Regulation of the growth of mouse Leydig cells by the inactive stereoisomer, 17α-estradiol: Lack of correlation between the elevated expression of ERα and difference in sensitivity to estradiol isomers

DuMond, James W.; Singh, Kamaleshwar P.; Roy, Deodutta

doi:10.3892/or.8.4.899

Cited by 9 publications

(9 citation statements)

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“…Estrogen receptor (ER)a is present in the Leydig cells and ERb is detected exclusively in the Sertoli cells (Saunders et al 1998, Pelletier et al 2000. Estradiol treatment suppressed progesterone synthesis (Freeman 1985), but stimulated proliferation of mouse Leydig tumor cells (Sato et al 1987, DuMond et al 2001. Furthermore, mice with a genetic disruption of ERa (a estrogen receptor knockout (aERKO)) appeared infertile, had lower sperm counts and elevated serum testosterone levels (Eddy et al 1996), and were not responsive to the estrogen benzoate-mediated decreases in both serum luteinizing hormone (LH) and androgen levels (Akingbemi et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells

Chen

Nagpal

Stocco

et al. 2007

Journal of Endocrinology

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This study was performed to compare the effects of three well-known phytoestrogens such as genistein, resveratrol, and quercetin on steroidogenesis in MA-10 mouse tumor Leydig cells. Addition of genistein or resveratrol to MA-10 cells resulted in decreases in the cAMP-stimulated progesterone secretion, but quercetin had an opposite response. Steroidogenic acute regulatory (StAR) mRNA expression and StAR promoter activity in transiently transfected MA-10 cells were significantly reduced by genistein or resveratrol, but increased by quercetin. Genistein was found to inhibit MA-10 cell proliferation, while resveratrol and quercetin had no effect. Quercetin-induced increase in cAMP-stimulated progesterone secretion was reversed by ICI 182,780, an estrogen receptor (ER) antagonist. However, ICI 182,780 had no effect on cAMP plus quercetin-stimulated StAR promoter activity. To examine whether non-ER factors are associated with quercetin-stimulated progesterone production, we treated MA-10 cells with EGTA to deprive them of extracellular Ca 2C. We found that EGTA inhibited quercetin-plus cAMP-stimulated progesterone secretion and StAR promoter activity. Blocking of Ca 2C influx through L-or Ttype voltage-gated Ca 2C channels with verapamil or mibefradil respectively, attenuated quercetin-stimulated progesterone secretion, while they had no effect on quercetinplus cAMP-stimulated StAR promoter activity. Blocking of intracellular Ca 2C efflux by sodium orthovanadate, a Ca 2C -pump inhibitor, blocked quercetin-plus cAMP-stimulated progesterone secretion and StAR promoter activity in MA-10 cells. Finally, EGTA or vanadate reduced quercetin and cAMP-increased in StAR mRNA expression in MA-10 cells, while ICI 182,780 had no effect. Taken together, these results indicate that phytoestrogens have differential effects on steroidogenesis in MA-10 cells.

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Section: Introductionmentioning

confidence: 99%

Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells

Chen

Nagpal

Stocco

et al. 2007

Journal of Endocrinology

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“…The development of a TEF for estrogenicity is particularly hampered by three recent developments, as noted previously. A second form of the ER has been identified (Chang and Prins 1999;Gustafsson 2000;Kuiper et al 1996), and the two forms of ER are activated differentially by some phytoestrogens and industrial chemicals (Kuiper et al 1998); cross-talk occurs among signaling pathways for different hormones (Safe 1998), and both genomic and nongenomic pathways of estrogen modulation are significant in estrogenresponsive cells (DuMond et al 2001). Thus, estrogenic responses are a complex integration of cell signaling via two ER receptor subtypes, genomic and nongenomic pathways, and crosstalk with other hormone-signaling pathways (DuMond et al 2001;Makela et al 2000;Safe 1998) rather than deriving from a single biologic pathway as required for application of a TEF/TEQ approach.…”

Section: Methods For Assessing Estrogenic Potency Of Mixturesmentioning

confidence: 99%

A critical review of methods for comparing estrogenic activity of endogenous and exogenous chemicals in human milk and infant formula.

Borgert¹,

LaKind²,

Witorsch³

2003

Environ Health Perspect

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In its review of hormonally active agents in the environment, the National Research Council (NRC 1999) recommended that further investigations of human exposure to natural and anthropogenic hormonally active agents be conducted to determine relative contributions of estrogen equivalents. The NRC (1999, p. 273) further recommended that the biological potency of hormonally active agents must be related to that of endogenous hormones in premenopausal and postmenopausal women and in men. Additional comparisons should be made with pharmacologic estrogens (hormonereplacement therapy and hormonal contraceptives) and phytoestrogens because large segments of the population are exposed to these compounds.In addition, the Endocrine Disruptor Screening and Testing Advisory Committee recommended that the U.S. Environmental Protection Agency (U.S. EPA) screen and potentially test "representative mixtures to which large . . . segments of the population are exposed," including human milk (EDSTAC 1998), which has raised questions regarding whether appropriate methods and data are available for performing such an assessment (LaKind and Berlin 2002).The assessment implied by the recommendations of those scientific bodies would involve using biological mechanistic information coupled with exposure data to assess overall human health risk for a particular mechanism. This concept is not new and has been used, for example, to evaluate risks to dioxin-like chemicals that are presumed or demonstrated to act through an aryl hydrocarbon (Ah) receptor-mediated mechanism (i.e., the toxic equivalents, or TEQ, approach). Similarly, Safe (1995) and NRC (1999) have compared the toxic potency of dietary and environmental estrogenic chemicals, using the concept of estrogen equivalents (EQs) where the substances are presumed to act though an estrogen receptor (ER)-mediated mechanism. On the basis of the EQ approach, Safe (1995) estimated that dietary intake of EQs from naturally occurring estrogenic compounds far exceeds dietary intake of man-made estrogenic compounds.In an extension of this approach, we initially sought to apply methods for estimating relative estrogenic potencies of endogenous and exogenous chemicals to assessing estrogenic risks for the two primary sources of infant nutrition: human milk and infant formulas. Both types of infant nutrition are complex mixtures of chemicals, and both contain an array of substances that have potential estrogenic activity. In combination with information on concentrations of endogenous and exogenous chemicals in these nutrition sources, estrogenic potency estimates would theoretically allow us to evaluate the relative magnitude of hormonal activity from naturally occurring substances compared with hormonal activity from exogenous substances. However, for reasons enumerated in this review, we believe that the current state of scientific understanding does not allow for accurate estimates by such methods. Although we recognize that hormonally active agents encompass a wide range of biochemical mecha...

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“…This has resulted in the need and therefore the development of non-breast cell lines that are estrogen sensitive. We have previously shown that the normalized mouse Leydig cell line, TM3, is estrogen sensitive (31,32). However, our previous studies have failed to detect a significant increase in the proliferative response when TM3 cells are exposed to relatively weak estrogens (Du Mond and Roy, The Society of Toxicology International Conference, New Orleans, LA, 1998; Du Mond and Roy, The American Association for Cancer Research International Conference, Philadelphia, PA, 1998).…”

Section: Introductionmentioning

confidence: 99%

Development of a self-proliferating Leydig cell line: a hyper-sensitive E-screening model

DuMond

Singh²,

Roy³

2006

Oncol Rep

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Abstract. The mechanisms of estrogenic endocrine disruption on the male reproductive tract are poorly understood. In order to examine estrogenic properties of xenobiotic chemicals on male tissues, we have developed a mouse Leydig cell line (TM3-SF) that self-proliferates under serum-free conditions. This cell line was derived from ATCC's cell line, TM3. The development of TM3-SF was accomplished over a 4-month period by a progressive serum starvation of the original TM3 cells. The newly established cell line was maintained under serum-free conditions for 20 passages prior to testing. Sensitivity of the TM3-SF cells to estrogens was assayed by cell proliferation studies. A total of four compounds, diethylstilbestrol (DES), 17ß-estradiol, 17·-estradiol, and Bis-phenol A, were tested. Significant increases in cell proliferation occurred at various concentrations ranging from 1 pg/ml to 100 ng/ml for all four compounds. The order of potency observed was DES >Bis-phenol A > 17ß-estradiol and > 17·-estradiol. In addition, we investigated the mechanism for the self-proliferative properties of TM3-SF. The results of these trials indicate that either inhibin or activin is a primary growth factor for this cell line as a 50% inhibition of growth was noted when cell cultures were exposed to the anti-ßa subunit of inhibin/activin. Furthermore, the addition of the anti-ßa subunit of inhibin/activin blocked the DES-induced proliferation of TM3-SF. We conclude that the growth of TM3-SF cells is estrogen sensitive and that either inhibin or activin is involved in the self-regulation of growth.

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Regulation of the growth of mouse Leydig cells by the inactive stereoisomer, 17α-estradiol: Lack of correlation between the elevated expression of ERα and difference in sensitivity to estradiol isomers

Cited by 9 publications

References 0 publications

Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells

Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells

A critical review of methods for comparing estrogenic activity of endogenous and exogenous chemicals in human milk and infant formula.

Development of a self-proliferating Leydig cell line: a hyper-sensitive E-screening model

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