title: Chlorotriazine herbicides and metabolites activate an ACTH-dependent release of corticosterone in male Wistar rats.
abstract: Previously, we reported that atrazine (ATR) alters steroidogenesis in male Wistar rats resulting in elevated serum corticosterone (CORT), progesterone, and estrogens. The increase in CORT indicated that this chlorotriazine herbicide may alter the hypothalamic-pituitary-adrenal axis. This study characterizes the temporal changes in adrenocorticotropic hormone (ACTH), CORT, and P4 in male Wistar rats following a single dose of ATR (0, 5, 50, 100, and 200 mg/kg), simazine (SIM; 188 mg/kg), propazine (PRO; 213 mg/kg), or primary metabolites, deisopropylatrazine (DIA; 4, 10, 40, 80, and 160 mg/kg), deethylatrazine (DEA; 173 mg/kg), and diamino-s-chlorotriazine (DACT; 3.37, 33.7, 67.5, and 135 mg/kg). The maximum dose for each chemical was the molar equivalent of ATR (200 mg/kg). Significant increases in plasma ACTH were observed within 15 min, following exposure to ATR, SIM, PRO, DIA, or DEA. Dose-dependent elevations in CORT and progesterone were also observed at 15 and 30 min post-dosing with these compounds indicating an activation of adrenal steroidogenesis. Measurement of the plasma concentrations of the parent compounds and metabolites confirmed that ATR, SIM, and PRO are rapidly metabolized to DACT. Although DACT had only minimal effects on ACTH and steroid release, dosing with this metabolite resulted in plasma DACT concentrations that were 60-fold greater than that observed following an equimolar dose of ATR and eightfold greater than equimolar doses of DIA or DEA, indicating that DACT is not likely the primary inducer of ACTH release. Thus, the rapid release of ACTH and subsequent activation of adrenal steroidogenesis following a single exposure to ATR, SIM, PRO, DIA, or DEA may reflect chlorotriazine-induced changes at the level of the brain and/or pituitary.
authors.affiliation: Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. laws.susan@epa.gov
authors.forename: Susan C
authors.initials: SC
authors.lastname: Laws
authors.forename: Michelle
authors.initials: M
authors.lastname: Hotchkiss
authors.forename: Janet
authors.initials: J
authors.lastname: Ferrell
authors.forename: Saro
authors.initials: S
authors.lastname: Jayaraman
authors.forename: Lesley
authors.initials: L
authors.lastname: Mills
authors.forename: Walker
authors.initials: W
authors.lastname: Modic
authors.forename: Nicole
authors.initials: N
authors.lastname: Tinfo
authors.forename: Melanie
authors.initials: M
authors.lastname: Fraites
authors.forename: Tammy
authors.initials: T
authors.lastname: Stoker
authors.forename: Ralph
authors.initials: R
authors.lastname: Cooper
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D003345:Corticosterone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000097:blood / Q000633:toxicity*; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D014227:Triazines / Q000097:blood / Q000633:toxicity*
chemical_list: D006540:Herbicides; D014227:Triazines; C060537:chlortriazine; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone