title: Transgenic Chickens Overexpressing Aromatase Have High Estrogen Levels but Maintain a Predominantly Male Phenotype.
abstract: Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterized steroidogenic pathway, which is a multistep process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation.
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Luke S
authors.initials: LS
authors.lastname: Lambeth
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Morris
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Terry G
authors.initials: TG
authors.lastname: Wise
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Cummins
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Terri E
authors.initials: TE
authors.lastname: O'Neil
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sinclair
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Doran
authors.affiliation: Murdoch Childrens Research Institute (L.S.L., A.H.S.), Royal Children's Hospital, Melbourne, Victoria 3052, Australia; Department of Paediatrics (A.H.S.), The University of Melbourne, Melbourne, Victoria 3010, Australia; Commonwealth Scientific and Industrial Research Organisation Health and Biosecurity Flagship (K.R.M., T.G.W., D.M.C., T.E.O., Y.C., T.J.D.), Australian Animal Health Laboratory, Geelong, Victoria 3219, Australia; and Department of Anatomy and Developmental Biology (C.A.S.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Smith
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D001715:Bird Diseases / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002645:Chickens / Q000097:blood / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D004967:Estrogens / Q000097:blood* / Q000378:metabolism; D005260:Female; D005262:Feminization / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000662:veterinary*; D008297:Male; D008856:Microscopy, Fluorescence / Q000662:veterinary; D009929:Organ Size; D010053:Ovary / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D012741:Sexual Maturation; D013737:Testis / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D015430:Weight Gain
chemical_list: D030161:Avian Proteins; D004967:Estrogens; D001141:Aromatase