title: Developmental exposure to progestins causes male bias and precocious puberty in zebrafish (Danio rerio).
abstract: Progestins are aquatic contaminants that in low concentrations can impair fish reproduction. The mechanisms are likely multiple since different progestins interact with other steroid receptors in addition to progesterone receptors. Puberty is the process when animals first acquire the capability to reproduce and it comprises maturation of sperm and eggs. In zebrafish, puberty is initiated around 45days post fertilization (dpf) in females and around 53-55 dpf in males, and is marked by increased production of pituitary gonadotropins. We exposed juvenile zebrafish from 20 to 80 dpf to the androgenic progestin levonorgestrel at concentrations of 5.5, 79 and 834ngL(-1) and to the non-androgenic progestin progesterone at concentrations of 3.7, 77 and 1122ngL(-1), during sexual differentiation and puberty. Levonorgestrel exposure caused 100% males even at the lowest concentration tested whereas progesterone did not affect the sex ratio. Transcript levels of the gonadal genes amh, CYP11B and CYP19a1a indicated that the masculinizing effect of levonorgestrel occurred very rapidly. Transcript concentrations of gonadotropins in pituitaries were low in control fish at 44 dpf, but high at 55 dpf and onward. In fish exposed to levonorgestrel or progesterone gonadotropin transcript concentrations were high already at 44 dpf, indicating that both progestins caused precocious puberty. Gonad histology at 50 dpf confirmed a well advanced sexual maturation, but only in males. Our results show that progestins can affect sexual development in fish and that the androgenic progestin levonorgestrel induces a male phenotype at concentrations similar to those detected in aquatic environments.
authors.affiliation: Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, SE-75 236, Uppsala, Sweden. Electronic address: johan.svensson@ebc.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Svensson
authors.affiliation: Department of Comparative Physiology, Uppsala University, Norbyvägen 18A, SE-75 236 Uppsala, Sweden.
authors.forename: Arshi
authors.initials: A
authors.lastname: Mustafa
authors.affiliation: Department of Chemistry, Umeå University, Linnaeus väg 6, Umeå, SE-90 187, Sweden.
authors.forename: Jerker
authors.initials: J
authors.lastname: Fick
authors.affiliation: Department of Comparative Physiology, Uppsala University, Norbyvägen 18A, SE-75 236 Uppsala, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Schmitz
authors.affiliation: Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, SE-75 236, Uppsala, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Brunström
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005819:Genetic Markers; D006066:Gonads / Q000187:drug effects; D016912:Levonorgestrel / Q000633:toxicity*; D008297:Male; D011374:Progesterone / Q000633:toxicity*; D011372:Progestins / Q000633:toxicity*; D012733:Sex Differentiation / Q000187:drug effects* / Q000235:genetics; D012744:Sex Ratio; D012741:Sexual Maturation / Q000187:drug effects* / Q000235:genetics; D018675:Toxicity Tests; D014158:Transcription, Genetic / Q000187:drug effects; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*
chemical_list: D005819:Genetic Markers; D011372:Progestins; D014874:Water Pollutants, Chemical; D011374:Progesterone; D016912:Levonorgestrel
keywords: Levonorgestrel; Progesterone; Progestins; Puberty; Sex differentiation; Zebrafish