Estrogen-induced Spermatogenic Cell Apoptosis Occurs via the Mitochondrial Pathway

Mishra, Durga Prasad; Shaha, Chandrima

doi:10.1074/jbc.m405970200

Cited by 109 publications

(97 citation statements)

References 49 publications

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“…Previous studies reported that exposure to non-physiological concentrations of estrogen, testosterone, and estrogenlike chemicals could stimulate the apoptotic pathway in animal germinal cells (Zhou et al 2001, Kim et al 2003, Nair & Shaha 2003, Jung et al 2004, Mishra & Shaha 2005, and cause DNA damage in human sperm (Anderson et al 2003). These reports support the correlations we observed for the European men, e.g.…”

Section: Xenobiotic-induced Receptor Activity Issuessupporting

confidence: 90%

Relation between serum xenobiotic-induced receptor activities and sperm DNA damage and sperm apoptotic markers in European and Inuit populations

Long¹,

Stronati²,

Bizzaro³

et al. 2007

Reproduction

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Persistent organic pollutants (POPs) can interfere with hormone activities and are suspected as endocrine disrupters involved in disorders, e.g. reproductive disorders. We investigated the possible relation between the actual integrated serum xenoestrogenic, xenoandrogenic and aryl hydrocarbon receptor (AhR) activities, and the sperm DNA damage and sperm apoptotic markers of 262 adult males (54 Inuits from Greenland, 69 from Warsaw (Poland), 81 from Sweden, and 58 from Kharkiv (Ukraine)) exposed to different levels of POPs. Xenobiotic-induced receptor activities were determined by receptor-mediated luciferase reporter gene expression. Sperm DNA damage was measured using terminal deoxynucleotidyl transferase-driven dUTP nick labeling assay (TUNEL) and pro-(Fas) and anti-apoptotic (Bcl-xL) markers were determined by immune methods. Different features of xenobiotic-induced receptor activity in serum and sperm DNA fragmentation and apoptotic markers existed between the Inuits and the European Caucasians. Negative correlations between xenobiotic-induced receptor activities and DNA damage were found for Inuits having relatively lower xenoestrogenic, lower dioxin-like activity, and lower sperm DNA damage, but higher xenoandrogenic activity. In contrast, in the European groups, xenobiotic-induced receptor activities were found to be positively correlated with the DNA damage. Further research must elucidate whether altered receptor activities in concerted action with genetic and/or nutrient factors may have protecting effect on sperm DNA damage of the Inuit population.

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Section: Xenobiotic-induced Receptor Activity Issuessupporting

confidence: 90%

Relation between serum xenobiotic-induced receptor activities and sperm DNA damage and sperm apoptotic markers in European and Inuit populations

Long¹,

Stronati²,

Bizzaro³

et al. 2007

Reproduction

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“…Furthermore, Hagen et al (44) reported that 2-methoxyestradiol, a naturally occurring metabolite of E2, inhibits mitochondrial respiration in both intact cells and submitochondrial particles and that this effect is due to inhibition of complex I of the mitochondrial electron transport chain. Recently, Mishra and Shaha (45) reported that estrogen-induced spermatogenic cell apoptosis occurs via the mitochondrial pathway. Although estrogen synthesis occurs in the mitochondria, exogenously added estrogen is also transported to this organelle.…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure

Moreira

Custódio

Moreno

et al. 2006

Journal of Biological Chemistry

119

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This study evaluated the action of tamoxifen and estradiol on the function of isolated liver mitochondria. We observed that although tamoxifen and estradiol per se did not affect mitochondrial complexes II, III, or IV, complex I is affected, this effect being more drastic (except for state 4 of respiration) when mitochondria were coincubated with both drugs. Furthermore, using two respiratory chain inhibitors, rotenone and diphenyliodonium chloride, we identified the flavin mononucleotide site of complex I as the target of tamoxifen and/or estradiol action(s). Tamoxifen (25 M) per se induced a significant increase in hydrogen peroxide production and state 4 of respiration. Additionally, a significant decrease in respiratory control ratio, transmembrane, and depolarization potentials were observed. Estradiol per se decreased carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated respiration, state 3 of respiration, and respiratory control ratio and increased lag phase of repolarization. With the exception of state 4 of respiration whose increase induced by tamoxifen was reversed by the presence of estradiol, the effects of tamoxifen were highly exacerbated when estradiol was present. We observed that 10 M tamoxifen in the presence of estradiol affected mitochondria significantly by decreasing FCCP-stimulated respiration, state 3 of respiration, respiratory control ratio, and ADP depolarization and increasing the lag phase of repolarization. All of the deleterious effects induced by 25 M tamoxifen were highly exacerbated in the presence of estradiol. Furthermore, we observed that the effects of both compounds were independent of estrogen receptors because the pure estrogen antagonist ICI 182,780 did not interfere with tamoxifen and/or estradiol detrimental effects. Altogether, our data provide a mechanistic explanation for the multiple cytotoxic effects of tamoxifen including its capacity to destroy tamoxifen-resistant breast cancer cells in the presence of estradiol. This new piece of information provides a basis for the development of new and promising anticancer therapeutic strategies.Selective estrogen receptor modulators, also known as tissue selective estrogens, are a class of drugs with mixed estrogen agonist/antagonist actions (1). They were originally classified as antiestrogens because of their ability to antagonize the proliferative effects of estrogens (2). It was later discovered that these compounds could antagonize the action of estrogen by binding to the estrogen receptor (ER) 2 to thereby block estradiol (E2) access (1, 3). It is now known that under certain circumstances and in certain tissues, in addition to acting as competitive inhibitors of endogenous estrogen, these same estrogen antagonists can exert estrogenic agonist properties (4 -6). These findings indicate that the mechanisms regulating ER function are not the same in all cells and that a compound can only be classified as an ER agonist or antagonist in relation to a specific cell type or process.It is known for a long ti...

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“…An inverted microscope [(TE-2000E) Nikon] equipped with a RetigaExi camera (Q-imaging) was used to acquire images and coefficient of colocalization was calculated from mask of colocalization using Image-Pro Plus software (Media Cybernetics). For TUNEL labeling, procedure was carried out as described previously (25).…”

Section: Histology and Immunocytochemistrymentioning

confidence: 99%

Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors

Tripathi

Samadder

Gupta

et al. 2011

Molecular Cancer Therapeutics

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Use of chemotherapeutic drug cisplatin is limited because of its toxicity. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin to reduce its effective treatment dose. This study evaluates the potential of fisetin, a flavonoid, to increase cisplatin cytotoxicity in human embryonal carcinoma NT2/D1 cells. Addition of fisetin to cisplatin enhanced cisplatin cytoxicity in vitro at four times lower dose than that required by cisplatin monotherapy for similar cytotoxic effects. Cisplatin, fisetin monotherapy, and addition of fisetin to cisplatin in a combination increased FasL expression. Cisplatin and fisetin as single agents activated caspases-8 and -3 and caspases-9 and -7, respectively, whereas combination treatment activated all 4 caspases. Increases in p53 and p21 and decreases in cyclin B1 and survivin occurred, all effects being more exaggerated with the combination. Fisetin, with or without cisplatin, increased expression of proapoptotic protein Bak and induced its mitochondrial oligomerization. Bid truncation and mitochondrial translocation of Bid and p53 was induced by fisetin in the presence or absence of cisplatin. Downregulation of p53 by short hairpin RNA during drug treatment decreased p21 levels but caused survivin increase, thus reducing cell death. Upstream to p53, inhibition of p38 phosphorylation reduced p53 phosphorylation and cell death. In a NT2/D1 mouse xenograft model, combination therapy was most effective in reducing tumor size. In summary, findings of this study suggest that addition of fisetin to cisplatin activates both the mitochondrial and the cell death receptor pathway and could be a promising regimen for the elimination of embryonal carcinoma cells. Mol Cancer Ther; 10(2); 255-68. Ó2011 AACR.

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Estrogen-induced Spermatogenic Cell Apoptosis Occurs via the Mitochondrial Pathway

Cited by 109 publications

References 49 publications

Relation between serum xenobiotic-induced receptor activities and sperm DNA damage and sperm apoptotic markers in European and Inuit populations

Relation between serum xenobiotic-induced receptor activities and sperm DNA damage and sperm apoptotic markers in European and Inuit populations

Tamoxifen and Estradiol Interact with the Flavin Mononucleotide Site of Complex I Leading to Mitochondrial Failure

Anticancer Activity of a Combination of Cisplatin and Fisetin in Embryonal Carcinoma Cells and Xenograft Tumors

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