Similarities and differences in uterine gene expression patterns caused by treatment with physiological and non-physiological estrogens

Watanabe, Hidenobu; Suzuki, Atsushi; Kobayashi, Mika; Lubahn, DB; Handa, Hiroshi; Iguchi, Taisen

doi:10.1677/jme.0.0310487

Cited by 43 publications

(24 citation statements)

References 29 publications

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“…Several doses were used since comparison of changes in gene expression at one dose cannot be used to validly estimate the activities of chemicals (Watanabe et al 2003). In summary, we demonstrated that (1) the estrogenic activity of nonylphenol could be estimated from gene expression profiling, and this was comparable with results obtained in the uterotrophic assay; (2) almost all genes activated by estradiol in the uterus were also activated by nonylphenol at a high dose; and (3) nonylphenol and estradiol have similar effects on gene expression in the uterus, but not in the liver.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific estrogenic and non-estrogenic effects of a xenoestrogen, nonylphenol

Watanabe

Suzuki²,

Goto³

et al. 2004

Journal of Molecular Endocrinology

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Alkylphenols perturb the endocrine system and are considered to have weak estrogenic activities. Although it is known that nonylphenol can bind weakly to the estrogen receptor, it is unclear whether all reported effects of nonylphenol are attributable to its estrogen receptor-binding activity. In order to examine whether alkylphenols have similar effects to the natural hormone, estradiol, we used a mouse model to examine the effects of nonylphenol on gene expression and compared it with estradiol. DNA microarray analysis revealed that, in the uterus, most of the genes activated by this alkylphenol at a high dose (50 mg/kg) were also activated by estradiol. At lower doses, nonylphenol (0·5 mg/kg and 5 mg/kg) had little effect on the genes that were activated by estradiol. Thus, we concluded that the effects of nonylphenol at a high dose (50 mg/kg) were very similar to estradiol in uterine tissue. Moreover, since evaluation of estrogenic activity by gene expression levels was comparable with the uterotrophic assay, it indicated that analysis of gene expression profiles can predict the estrogenic activities of chemicals. In contrast to the similar effects of nonylphenol and estradiol observed in the uterus, in the liver, gene expression was more markedly affected by nonylphenol than by estradiol. This indicated that, in the liver, nonylphenol could activate another set of genes that are distinct from estrogen-responsive genes. These results indicated that nonylphenol has very similar effects to estradiol on gene expression in uterine but not in liver tissue, indicating that tissue-specific effects should be considered in order to elucidate the distinct effects of alkylphenols.

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Section: Discussionmentioning

confidence: 99%

Tissue-specific estrogenic and non-estrogenic effects of a xenoestrogen, nonylphenol

Watanabe

Suzuki²,

Goto³

et al. 2004

Journal of Molecular Endocrinology

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“…STIP1, DPYL2, and TRAP1 were also decreased by DEHP exposure. STIP1 has been shown to be directly regulated by estradiol (Watanabe et al 2003), while DPYL2 is dependent on estradiolmediated App expression (Manthey et al 2001). TRAP1 expression is regulated by MYC (McConnell et al 2003), which in turn is known to be regulated by estradiol (Wang et al 2011).…”

Section: Biomarkers Of Dysgenesis In Fetal Rat Testismentioning

confidence: 99%

Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol

Klinefelter¹,

Laskey²,

Winnik³

et al. 2012

Reproduction

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Significant research has been focused on phthalate-induced alterations in male reproductive development. Studies on rodents have prompted the notion that a syndrome exists in the human male which includes phenotypic alterations such as hypospadias, cryptorchidism, poor semen quality, and even testicular cancer. Each phenotype in this 'testicular dysgenesis syndrome' is predicated on reduction in testosterone production by the fetal Leydig cell. We sought to examine the relationship between dysgenesis and steroidogenic capacity in the fetal rat testis more stringently by incorporating lower exposures than those typically used, conducting a comprehensive, non-targeted quantitative evaluation of the fetal testis proteome, and relating alterations in individual proteins to the capacity of the fetal Leydig cell to produce testosterone, and histopathology of the fetal testis. Pregnant dams were dosed orally from gestation day (GD) 13-19 with 0, 10, or 100 mg diethylhexyl phthalate (DEHP)/kg body weight per day. Each endpoint was represented by 16 l. Clustering of Leydig cells occurred before any significant decrease in the capacity of the GD19 Leydig cell to produce testosterone. At 100 mg DEHP/kg, testosterone production was reduced significantly, Leydig cell clusters became quite large, and additional dysgenetic changes were observed in the fetal testis. Of 23 proteins whose expression was altered significantly at both DEHP exposure levels, seven were found to be correlated with and predictive of the quantified endpoints. None of these proteins have been previously implicated with DEHP exposure. Notably, pathway analysis revealed that these seven proteins fit a pathway network in which each is regulated directly or indirectly by estradiol.

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“…Recently, the effect of estrogen on the uterus has been studied at the level of gene expression by DNA microarray analysis (Watanabe et al 2002). As a result, hundreds of genes have been listed as being estrogen-responsive and the temporal changes in their expression after estrogen exposure have been analyzed (Watanabe et al 2003). This has vastly aided our understanding of the effect of estrogen on the uterus at the genetic level.…”

Section: Introductionmentioning

confidence: 99%

The estrogen-responsive adrenomedullin and receptor-modifying protein 3 gene identified by DNA microarray analysis are directly regulated by estrogen receptor

Watanabe¹,

Takahashi²,

Kobayashi³

et al. 2006

Journal of Molecular Endocrinology

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Recent studies have revealed that hundreds of genes in the uterus are activated by estrogen. Their expression profiles differ over time and doses and it is not clear whether all these genes are directly regulated by estrogen via the estrogen receptor. To select the genes that may be regulated by estrogen, we treated mice with several doses of estrogen and searched for those genes whose dose-response expression pattern mirrored the uterine growth pattern. Among those genes, we found that the dose-dependent expression of the adrenomedullin (ADM) gene correlated well with the uterotrophic effect of estrogen. ADM expression is induced early after estrogen administration and is restricted to the endometrial stroma. The spatiotemporal gene expression pattern of ADM was similar to that of receptor-modifying protein 3 (RAMP3). RAMP3 is known to modify calcitonin gene-related receptor (CRLR) so that it can then serve as an ADM receptor. Chromatin immunoprecipitation assays indicated that the estrogen receptor binds directly to the ADM promoter region and RAMP3 intron after estrogen administration. It was also shown that neither the ADM nor RAMP3 gene could be activated in estrogen receptor--null mouse. Although uterine ADM expression has been reported to occur in the myometrium, our observations indicate that estrogen-induced ADM is also expressed in the uterine stroma and that such variable, spatiotemporally regulated ADM expression contributes to a wider range of biological effects than previously expected.

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Similarities and differences in uterine gene expression patterns caused by treatment with physiological and non-physiological estrogens

Cited by 43 publications

References 29 publications

Tissue-specific estrogenic and non-estrogenic effects of a xenoestrogen, nonylphenol

Tissue-specific estrogenic and non-estrogenic effects of a xenoestrogen, nonylphenol

Novel molecular targets associated with testicular dysgenesis induced by gestational exposure to diethylhexyl phthalate in the rat: a role for estradiol

The estrogen-responsive adrenomedullin and receptor-modifying protein 3 gene identified by DNA microarray analysis are directly regulated by estrogen receptor

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