title: Ketamine attenuates cytochrome p450 aromatase gene expression and estradiol-17β levels in zebrafish early life stages.
abstract: Ketamine, a dissociative anesthetic, is a noncompetitive antagonist of N-methyl-D-aspartate-type glutamate receptors. In rodents and non-human primates as well as in zebrafish embryos, ketamine has been shown to be neurotoxic. In cyclic female rats, ketamine has been shown to decrease serum estradiol-17β (E2) levels. E2 plays critical roles in neurodevelopment and neuroprotection. Cytochrome p450 (CYP) aromatase catalyzes E2 synthesis from androgens. Although ketamine down-regulates a number of CYP enzymes in rodents, its effect on the CYP aromatase (CYP19) is not known. Zebrafish have been used as a model system for examining mechanisms underlying drug effects. Here, using wild-type (WT) zebrafish (Danio rerio) embryos, we demonstrate that ketamine significantly reduced E2 levels compared with the control. However, the testosterone level was elevated in ketamine-treated embryos. These results are concordant with data from mammalian studies. Ketamine also attenuated the expression of the ovary form of CYP aromatase (cyp19a1a) at the transcriptional level but not the brain form of aromatase, cyp19a1b. Exogenous E2 potently induced the expression of cyp19a1b and vtg 1, both validated biomarkers of estrogenicity and endocrine disruption, but not cyp19a1a expression. Attenuation of activated ERK/MAPK levels, reportedly responsible for reduced human cyp19 transcription, was also observed in ketamine-treated embryos. These results suggest that reduced E2 levels in ketamine-treated embryos may have resulted from the suppression of cyp19a1a transcription.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR road, Jefferson, AR, 72079, USA; Toxicologic Pathology Associates, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR road, Jefferson, AR, 72079, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Trickler
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guo
authors.forename: Elvis
authors.initials: E
authors.lastname: Cuevas
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Kanungo
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004958:Estradiol / Q000032:analysis*; D015870:Gene Expression / Q000187:drug effects*; D007649:Ketamine / Q000633:toxicity*; D015027:Zebrafish / Q000097:blood / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D029961:Zebrafish Proteins; D004958:Estradiol; D007649:Ketamine; D001141:Aromatase; C440729:Cyp19a1a protein, zebrafish; C440728:Cyp19a1b protein, zebrafish
keywords: CYP aromatase; estradiol-17β; gene expression; ketamine; testosterone; zebrafish