title: Environmental Progestins Progesterone and Drospirenone Alter the Circadian Rhythm Network in Zebrafish (Danio rerio).
abstract: Progestins alter hormone homeostasis and may result in reproductive effects in humans and animals. Thus far, studies in fish have focused on the hypothalamic-pituitary-gonadal (HPG)-axis and reproduction, but other effects have little been investigated. Here we report that progesterone (P4) and drospirenone (DRS) interfere with regulation of the circadian rhythm in fish. Breeding pairs of adult zebrafish were exposed to P4 and DRS at concentrations between 7 and 13 650 ng/L for 21 days. Transcriptional analysis revealed significant and dose-dependent alterations of the circadian rhythm network in the brain with little effects in the gonads. Significant alterations of many target transcripts occurred even at environmental relevant concentrations of 7 ng/L P4 and at 99 ng/L DRS. They were fully consistent with the well-described circadian rhythm negative/positive feedback loops. Transcriptional alterations of the circadian rhythm network were correlated with those in the HPG-Liver-axis. Fecundity was decreased at 742 (P4) and 2763 (DRS) ng/L. Dose-dependent alterations in the circadian rhythm network were also observed in F1 eleuthero-embryos. Our results suggest a potential target of environmental progestins, the circadian rhythm network, in addition to the adverse reproductive effects. Forthcoming studies should show whether the transcriptional alterations in circadian rhythm translate into physiological effects.
authors.affiliation: †University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, Switzerland.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: ‡IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Environmental Biomarkers Unit, Department of Environmental Health Sciences, Via La Masa 19, I-20156, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Castiglioni
authors.affiliation: †University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz, Switzerland.|§Swiss Federal Institute of Technology (ETH Zürich), Institute of Biogeochemistry and Pollution Dynamics, Department of Environmental System Sciences, CH-8092 Zürich, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Fent
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000736:Androstenes / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects; D006066:Gonads / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D011374:Progesterone / Q000633:toxicity*; D011372:Progestins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015027:Zebrafish / Q000502:physiology*
chemical_list: D000736:Androstenes; D004785:Environmental Pollutants; D011372:Progestins; D012333:RNA, Messenger; D011374:Progesterone; C035144:drospirenone