Triadimefon suppresses fetal adrenal gland development after in utero exposure

Illustration of the signaling pathway to regulate adrenal cortex development after triadimefon (TDM) exposure. TDM increases the generation of ROS to cause the following actions: 1) down-regulating IGF1, which can activate AKT1 signaling for the growth of the adrenal gland; 2) down-regulating AT1R and MC2R, which can activate ERK1/2 for the growth and survival of the adrenal gland; 3) down-regulating NR5A1, which can activate steroidogenesis via up-regulating the expression of steroidogenesis-related genes; 4) activating the phosphorylation of AMPK, which is a negative signal to control adrenal steroidogenesis mainly via down-regulating Star, Cyp11b1, Cyp11b2 expression, eventually leading to reduced synthesis of aldosterone (ALDO) and corticosterone (CORT) [Display omitted] •Triadimefon reduces serum ACTH level in male fetuses after in utero exposure.•Triadimefon reduces serum corticosterone and aldosterone levels in male fetuses.•Triadimefon down-regulates adrenal gland steroidogenesis-related gene expression.•Triadimefon induces AMPK phosphorylation in adrenal gland of male fetuses.•Triadimefon reduces AKT1 and ERK1/2 phosphorylation in adrenal gland of male fetuses. Triadimefon is a broad-spectrum antifungal agent, which is widely used in agriculture to control mold and fungal infections. It is considered an endocrine disruptor. Whether triadimefon exposure can inhibit the development of fetal adrenal glands and the underlying mechanism remain unclear. Thirty-two pregnant female Sprague-Dawley rats were randomly divided into four groups. Dams were gavaged triadimefon (0, 25, 50, and 100 mg/kg/day) daily for 10 days from gestational day (GD) 12 to GD 21. Triadimefon significantly reduced the thickness of the zona fasciculata of male fetuses at 100 mg/kg, although it did not change the thickness of the zona glomerulosa. It significantly reduced the serum aldosterone levels of male fetuses at a dose of 100 mg/kg, and significantly reduced serum corticosterone and adrenocorticotropic hormone levels at doses of 50 and 100 mg/kg. Triadimefon significantly down-regulated the expression of Agtr1, Mc2r, Star, Cyp11b1, Cyp11b2, Igf1, Nr5a1, Sod2, Gpx1, and Cat, but did not affect the mRNA levels of Scarb1, Cyp11a1, Cyp21, Hsd3b1, and Hsd11b2. Triadimefon markedly reduced AT1R, CYP11B2, IGF1, NR5A1, and MC2R protein levels. Triadimefon significantly reduced the phosphorylation of AKT1 and ERK1/2 at 100 mg/kg without affecting the phosphorylation of AKT2. In contr