Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders.

TitleCytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders.
Publication TypeJournal Article
Year of Publication2016
AuthorsLemaire, B, Kubota, A, O'Meara, CM, Lamb, DC, Tanguay, RL, Goldstone, JV, Stegeman, JJ
JournalToxicol Appl Pharmacol
Date Published2016 Apr 01
KeywordsAmino Acid Sequence, Animals, Chickens, Cloning, Molecular, Cytochrome P-450 Enzyme System, Gene Knockdown Techniques, Humans, Molecular Sequence Data, Psychomotor Agitation, Rats, Xenobiotics, Xenopus, Zebrafish, Zebrafish Proteins

Cytochrome P450 (CYP) enzymes for which there is no functional information are considered "orphan" CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to "deorphanization", that is, identifying CYP20A1 functions and its roles in health and disease.

Alternate JournalToxicol. Appl. Pharmacol.
PubMed ID26853319
PubMed Central IDPMC4807407
Grant ListP42 ES007381 / ES / NIEHS NIH HHS / United States
P01 ES021923 / ES / NIEHS NIH HHS / United States
P01ES021923 / ES / NIEHS NIH HHS / United States
U41 HG003345 / HG / NHGRI NIH HHS / United States
P30ES000210 / ES / NIEHS NIH HHS / United States
P42ES007381 / ES / NIEHS NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States