Variation in phenotype due to random intrauterine positioning of male and female fetuses in rodents

Saal, Frederick S. vom

doi:10.1530/jrf.0.0620633

Cited by 180 publications

(70 citation statements)

References 82 publications

(99 reference statements)

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“…Alternatively, higher potency could lead to intragenomic conflict with female-specific genes and so impair daughter fitness (62). Genes that contribute to variation in male-specific traits, including hormone-dependent behaviors and social competencies § (63), may also be subject to intrasexual selection (such as in male dominance hierarchies) or intersexual selection (female mate choice) (64).…”

Section: Discussionmentioning

confidence: 99%

Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold

Chen¹,

Racca²,

Phillips³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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Human testis determination is initiated by SRY (sex determining region on Y chromosome). Mutations in SRY cause gonadal dysgenesis with female somatic phenotype. Two subtle variants (V60L and I90M in the high-mobility group box) define inherited alleles shared by an XY sterile daughter and fertile father. Whereas specific DNA binding and bending are unaffected in a rat embryonic pre-Sertoli cell line, the variants exhibited selective defects in nucleocytoplasmic shuttling due to impaired nuclear import (V60L; mediated by Exportin-4) or export (I90M; mediated by chromosome region maintenance 1). Decreased shuttling limits nuclear accumulation of phosphorylated (activated) SRY, in turn reducing occupancy of DNA sites regulating Sertoli-cell differentiation [the testis-specific SRY-box 9 (Sox9) enhancer]. Despite distinct patterns of biochemical and cell-biological perturbations, V60L and I90M each attenuated Sox9 expression in transient transfection assays by twofold. Such attenuation was also observed in studies of V60A, a clinical variant associated with ovotestes and hence ambiguity between divergent cell fates. This shared twofold threshold is reminiscent of autosomal syndromes of transcription-factor haploinsufficiency, including XY sex reversal associated with mutations in SOX9. Our results demonstrate that nucleocytoplasmic shuttling of SRY is necessary for robust initiation of testicular development. Although also characteristic of ungulate orthologs, such shuttling is not conserved among rodents wherein impaired nuclear export of the high-mobility group box and importdependent phosphorylation are compensated by a microsatellite-associated transcriptional activation domain. Human sex reversal due to subtle defects in the nucleocytoplasmic shuttling of SRY suggests that its transcriptional activity lies near the edge of developmental ambiguity.organogenesis | sex determination | gonadogenesis | gene-regulatory network | protein-DNA interaction

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Section: Discussionmentioning

confidence: 99%

Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold

Chen¹,

Racca²,

Phillips³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Wolffian ducts also persist for a considerable period in female fetuses despite an apparent lack of androgen stimulation (Inomata et al 1993) suggested both by the delay of ovarian differentiation noted here and by the feminine positioning of the retractor penis muscles. It is also well known that androgen production by differentiating male fetuses can affect female siblings in utero, at least in some litter-bearing species (vom Saal 1981). Placental aromatase activity likely modulates the effects of androgens on female differentiation, given that female babies with congenital P450arom deficiency are severely virilized (Grumbach & Auchus 1999).…”

Section: Discussionmentioning

confidence: 99%

Endocrine differentiation of fetal ovaries and testes of the spotted hyena (Crocuta crocuta): timing of androgen-independent versus androgen-driven genital development

Browne¹,

Place²,

Vidal³

et al. 2006

Reproduction

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Female spotted hyenas (Crocuta crocuta) have an erectile peniform clitoris and a pseudoscrotum but no external vagina, all established by day 35 of a 110-day gestation. Recent studies indicate that these events are androgen-independent, although androgen secretion by fetal ovaries and testis was hypothesized previously to induce phallic development in both sexes. We present the first data relating to the capacity of the ovaries and testes of the spotted hyena to synthesize androgens at different stages of fetal life. Specifically, spotted hyena fetal gonads were examined by immunohistochemistry at GD 30, 45, 48, 65, and 95 for androgen-synthesizing enzymes, as related to the morphological development. Enzymes included 17a-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5, 3b-hydroxysteroid dehydrogenase (3bHSD), and cholesterol side-chain cleavage cytochrome P450 (P450scc). Anti-Mü llerian-hormone (AMH) expression was also examined. AMH was strongly expressed in fetal Sertoli cells from GD 30 and after. P450c17 expression was detected in Leydig cells of developing testes and surprisingly in Mü llerian duct epithelium. Fetal ovaries began to organize and differentiate by GD 45, and medullary cells expressed P450c17, cytochrome b5, 3bHSD, and P450scc. The findings support the hypothesis that external genital morphology is probably androgen-independent initially, but that fetal testicular androgens modify the secondary, male-specific phallic form and accessory organs. Fetal ovaries appear to develop substantial androgen-synthesizing capacity but not until phallic differentiation is complete, i.e. after GD 45 based on circulating androstenedione concentrations. During late gestation, fetal ovaries and testes synthesize androgens, possibly organizing the neural substrates of aggressive behaviors observed at birth in spotted hyenas. These data provide an endocrine rationale for sexual dimorphisms in phallic structure and reveal a potential source of androgenic support for neonatal aggression in female and male C. crocuta. Reproduction (2006) 132 649-659

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“…Similarly, in rodents, developmental events in fetal life appear to influence late-life functions and morphology, like induction of testicular (Newbold et al 1987) or uterine tumors (McLachlan et al 1980) and differentiation defects in SVs of mice exposed to DES prenatally (Newbold et al 1989). In addition, exposure to low sex steroid concentrations due to fetal position in utero, may modify structure and function of the mature prostate (vom Saal 1981(vom Saal , 1989. Developmental exposure to DES evokes long-term effects in a wide range of tissues such as disruption of reproductive function in adult rats (Khan et al 1998), induction of long-range changes in the uterine target cells (Newbold et al 1990) and alteration of bone density in female mice (Migliaccio et al 1992(Migliaccio et al , 1995.…”

Section: Discussionmentioning

confidence: 99%

Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate

Singh

Handelsman²

1999

Journal of Endocrinology

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Estrogens play an important role in prostate physiology and neonatal exposure to estrogens has profound effects on the mature structure and hormonal sensitivity of rodent prostate. We aimed to determine the long-term effects of neonatal estrogens on the ductal architecture, morphology and hormonal sensitivity of the mature mouse prostate. Newborn mice (day 1-2) were administered a single injection (s.c.) of estrogens (estradiol benzoate (EB), diethylstilbestrol (DES)) with or without concomitant anti-estrogens (tamoxifen (TAM) or ICI 182 780 (ICI)) TAM or ICI alone, GnRH-antagonist (GnRH-A) or vehicle. At 7 weeks of age, ventral prostates (VP) were microdissected to estimate branch tip numbers and processed for stereologic analysis of volume fractions and diameters of various tissue components. Estrogens induced permanently reduced branching morphogenesis leading to reduced VP weights and these effects were fully reproduced by GnRH-A, consistent with an indirect effect. Stereologically, neonatal estrogens induced epithelial and stromal hyperplasia and significantly reduced (P<0·05) the diameters of VP glandular tubules and lumen compared with controls and these regressive effects were not reversed either by TAM or ICI. These studies confirm that a single neonatal dose of both DES and EB produces imprinting in the mature mouse prostate and indicate that neonatal estrogen effects involve both direct as well as indirect effects. In addition, both TAM and ICI act as partial agonists to the estrogen receptor in the ventral prostate of neonatal mouse.

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Variation in phenotype due to random intrauterine positioning of male and female fetuses in rodents

Cited by 180 publications

References 82 publications

Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold

Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold

Endocrine differentiation of fetal ovaries and testes of the spotted hyena (Crocuta crocuta): timing of androgen-independent versus androgen-driven genital development

Morphometric studies of neonatal estrogen imprinting in the mature mouse prostate

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