Recent advances in the toxicological effects of difenoconazole: A focus on toxic mechanisms in fish and mammals

The toxicological study of pesticides at sub-lethal and environment-relevant concentrations has become increasingly crucial for human and environmental health. Toxic mechanisms of agrochemicals contribute to discovering green pesticides, assessing the hazards of pesticides comprehensively, and supporting legitimate regulatory decisions. However, the toxicological effects of difenoconazole are not yet fully understood despite being frequently detected in fruits, vegetables, waters, and soils and posing hazards to humans and the environment. This lack of knowledge could lead to flawed risk assessment and administrative oversight. Thus, the review aimed to provide some investigation perspectives for clarifying the toxicological effects of difenoconazole by synthesizing the toxic data of difenoconazole on various organisms, such as bees, Daphnia magna, fish, earthworms, mammals, and plants and summarizing the toxicological mechanisms of difenoconazole, especially in fish and mammals from peer-reviewed publications. Evidence revealed that difenoconazole caused multiple toxicological effects, including developmental toxicity, reproductive toxicity, endocrine disruption effects, neurotoxicity, and transgenerational toxicity. The toxic mechanisms involved in metabolic disturbance, oxidative stress, inflammation, apoptosis, and autophagy by activating reactive oxygen species-mediated signaling pathways and mitochondrial apoptosis routes, disturbing amino acids, lipid, and nucleotide metabolism, and regulating gene transcription and expression in mammals and fish. Based on the review, further studies better focus on the toxic differences of difenoconazole stereoisomers, the toxicological effects of transformation products of difenoconazole, and the mechanism of action of difenoconazole on sex-specific endocrine disruption effects, intestinal damage, and gut dysbacteriosis for its hazard assessment and management synthetically.