Genetic Sensitivity to Estrogens:
Can we improve reproductive health by tailoring estrogen and other hormonal treatments to each individual’s genotype?
Estrogens have important uses for Hormone Replacement Therapy (HRT) to help maintain bone density and cardiovascular health in postmenopausal women, as well as, as contraceptives to aid in family planning for younger women. Unfortunately, estrogens can also have adverse health effects on a small percentage of users, including increased incidence of breast and reproductive tract cancers, and increased incidence of strokes in women who are obese or who smoke.
The incidence of strokes is also increased by hormone replacement therapy (HRT) with Premarin in women who initiated HRT long after menopause, but not in those that started HRT at menopause. Unlike true estrogens such as estradiol or 17-ethinyl estradiol, Premarin is mixture of estrone sulfate and other estrogen conjugates that are purified from horse urine. Thus, the estrogenic activity of Premarin depends on the enzyme steroid sulfatase cleaving off the sulfate to form biologically active estrogens. However, the activity of this and other enzymes involved with estrogen metabolism, including estrogen sulfotransferase, vary markedly between individuals.
Estrogens and other steroid treatments can also have dramatic effects on mood, behavior and other quality of life endpoints. Unfortunately, we do not fully understand why these reproductive and behavioral responses differ so markedly between individuals.
Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen have also been developed to help protect against the development of breast cancer, but result in increased risk of uterine cancer. Inhibiting the synthesis of estrogen with aromatase inhibitors is also an important defense against the growth of breast and other estrogen-dependent cancers. Unfortunately, we do not fully understand why some individuals develop reproductive disease while others remain healthy following exposure to estrogenic compounds.
The observation that the reproductive and pathological effects of estrogens and of SERMs differ markedly between and within mammalian species (Hart 1990), shows the importance of genetic variation in sensitivity to estrogenic compounds. Strains of laboratory animals also differ markedly in sensitivity to estrogens, xenoestrogens and SERMS (Nakai et al. 1999; Spearow et al. 1999; Long et al. 2000; Putz et al. 2001b). Human polymorphisms in estrogen receptors, aromatase, and several enzymes involved in estrogen and catechol estrogen metabolism have also been associated with susceptibility to breast and reproductive tract cancers and disorders (Hanna et al. 2000; Huber et al. 2002; Saintot et al. 2003; Spearow 2005). An enzyme involved in estrogen metabolism, estrogen sulfotransferase, differs markedly between individual humans, and between strains of mice, and has been proposed as a genetic marker for sensitivity to estrogenic agents (Spearow et al. 2001a; Adjei et al. 2003). Unfortunately, our understanding of the genetic biodiversity in sensitivity to estrogens, SERMs and xenoestrogens is far from complete.
Genetically diverse rodent strains provide animal models for improving our understanding of the genetic mechanisms controlling sensitivity to estrogenic compounds. For example, strains of mice differ in developmental, neuroendocrine and immunological responses to estrogenic agents (Griffith et al. 1997; Nakai et al. 1999; Lephart et al. 2001; Clemons et al., 2004). Strains of rats also differ in the effects of estrogens, and xenoestrogens such as Bisphenol A (BPA) on reproductive development (Steinmetz et al. 1997; Steinmetz et al. 1998; Long et al. 2000).
Thus, Dr. Spearow developed and characterized several estrogen-sensitive and estrogen-resistant strains of mice for use as animal models. Unselected C57Bl/6 (B6) strain mice are very sensitive, while large litter size selected CD-1 strain mice are very resistant to the effects of estrogens on pubertal reproductive development (Spearow et al, 1999). For example, B6 and CD-1 strain mice differ greater than 16-fold in sensitivity to the inhibition of sperm maturation and testes weight by pubertal exposure to estrogen (Spearow et al. 1999; Spearow et al. 2001a). Females of these strains differ markedly in the effects of estrogens on uterine weight and the disruption of gestation. These strains also differ markedly in the ability of estrogen primed females to resist vaginal yeast (Candidia albicans) infections (Clemons et al. 2004). These and other estrogen-resistant CD inbred strains of mice developed by Dr. Spearow provide ideal animal models for identifying the genetic factors controlling differential susceptibility to the beneficial and the pathogenic effects of estrogens.
Dr. Susan Nagel developed the Estrogen Receptor action INdicator (ERIN) transgenic mouse to enable detailed analysis of the transcriptional activation of estrogen receptors by natural and xeno-estrogens (Nagel et al. 2001). This transgene has a 3X estrogen response element (ERE) that drives a E. coli b-Galactosidase reporter gene. Since mammalian cells lack the b-galactosidase enzyme, measuring the activity of this enzyme in ERIN transgenic cells or tissues provides a rapid and sensitive means of monitoring estrogenic responses (Nagel et al. 2001). In collaboration with Dr. Susan Nagel, Dr. Spearow repeatedly backcrossed the Estrogen Receptor action Indicator (ERIN) transgene: 1) on to the estrogen-sensitive B6 strain to develop B6.ERIN transgenic mice; and, 2) on to the estrogen-resistant CD10 inbred strain to develop CD10.ERIN transgenic mice. These strains of mice provide unique tools for investigating the transcriptional effects of estrogens on genetically sensitive, and on genetically resistant strains and individuals. One of the advantages of the ERIN mouse is that it allows comparison of Estrogen Receptor activation endpoints with classic tissue response phenotypes such as uterine weight. This is important for examining the effects of SERMs, such as Tamoxifen, and xenoestrogens, such as Bisphenol A, since estrogen-induced increases in uterine estrogen receptor transcriptional activity were not accurately reflected by changes in uterine weight (Nagel et al. 2001). Preliminary studies are underway characterizing the ERIN transcriptional responses of estrogen-sensitive B6.ERIN strain mice and estrogen-resistant CD10.ERIN males and females to estrogenic agents.
These animal models will aid in understanding the genetic and biological mechanisms involved in sensitivity to estrogens. Once identified in mice, it will be much easier to test the corresponding genes as markers for sensitivity to estrogens in other species, including humans. Better genetic markers for sensitivity to estrogens will enable improving reproductive health through optimizing estrogen and SERM treatments according to each individual's estrogen-sensitivity genotype.
The continuation of this pharmacogenetic research on genetic differences in sensitivity to estrogens and estrogen mimics is highly dependent on funding. If you find this approach interesting, please tell others. If you would consider making a tax-deductible contribution to the University of California to support this research on genetic variation in sensitivity to estrogens, please contact Dr. Jimmy Spearow at (530) 754-8940 or by Email jlspearow@ucdavis.edu If you email, please include “Reproductive Genetics” in the subject line.
Literature cited:
Adjei, A. A., B. A. Thomae, et al. (2003). "Human estrogen sulfotransferase (SULT1E1) pharmacogenomics: gene resequencing and functional genomics." Br J Pharmacol 139(8): 1373-82.
Clemons, K. V., J. L. Spearow, et al. (2004). "Genetic Susceptibility of Mice to Candida albicans Vaginitis Correlates with Estrogen Sensitivity." Infection and Immunity 72(8): 4878-80.
Griffith, J. S., S. M. Jensen, et al. (1997). "Evidence for the genetic control of estradiol-regulated responses. Implications for variation in normal and pathological hormone-dependent phenotypes." Am J Pathol 150(6): 2223-30.
Hanna, I. H., S. Dawling, et al. (2000). "Cytochrome P450 1B1 (CYP1B1) pharmacogenetics: association of polymorphisms with functional differences in estrogen hydroxylation activity." Cancer Res 60(13): 3440-4.
Hart, J. E. (1990). "Endocrine pathology of estrogens: species differences." Pharmacol Ther 47(2): 203-18.
Huber, J. C., C. Schneeberger, et al. (2002). "Genetic modeling of estrogen metabolism as a risk factor of hormone-dependent disorders." Maturitas 41 Suppl 1: S55-64.
Lephart, E. D., S. B. Call, et al. (2001). "Neuroendocrine Regulation of Sexually Dimorphic Brain Structure and Associated Sexual Behavior in Male Rats Is Genetically Controlled." Biol Reprod 64(2): 571-578.
Long, X., R. Steinmetz, et al. (2000). "Strain differences in vaginal responses to the xenoestrogen bisphenol A." Environ Health Perspect 108(3): 243-7.
Nagel, S. C., J. L. Hagelbarger, et al. (2001). "Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and Xenobiotics." Endocrinology 142(11): 4721-8.
Nakai, M., K. Uchida, et al. (1999). "The development of male reproductive organ abnormalities after neonatal exposure to tamoxifen is genetically determined." J Androl 20(5): 626-34.
Putz, O., C. B. Schwartz, et al. (2001b). "Neonatal low- and high-dose exposure to estradiol benzoate in the male rat: II. Effects on male puberty and the reproductive tract." Biol Reprod 65(5): 1506-17.
Saintot, M., C. Malaveille, et al. (2003). "Interactions between genetic polymorphism of cytochrome P450-1B1, sulfotransferase 1A1, catechol-o-methyltransferase and tobacco exposure in breast cancer risk." Int J Cancer 107(4): 652-7.
Spearow, J. L. (2005). Reviewer's Appendix to the White Paper on Species/Strain/Stock in Endocrine Disruptor Assays, Battelle Memorial Institute.
Spearow, J. L., P. Doemeny, et al. (1999). "Genetic Variation in Susceptibility to Endocrine Disruption by Estrogen in Mice." Science 285(5431): 1259-1261.
Spearow, J. L., P. O'Henley, et al. (2001a). "Genetic variation in physiological sensitivity to estrogen in mice." Apmis 109(5): 356-64.
Steinmetz, R., N. G. Brown, et al. (1997). "The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo." Endocrinology 138(5): 1780-6.
Steinmetz, R., N. A. Mitchner, et al. (1998). "The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract." Endocrinology 139(6): 2741-7.
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