Molecular mechanisms of induction of persistent changes by estrogenic chemicals on female reproductive tracts and external genitalia

Miyagawa, Shinichi; Satô, Masaru; Iguchi, Taisen

doi:10.1016/j.jsbmb.2011.03.009

Cited by 18 publications

(10 citation statements)

References 118 publications

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“…The daughters of women given DES while pregnant were early shown to have rare cervicovaginal cancers (Barclay, 1979;Herbst et al, 1971), decreased fertility and an increased rate of ectopic pregnancies (Goldberg and Falcone, 1999), and early menopause (Hatch et al, 2006). Later, experimental studies on animal models exposed to DES during gestation supported these antecedents (Kim et al, 2009;Miyagawa et al, 2011;Newbold, 2008;Newbold et al, 2007). In accordance with these observations, we found that the female rats neonatally exposed to a low dose of DES exhibited uterine functional abnormalities that compromised fertility.…”

Section: Discussionsupporting

confidence: 77%

Neonatal exposure to low doses of endosulfan induces implantation failure and disrupts uterine functional differentiation at the pre-implantation period in rats

Milesi

Alarcón

Ramos

et al. 2015

Molecular and Cellular Endocrinology

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Section: Discussionsupporting

confidence: 77%

Neonatal exposure to low doses of endosulfan induces implantation failure and disrupts uterine functional differentiation at the pre-implantation period in rats

Milesi

Alarcón

Ramos

et al. 2015

Molecular and Cellular Endocrinology

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“…It is evident from administration to pregnant women and animal experiments that DES has various detrimental effects to offspring during the perinatal period 16 . Prenatal DES exposure causes reproductive organ malformation and dysfunction, low fertility and reproductive tract tumors during later life 17 , 18 . In animal models, these adverse effects appeared even with very low dosage of DES.…”

Section: Introductionmentioning

confidence: 99%

Diethylstilbestrol administration inhibits theca cell androgen and granulosa cell estrogen production in immature rat ovary

Imamichi

Sekiguchi

Kitano

et al. 2017

Sci Rep

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Diethylstilbestrol (DES), a strong estrogenic compound, is well-known to affect the reproductive system. In this study, we investigated the effects of DES administration on gonadotropin levels and ovarian steroidogenesis in prepubertal rats. DES treatment acutely reduced serum LH levels, followed by a reduction in the expression of various steroidogenesis-related genes in theca cells. Serum FSH levels were almost unaffected by DES-treatment, even though Cyp19a1 expression was markedly reduced. Serum progesterone, testosterone and estradiol levels were also declined at this time. LH levels recovered from 12 h after DES-treatment and gradually increased until 96 h with a reduction of ERα expression observed in the pituitary. Steroidogenesis-related genes were also up-regulated during this time, except for Cyp17a1 and Cyp19a1. Consistent with observed gene expression pattern, serum testosterone and estradiol concentrations were maintained at lower levels, even though progesterone levels recovered. DES-treatment induced the inducible nitric oxide synthase (iNOS) in granulosa cells, and a nitric oxide generator markedly repressed Cyp19a1 expression in cultured granulosa cells. These results indicate that DES inhibits thecal androgen production via suppression of pituitary LH secretion and ovarian Cyp17a1 expression. In addition, DES represses Cyp19a1 expression by inducing iNOS gene expression for continuous inhibition of estrogen production in granulosa cells.

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“…Inasmuch as the thymus is the primary organ for the development of T cells that are long-lived and vital for immune competence, any alterations in this organ may have notable immunological consequences. DES initiates early signaling primarily through the estrogen receptor (ER) and regulate the expression of various genes (Brown et al, 2006a,b;Miyagawa et al, 2011). Previous studies have demonstrated that DES caused a decrease in prothymocyte stem cells (Holladay et al, 1993) and a decrease in double positive CD4…”

Section: Introductionmentioning

confidence: 99%

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

Singh

Nagarkatti

2012

J Pharmacol Exp Ther

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Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor B (NF-B), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-B, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-B2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions.

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Molecular mechanisms of induction of persistent changes by estrogenic chemicals on female reproductive tracts and external genitalia

Cited by 18 publications

References 118 publications

Neonatal exposure to low doses of endosulfan induces implantation failure and disrupts uterine functional differentiation at the pre-implantation period in rats

Neonatal exposure to low doses of endosulfan induces implantation failure and disrupts uterine functional differentiation at the pre-implantation period in rats

Diethylstilbestrol administration inhibits theca cell androgen and granulosa cell estrogen production in immature rat ovary

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

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