title: Effects of embryonic cyclosporine exposures on brain development and behavior.
abstract: Cyclosporine, a calcineurin inhibitor, is successfully used as an immunosuppressant in transplant medicine. However, the use of this pharmaceutical during pregnancy is concerning since calcineurin is thought to play a role in neural development. The risk for human brain development is difficult to evaluate because of a lack of basic information on the sensitive developmental times and the potentially pleiotropic effects on brain development and behavior. In the present study, we use zebrafish as a model system to examine the effects of embryonic cyclosporine exposures. Early embryonic exposures reduced the size of the eyes and brain. Late embryonic exposures did not affect the size of the eyes or brain, but did lead to substantial behavioral defects at the larval stages. The cyclosporine-exposed larvae displayed a reduced avoidance response to visual stimuli, low swim speeds, increased resting, an increase in thigmotaxis, and changes in the average distance between larvae. Similar results were obtained with the calcineurin inhibitor FK506, suggesting that most, but not all, effects on brain development and behavior are mediated by calcineurin inhibition. Overall, the results show that cyclosporine can induce either structural or functional brain defects, depending on the exposure window. The observed functional brain defects highlight the importance of quantitative behavioral assays when evaluating the risk of developmental exposures.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Clift
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Thorn
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Passarelli
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Kapoor
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: LoPiccolo
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Richendrfer
authors.affiliation: Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Colwill
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Electronic address: Robbert_Creton@brown.edu.
authors.forename: Robbert
authors.initials: R
authors.lastname: Creton
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000254:growth & development*; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D005123:Eye / Q000187:drug effects / Q000254:growth & development; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D008297:Male; D011247:Pregnancy; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014785:Vision, Ocular / Q000187:drug effects; D015027:Zebrafish / Q000254:growth & development
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus
keywords: Behavior; Brain; Calcineurin; Cyclosporin; Cyclosporine; Zebrafish