Effect of triadimefon on rat placental morphology, function, and gene expression. (1st December 2022)

• Record Type: Journal Article
• Authors: Chen, Quanxu; Lin, Liben; Xu, Qiang; Tong, Chenglin; Li, Mengli; Wang, Yiyan; Zhu, Yang; Zhao, Zhiguang; Ge, Ren-Shan
• Is Part Of: Toxicology letters. Volume 371(2022)
• Page Start: 25
• Page End: 37
• Publication Date: 2022-12-01
• Subjects: Triadimefon -- Fungicide -- Placental function -- Gene expression -- Pathological change; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.09.009
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Triadimefon is a fungicide that is broadly used to treat fungal diseases of plants. It causes developmental toxicity in the animal model. Whether triadimefon disrupts the placental function and the underlying mechanism remains unclear. Thirty-six female pregnant Sprague-Dawley rats were randomly assigned into four groups and were orally administered via gavage of triadimefon (0, 25, 50, and 100 mg/kg/day) for 10 days from gestational day (GD) 12–21. Triadimefon disrupted the structure of the placenta, leading to hypertrophy, abnormal hemodynamics, including fibrin exudation, edema, hemorrhage, infarction, and inflammation. RNA-seq analysis showed that triadimefon down-regulated the expression of developmental and metabolic genes, while up-regulating the immune/inflammatory genes. The qPCR showed that triadimefon markedly down-regulated the expression of Cpt1c, Scd2, Ldlr, Dvl1, Flt4, and Vwf and their proteins, while up-regulating the expression of Cyp1a1, Star, Ccl5, and Cx3cr1 and their proteins at 25–100 mg/kg. Western blot showed that triadimefon reduced the level of STAT3 at doses of 50 and 100 mg/kg and the phosphorylation of AMPK at 100 mg/kg. In conclusion, triadimefon severely damages the structure and function of the placenta, leading to placental hypertrophy, local blood circulation disorders, and inflammation and this may be associated with its down-regulation of genes related to metabolism and nutrient transport and the up-regulation of inflammatory genes via STAT3 and AMPK signals. Graphical Abstract: Illustration of the mode of action of triadimefon (TDM) exposure on placenta. TDM inhibits AMPK phosphorylation and STAT3 level, thus down-regulating the expression of Cpt1c, Scd2, Ldlr, Dvl1, Flt4, and Vwr thereby leading to nutrient transport disfunction and developmental failure and causing bleeding, and up-regulating the expression of Ccl5, Cx3cr1, Cyp1a1, and Star thereby causing the inflammation and steroid metabolism. We also randomly selected unaltered mRNAs, including nutrient transporters ( Slc1a5, Slc38a1, Slc38a2, Cd36, Cd34, Glut1 ) and metabolic functions ( Echs1, Hadhb ), developmental regulation ( Jag1, Gas6 ) and structural proteins ( Tln1, Gjb2 ). ga1 Highlights: Triadimefon reduces placental efficiency after gestational exposure. Triadimefon increases placental thickness. Triadimefon down-regulates the expression of nutrient transporter genes. Triadimefon up-regulates the expression of inflammatory genes. Triadimefon reduces AMPK phosphorylation and STAT3.