title: In utero exposure to TCDD alters Wnt signaling during mouse prostate development: linking ventral prostate agenesis to downregulated β-catenin signaling.
abstract: In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes ventral prostate agenesis in C57BL/6J mice by preventing ventral prostatic budding in the embryonic urogenital sinus (UGS). TCDD (5 μg/kg, po) administered to pregnant dams on embryonic day 15.5 (E15.5) activates the aryl hydrocarbon receptor in the UGS mesenchyme, disrupting the mesenchymally derived paracrine signaling that instructs epithelial prostatic budding. How TCDD alters the mesenchymal milieu is not well understood. We previously showed that TCDD disrupts some aspects of Wnt signaling in UGSs grown in vitro. Here we provide the first comprehensive, in vivo characterization of Wnt signaling in male E16.5 UGSs during normal development, and after in utero TCDD exposure. Vehicle- and TCDD-exposed UGSs were probed by in situ hybridization to assess relative abundance and localization of RNA from 46 genes that regulate Wnt signaling. TCDD altered the staining pattern of five genes, increasing staining for Wnt10a and Wnt16 and decreasing staining for Ror2, Rspo2, and Wif1. We also used immunohistochemistry to show, for the first time, activation of β-catenin (CTNNB1) signaling in ventral basal epithelium of control UGSs at E16.5. This onset of CTNNB1 signaling occurred immediately prior to the initiation of ventral prostatic budding and is characterized by a pronounced increase in CTNNB1 nuclear localization and subsequent expression of the CTNNB1 signaling target gene, Lef1. In utero TCDD exposure prevented the onset of CTNNB1 signaling and LEF1 expression in the ventral basal epithelium, thereby elucidating a likely mechanism by which TCDD contributes to failed prostatic budding in the ventral UGS.
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schneider
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Moore
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Branam
authors.affiliation: School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Abler
authors.affiliation: School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Keil
authors.affiliation: School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Vatsal
authors.initials: V
authors.lastname: Mehta
authors.affiliation: School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Vezina
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705 repeterson@pharmacy.wisc.edu.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
mesh_terms: D000818:Animals; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008810:Mice, Inbred C57BL; D038081:Organogenesis / Q000187:drug effects*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011467:Prostate / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D051153:Wnt Proteins; D051176:beta Catenin
keywords: CTNNB1; TCDD; Wnt; development; mouse; prostate