title: Differential response to abiraterone acetate and di-n-butyl phthalate in an androgen-sensitive human fetal testis xenograft bioassay.
abstract: In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75 mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500 mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Spade
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Camelia M
authors.initials: CM
authors.lastname: Saffarini
authors.forename: Susan M
authors.initials: SM
authors.lastname: Huse
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: McDonnell
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
mesh_terms: D000069501:Abiraterone Acetate; D000726:Androgen Antagonists / Q000633:toxicity*; D000730:Androstadienes / Q000633:toxicity*; D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003993:Dibutyl Phthalate / Q000633:toxicity*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D064593:Heterografts / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D025341:Principal Component Analysis; D013737:Testis / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood; D059467:Transcriptome / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D000726:Androgen Antagonists; D000730:Androstadienes; D006063:Chorionic Gonadotropin; D003993:Dibutyl Phthalate; D013739:Testosterone; D000069501:Abiraterone Acetate
keywords: CYP17A1.; Hershberger assay; abiraterone acetate; antiandrogen; di-n-butyl phthalate; xenograft