A novel method for determining sex in late term gestational mice based on the external genitalia

Murdaugh, Laura B.; Mendoza-Romero, Haley N.; Fish, Eric W.; Parnell, Scott E.

doi:10.1371/journal.pone.0194767

Cited by 13 publications

(6 citation statements)

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“…Because sex-specific differences are well known in hyperoxic lung injury, we selected only male pups to exclude the bias effect from the sex difference 57,58 . The sex of mice was determined based on the morphological features of external genitalia 59 . In total, 54 mouse pups from 10 pregnant mice were used in the experiment.…”

Section: Methodsmentioning

confidence: 99%

S-endoglin expression is induced in hyperoxia and contributes to altered pulmonary angiogenesis in bronchopulmonary dysplasia development

Lee

Nam

et al. 2020

Sci Rep

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Altered pulmonary angiogenesis contributes to disrupted alveolarization, which is the main characteristic of bronchopulmonary dysplasia (BPD). Transforming growth factor β (tGfβ) plays an important role during lung vascular development, and recent studies have demonstrated that endoglin is engaged in the modulation of tGfβ downstream signalling. Although there are two different isoforms of endoglin, L-and S-endoglin, little is known about the effect of S-endoglin in developing lungs. We analysed the expression of both L-and S-endoglin in the lung vasculature and its contribution to tGfβ-activin-like kinase (ALK)-Smad signalling with respect to BPD development. Hyperoxia impaired pulmonary angiogenesis accompanied by alveolar simplification in neonatal mouse lungs. S-endoglin, phosphorylated Smad2/3 and connective tissue growth factor levels were significantly increased in hyperoxia-exposed mice, while L-endoglin, phosphor-Smad1/5 and platelet-endothelial cell adhesion molecule-1 levels were significantly decreased. Hyperoxia suppressed the tubular growth of human pulmonary microvascular endothelial cells (ECs), and the selective inhibition of ALK5 signalling restored tubular growth. These results indicate that hyperoxia alters the balance in two isoforms of endoglin towards increased S-endoglin and that S-endoglin attenuates TGFβ-ALK1-Smad1/5 signalling but stimulates tGfβ-ALK5-Smad2/3 signalling in pulmonary ECs, which may lead to impaired pulmonary angiogenesis in developing lungs. open Scientific RepoRtS | (2020) 10:3043 | https://doi.org/10.1038/s41598-020-59928-x www.nature.com/scientificreports www.nature.com/scientificreports/ through enhancement of the TGFβ-ALK1-Smad1/5 pathway, while connective tissue growth factor (CTGF) expression increases through enhancement of the TGFβ-ALK5-Smad2/3 pathway [27][28][29][30][31] .Several independent findings have demonstrated that endoglin is engaged in TGFβ receptor complex formation and the modulation of downstream signalling [32][33][34][35] . The expression of two alternatively spliced isoforms, long (L-) endoglin and short (S-) endoglin, has been demonstrated in human and mouse lung tissues in vivo 33,34,36,37 . L-endoglin is the predominant isoform, and its pre-mRNA can be alternatively spliced by intron retention, producing the less abundant form, S-endoglin 36,37 . Evidence indicates that L-endoglin, the predominant isoform in ECs, promotes EC proliferation via TGFβ-ALK1 signalling, whereas S-endoglin acts as an antagonist of L-endoglin via activation of the TGFβ-ALK5 pathway 32,33,36,37 .To date, most studies published on endoglin have focused on L-endoglin. It has been found that L-endoglin enhances ALK1-Smad1/5 signalling in ECs, leading to proliferation and migration, which are the main characteristics of the activation phase of angiogenesis 15,18,20,22,[38][39][40][41][42][43] . However, a role of S-endoglin during endothelial senescence was recently described 36,37 . The S-endoglin:L-endoglin ratio increases during the senescence of ECs in vitro as well ...

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Section: Methodsmentioning

confidence: 99%

S-endoglin expression is induced in hyperoxia and contributes to altered pulmonary angiogenesis in bronchopulmonary dysplasia development

Lee

Nam

et al. 2020

Sci Rep

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“…The tail was examined for any irregular shapes to rule out posterior neural tube defects. Fetal sex was determined through examination of the external genitalia at E17 for presence of the urethral meatus to indicate female or the urethral seem to indicate male (Murdaugh et al, 2018). Photographs of the face, each eye, tail, and genitals were taken using Nikon (Tokyo, Japan) camera microscope (Model SM-LW61Ji4).…”

Section: Methodsmentioning

confidence: 99%

Gastrulation‐stage alcohol exposure induces similar rates of craniofacial malformations in male and female C57BL/6J mice

Boschen,

Dragicevich,

Fish

et al. 2023

Birth Defects Research

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BackgroundPrenatal alcohol exposure during gastrulation (embryonic day [E] 7 in mice, ~3rd week of human pregnancy) impairs eye, facial, and cortical development, recapitulating birth defects characteristic of Fetal Alcohol Syndrome (FAS). However, it is not known whether the prevalence or severity of craniofacial features associated with FAS is affected by biological sex.MethodsThe current study administered either alcohol (2.9 g/kg, two i.p. doses, 4 hr apart) or vehicle to pregnant C57BL/6J females on E7, prior to gonadal sex differentiation, and assessed fetal morphology at E17.ResultsWhereas sex did not affect fetal size in controls, alcohol‐exposed females were smaller than both control females and alcohol‐treated males. Alcohol exposure increased the incidence of eye defects to a similar degree in males and females. Together, these data suggest that females might be more sensitive to the general developmental effects of alcohol, but not effects specific to the craniofacies. Whole transcriptomic analysis of untreated E7 embryos found 214 differentially expressed genes in females vs. males, including those in pathways related to cilia and mitochondria, histone demethylase activity, and pluripotency.ConclusionGastrulation‐stage alcohol induces craniofacial malformations in male and female mouse fetuses at similar rates and severity, though growth deficits are more prevalent females. These findings support the investigation of biological sex as a contributing factor in prenatal alcohol studies.

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“…(For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) feature allowing sex identification at birth (Murdaugh et al, 2018), and this feature has been attributed to androgen action (Hotchkiss et al, 2007;Hotchkiss and Vandenbergh, 2005). However, perineal appendage size is only marginally greater in males than females at birth and later in adulthood.…”

Section: Development Of Mouse External Genitaliamentioning

confidence: 99%

Androgen-independent events in penile development in humans and animals

et al. 2020

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The common view on penile development is that it is androgen-dependent, based first and foremost on the fact that the genital tubercle forms a penis in males and a clitoris in females. However, critical examination of the complex processes involved in human penile development reveals that many individual steps in development of the genital tubercle are common to both males and females, and thus can be interpreted as androgen-independent. For certain developmental events this conclusion is bolstered by observations in androgen-insensitive patients and androgen receptor mutant mice. Events in genital tubercle development that are common to human males and females include: formation of (a) the genital tubercle, (b) the urethral plate, (c) the urethral groove, (d) the glans, (e) the prepuce and (f) the corporal body. For humans 6 of 13 individual developmental steps in penile development were interpreted as androgen-independent. For mice 5 of 11 individual developmental steps were found to be androgen-independent, which were verified through analysis of androgen-insensitive mutants. Observations from development of external genitalia of other species (moles and spotted hyena) provide further examples of androgen-independent events in penile development. These observations support the counter-intuitive idea that penile development involves both androgen-independent and androgen-dependent processes.

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A novel method for determining sex in late term gestational mice based on the external genitalia

Cited by 13 publications

References 13 publications

S-endoglin expression is induced in hyperoxia and contributes to altered pulmonary angiogenesis in bronchopulmonary dysplasia development

S-endoglin expression is induced in hyperoxia and contributes to altered pulmonary angiogenesis in bronchopulmonary dysplasia development

Gastrulation‐stage alcohol exposure induces similar rates of craniofacial malformations in male and female C57BL/6J mice

Androgen-independent events in penile development in humans and animals

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