are exposed to pesticide residues and other food contaminants via the diet. Both can exert adverse effects on different target organs via the activation of nuclear receptor pathways. Hepatotoxic effects of the widely used triazole fungicide propiconazole (Pi) are generally attributed to the activation of the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR).

Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells.

Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints.

Hepatotoxic effects of cyproconazole and prochloraz in wild-type and hCAR/hPXR mice.

The agricultural fungicides cyproconazole and prochloraz exhibit hepatotoxicity in rodent studies and are tumorigenic following chronic exposure. Both substances are suspected to act via a CAR (constitutive androstane receptor)/PXR (pregnane-X-receptor)-dependent mechanism. Human relevance of these findings is under debate.