Thyroid Dysfunction Induced by Fungicide Famoxadone Exposure Contributes to Nonalcoholic Fatty Liver Disease in Male Mice: In Vivo, In Vitro, and In Silico Studies.

Thyroid dysfunction has become a serious public health problem, which is considered a trigger of nonalcoholic fatty liver disease (NAFLD). Pesticide exposure could contribute to thyroid dysfunction and NAFLD, but the relationship between these factors remains unclear. In this study, the effects of subchronic famoxadone exposure on thyroid and liver at no observed adverse effect level (NOEL) related concentrations were investigated using in vivo, in vitro, and in silico models. Famoxadone caused hepatic steatosis, lipid metabolism disorder, and liver oxidative stress and induced NAFLD in male mice. The suppression of hepatic fatty acid ß-oxidation was the key factor of NAFLD, which was highly associated with hypothalamic-pituitary-thyroid (HPT) axis hormones disorder. Famoxadone disrupted thyroid hormone biosynthesis by causing thyroid follicle aberrations and abnormal HPT axis-related gene expression. In vitro studies confirmed that famoxadone inhibited the transport of thyroxine (T4) into hepatocytes and the conversion of T4 to triiodothyronine (T3). In silico studies verified that famoxadone interfered with the binding of thyroid hormones to proteins mediating thyroid hormone transport, conversion, and activation. This study comprehensively reported the association between NAFLD and thyroid dysfunction caused by famoxadone, providing new perspectives for the health risk evaluation of pesticides with a similar structure in mammals.

Enantioselective bioaccumulation and toxicological effects of chiral neonicotinoid sulfoxaflor in rats.

Sulfoxaflor is a widely used fourth-generation neonicotinoid pesticide, which has been detected in biological and environmental samples. Sulfoxaflor can potentially be exposed to humans via the food chain, thus understanding its toxic effects and enantioselective bioaccumulation is crucial. In this study, toxicokinetics, bioaccumulation, tissue distribution and enantiomeric profiles of sulfoxaflor in rats were investigated through single oral exposure and 28-days continuous exposure experiment. Sulfoxaflor mainly accumulated in liver and kidney, and the (-)-2R,3R-sulfoxaflor and (-)-2S,3R-sulfoxaflor had higher enrichment than their enantiomers in rats. The toxicological effects were evaluated after 28-days exposure. Slight inflammation in liver and kidney were observed by histopathology. Sphingolipid, amino acid, and vitamin B6 metabolism pathways were significantly disturbed in metabonomics analysis. These toxicities were in compliance with dose-dependent effects. These results improve understanding of enantioselective bioaccumulation and the potential health risk of sulfoxaflor.

Systematic health risks assessment of chiral fungicide famoxadone: Stereoselectivities in ferroptosis-mediated cytotoxicity and metabolic behavior.

Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R-famoxadone caused its preferential accumulation. Overall, R-famoxadone poses a higher risk than S-famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.

Bioaccumulation, metabolism and toxicological effects of chiral insecticide malathion and its metabolites in zebrafish (Danio rerio).

The bioaccumulation, metabolism, tissue-specific distribution and toxicity of the widely used organophosphorous pesticide malathion to zebrafish were investigated on an enantiomeric level for evaluating the environmental risks. The metabolites were also monitored and evaluated. Malathion was metabolized by zebrafish very fast with the half-life of 0.12 d and showed a middle accumulation capacity in zebrafish with bioaccumulation factor (BCF) of 12.9 after a 15-d exposure. Brain could enrich higher concentration of malathion than other tissues. The metabolites malaoxon, malathion/malaoxon monocarboxylic acid (DMA), malathion/malaoxon dicarboxylic acid (DCA), dimethylthiophosphate (DMTP) and dimethyldithiophosphate (DMDTP) were found, in which DMTP and DCA were in higher level, indicating the metabolism was mainly induced by carboxylesterase degradation. The accumulation of malathion and malaoxon was stereoselective in zebrafish tissues, exhibiting S-enantiomer preferentially enriched. The acute toxicity test showed rac-malathion was low toxic to zebrafish, which was 1.2 and 1.6 folds more toxic than S-malathion and R-malathion respectively. Malaoxon was highly toxic to zebrafish and approximately 32 times more toxic than malathion. The toxicity of other metabolites was lower than malathion. Malathion could cause an apparent developmental toxicity to zebrafish embryo, including bradycardia, hatchability reduction and deformity, and abnormal movement patterns in zebrafish larva. Chronic toxicity indicated that malathion and malaoxon induced oxidative damage and neurotoxicity in the liver, brain and gill of zebrafish, and malaoxon exhibited a relatively high injury to the zebrafish brain. The results can provide information for the comprehensive assessment of the potential risk of malathion to aquatic organisms and highlight the necessity of consideration of stereoselectivity and metabolites when systemically evaluating pesticides.

A Simple Method for the Determination of Pharmaceutical and Personal Care Products in Fish Tissue Based on Matrix Solid-Phase Dispersion.

A simple and effective pretreatment method based on matrix solid-phase dispersion was developed for the determination of pharmaceutical and personal care products (PPCPs) and their metabolites in fish by high-performance liquid chromatography tandem mass spectrometry. The type and amount of dispersant, adsorbent, and eluting solvent were optimized by a single-factor experiment and Box-Behnken design. Under the optimal conditions with 2.5 g of Florisil as a dispersant, 500 mg of C18 as an adsorbent, and 5 mL of acetonitrile as an eluting solvent, the recoveries ranged from 70.4 to 99.9% with relative standard deviations less than 10.5%, and the limits of quantitation ranged from 0.13 to 1.01 µg/kg. The developed method was successfully applied to detect PPCPs in marketed fish, and five PPCPs, including triclocarban, sulfadiazine, sulfadimidine, sulfamethoxazole, and carbamazepine, were detected at trace levels. The proposed method, which has the advantages of short analysis time, less solvent consumption, and high sensitivity, can be used for the determination of trace PPCPs in fish.