p21 and Notch signalings in the persistently altered vagina induced by neonatal diethylstilbestrol exposure in mice
2012 Study Abstract
Female reproductive organs show organ-specific morphological changes during estrous cycles. Perinatal exposure to natural and synthetic estrogens including diethylstilbestrol (DES) or estrogenic chemicals induces estrogen-independent persistent proliferation of vaginal epithelium in mice.
To understand the underlying mechanism of the estrogen-independent persistent vaginal changes induced by perinatal DES exposure, we examined global gene expressions in the vaginae of ovariectomized adult mice exposed neonatally to DES using a microarray.
The cell cycle-related gene, p21, a cyclin-dependent kinase inhibitor, showed upregulation in the vagina, and p21 protein was localized in the basal layer of the vaginal epithelium in mice exposed neonatally to DES and an estrogen receptor α agonist, propyl pyrazole triol (PPT).
The expressions of Notch receptors and Notch ligands were unchanged; however, the mRNAs of hairy-related basic helix-loop-helix (bHLH) transcription factor genes, Hes1, Hey1 and Heyl were persistently downregulated in the vagina, indicating estrogen-independent epithelial cell proliferation in mice exposed neonatally to DES and PPT.
In conclusion, we demonstrated that the expressions of both p21 mRNA and p21 protein are permanently upregulated and the Hes1, Hey1 and Heyl mRNAs are permanently downregulated in the vagina exposed neonatally to DES.
Additional elucidation of the molecular mechanism of the irreversible proliferation in vaginal epithelial cells is essential in the near future.
Sources and more information
- Full text (free access) : p21 and Notch signalings in the persistently altered vagina induced by neonatal diethylstilbestrol exposure in mice, Laboratory Animal Science, NCBI PubMed PMID: 22850433, 2012 Jul 24.
- Immunohistochemistry of p21. Vaginae of 15-week-old ovariectomized mice exposed neonatally to 2.5 µg DES (A, B) or the oil vehicle alone (C, D). p21 was immunostained in the neonatally DES-exposed vagina (A) and the age-matched control mouse vagina (C). featured image credit jvms/74/12/74_12-0182.