title: Diethylstilbestrol-induced mouse hypospadias: "window of susceptibility".
abstract: This review presents published and novel results that define the programming window for diethylstilbestrol (DES)-induced abnormal development of the mouse penis. These data indicate that DES has its greatest effect during the period of most intense penile morphogenesis, namely postnatal days 0-15 (P0-P15). Pregnant mice and their neonatal pups were injected subcutaneously with 200 ng/gbw DES every other day from embryonic day 12-18 (DES E12-E18), postnatal day 0-10 (DES P0-P10), embryonic day 12 to postnatal day 10 (DES E12-P10), postnatal day 5-15 (DES P5-P15), and postnatal day 10-20 (DES P10-P20). Aged-matched controls received sesame oil vehicle. After euthanasia at 10, 15, 20 and 60 days, penises were analyzed by gross morphology, histology and morphometry. Penises of all 5 groups of DES-treated mice were reduced in size, which was confirmed by morphometric analysis of internal penile structures. The most profound effects were seen in the DES E12-P10, DES P0-P10, and DES P5-P15 groups, thus defining a DES "programming window". For all parameters, DES treatment from P10 to P20 showed the most mild of effects. Adverse effects of DES on the MUMP cartilage and erectile bodies observed shortly after the last DES injection reverted to normality in the DES P5-P15, but not in the E12-P10 and P0-P10 groups, in which MUMP cartilage and erectile body malformations persisted into adulthood, again emphasizing a "window of susceptibility" in the early neonatal period.
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Adriane Watkins
authors.initials: AW
authors.lastname: Sinclair
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States.
authors.forename: Laurence
authors.initials: L
authors.lastname: Baskin
authors.affiliation: Department of Urology, University of California San Francisco, 400 Parnassus Avenue, Box A610, San Francisco, CA 94143, United States. Electronic address: gerald.cunha@ucsf.edu.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004054:Diethylstilbestrol / Q000633:toxicity; D004198:Disease Susceptibility / Q000139:chemically induced / Q000473:pathology*; D004968:Estrogens, Non-Steroidal; D005260:Female; D006801:Humans; D007021:Hypospadias / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D010413:Penis / Q000254:growth & development / Q000473:pathology*; D011247:Pregnancy
chemical_list: D004968:Estrogens, Non-Steroidal; D004054:Diethylstilbestrol
keywords: Diethylstilbestrol; Estrogen; Mouse penile development; Urethra
references.citation: Dev Biol. 2008 Jun 1;318(1):143-52
references.pmid: 18439576
references.citation: J Androl. 2008 Sep-Oct;29(5):499-505
references.pmid: 18497336
references.citation: Toxicol Pathol. 2009 Jan;37(1):100-13
references.pmid: 19147833
references.citation: Environ Health Perspect. 2009 Feb;117(2):303-7
references.pmid: 19270804
references.citation: Int J Androl. 2010 Feb;33(1):e144-52
references.pmid: 19656234
references.citation: Int J Androl. 2010 Apr;33(2):279-87
references.pmid: 20002220
references.citation: J Urol. 2010 Oct;184(4 Suppl):1604-9
references.pmid: 20728117
references.citation: Mol Cell Endocrinol. 2011 Mar 30;335(2):89-95
references.pmid: 21256920
references.citation: Biol Reprod. 2011 Dec;85(6):1216-21
references.pmid: 21918128
references.citation: Differentiation. 2012 Oct;84(3):269-79
references.pmid: 22925506
references.citation: J Urol. 2013 Jul;190(1):251-5
references.pmid: 23376710
references.citation: Anat Rec (Hoboken). 2013 Jul;296(7):1127-41
references.pmid: 23653160
references.citation: J Urol. 2013 Oct;190(4 Suppl):1610-7
references.pmid: 23473905
references.citation: J Urol. 2014 Mar;191(3):783-9
references.pmid: 24096117
references.citation: J Pediatr Urol. 2014 Aug;10(4):699-705
references.pmid: 24768568
references.citation: Differentiation. 2014 Sep-Oct;88(2-3):51-69
references.pmid: 25449352
references.citation: Differentiation. 2014 Sep-Oct;88(2-3):70-83
references.pmid: 25449353
references.citation: J Urol. 2015 Apr;193(4):1353-59
references.pmid: 25286011
references.citation: Nat Rev Urol. 2015 May;12(5):271-80
references.pmid: 25850792
references.citation: J Urol. 2000 Mar;163(3):951-6
references.pmid: 10688029
references.citation: Novartis Found Symp. 2001;232:23-36; discussion 36-46
references.pmid: 11277083
references.citation: Cell Tissue Res. 2001 Sep;305(3):379-87
references.pmid: 11572091
references.citation: Environ Health Perspect. 2001 Nov;109(11):1175-83
references.pmid: 11713004
references.citation: J Urol. 2002 Mar;167(3):1532-7
references.pmid: 11832783
references.citation: Toxicol Sci. 2003 Aug;74(2):393-406
references.pmid: 12773767
references.citation: BJU Int. 2003 Dec;92(9):1016-21
references.pmid: 14632867
references.citation: Br J Plast Surg. 2004 Apr;57(3):203-14
references.pmid: 15006521
references.citation: Environ Res. 2004 Mar;94(3):267-75
references.pmid: 15016594
references.citation: Br J Plast Surg. 2004 Mar;57(2):112-21
references.pmid: 15037165
references.citation: Curr Top Dev Biol. 1980;14(Pt 2):199-225
references.pmid: 6161753
references.citation: Hum Genet. 1981;58(1):78-84
references.pmid: 6895207
references.citation: Biol Res Pregnancy Perinatol. 1983;4(2):56-70
references.pmid: 6882849
references.citation: J Steroid Biochem. 1985 Jan;22(1):29-37
references.pmid: 3974227
references.citation: Teratology. 1990 Jul;42(1):91-100
references.pmid: 2168096
references.citation: J Endocrinol. 1991 Mar;128(3):395-401
references.pmid: 2013746
references.citation: Toxicol Appl Pharmacol. 1993 Mar;119(1):34-40
references.pmid: 8385814
references.citation: Toxicol Appl Pharmacol. 1994 Nov;129(1):46-52
references.pmid: 7974495
references.citation: Pediatrics. 1997 Nov;100(5):831-4
references.pmid: 9346983
references.citation: J Urol. 1998 Sep;160(3 Pt 2):1108-15; discussion 1137
references.pmid: 9719287
references.citation: Endocrinology. 1998 Oct;139(10):4345-52
references.pmid: 9751518
references.citation: Environ Health Perspect. 1999 Apr;107(4):297-302
references.pmid: 10090709
references.citation: Toxicol Ind Health. 1999 Jan-Mar;15(1-2):80-93
references.pmid: 10188193
references.citation: Toxicol Ind Health. 1999 Jan-Mar;15(1-2):94-118
references.pmid: 10188194
references.citation: Obstet Gynecol. 2005 Apr;105(4):773-8
references.pmid: 15802404
references.citation: Toxicol Sci. 2005 Jun;85(2):1024-32
references.pmid: 15788718
references.citation: J Bone Miner Res. 2005 Sep;20(9):1624-36
references.pmid: 16059634
references.citation: Arch Pediatr Adolesc Med. 2005 Oct;159(10):957-62
references.pmid: 16203941
references.citation: J Urol. 2006 Feb;175(2):723-6
references.pmid: 16407038
references.citation: J Pediatr Surg. 2006 Mar;41(3):463-72
references.pmid: 16516617
references.citation: Environ Health. 2006;5:4
references.pmid: 16504050
references.citation: J Urol. 2006 Aug;176(2):728-33
references.pmid: 16813932
references.citation: Nat Clin Pract Urol. 2007 May;4(5):270-9
references.pmid: 17483812
references.citation: Endocrinology. 2007 Jul;148(7):3185-95
references.pmid: 17431008
references.citation: J Urol. 2007 Aug;178(2):722-7
references.pmid: 17574608
references.citation: Int J Androl. 2008 Apr;31(2):249-62
references.pmid: 18205796
references.citation: J Clin Invest. 2008 Apr;118(4):1479-90
references.pmid: 18340380