title: Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains.
abstract: Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5-120 days postnatal to evaluate ExG malformations. Of 23 adult (>60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18% to 100% in prenatally DES-exposed CD-1 males and 31% to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed only slightly in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation.
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Phitsanu
authors.initials: P
authors.lastname: Mahawong
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Adriane
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Schlomer
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Esequiel
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Max M
authors.initials: MM
authors.lastname: Ferretti
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Baomei
authors.initials: B
authors.lastname: Liu
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Baskin
authors.affiliation: Division of Pediatric Urology, University of California, San Francisco, CA 94143, United States. Electronic address: cunhag@urology.ucsf.edu.
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D004054:Diethylstilbestrol / Q000633:toxicity*; D005260:Female; D005836:Genitalia, Female / Q000002:abnormalities*; D005837:Genitalia, Male / Q000002:abnormalities*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects
chemical_list: D004054:Diethylstilbestrol
keywords: Diethylstilbestrol; External genitalia; Hypospadias; Mice; Prenatal; Trans-generational effect