Yoshiko Yasuda*Cancer Center, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyou-ku, Kyoto, Japan
*Corresponding author: Yoshiko Yasuda, Cancer Center, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyou-ku, Kyoto, 606-8566, Japan, Tel: 81-75-251-5208; E-mail: firstname.lastname@example.org
Prenatal exposure; EE2; DES; Environmental chemicals; Carcinogenesis; Sterility
Erythropoietin (Epo), by binding to its receptor (EpoR), protects erythroid progenitor cells from apoptotic death and stimulates their proliferation and differentiation into hemoglobin-containing erythrocytes. In the body, the production of Epo in the kidney depends on the oxygen concentration in the circulating blood, i.e. Epo is induced by hypoxia. However, we found that Epo production is induced by estradiol (E2) more than by hypoxia in the mouse uterus  and that the human ovaries, uterus, and cervix can produce Epo through the expression of Epo mRNA with Epo-EpoR signaling . Deprivation of Epo signaling destroyed the surgically resected specimens of ovarian, uterine and cervical cancers through anti-Epo antibody and soluble form of EpoR which can bind to Epo secreted from cancer cells in vivo in nude mice  and in vitro . Twenty-four malignant human cell lines including leukemia cell lines examined expressed Epo and EpoR mRNAs with respective proteins, regardless of their origin, type, genetic characteristics, and biological properties. Furthermore, deprivation of Epo signaling in xenografts of stomach choriocarcinoma and melanoma cell lines using the EpoR antagonist, EMP9, led to the destruction of these xenografts . Epo-EpoR signaling has been found in breast cancers [6,7], prostate cancers  and many other cancers .
In 1971, Herbst et al.  reported that diethylstilbestrol, a synthetic estrogen, acts as a transplacental carcinogen causing vaginal adenocarcinoma in females born to mothers who were prescribed the drug during their pregnancy. Since then, we have been studying the effects of prenatal exposure to ethinyl estradiol (EE2), which is the most effective synthetic estrogen and is now used as a component of oral contraceptives.
We found various effects of EE2 in mature female mice, such as cystic glandular hyperplasia of endometrium and loss of primordial follicles in the ovary ; and, we also detected endometriotic changes of the uterine endometrium . In the testes of mature male mice, EE2 was found to cause drastic conversion of testosterone to estradiol which occurred concomitantly with the production of adenocarcinomatous lesions in the epididymis .
Transplacental effects of EE2 on fetal development detected at term, were hypertrophic nipples in females , gonadal dysgeneses such as ovotestis, intra-abdominal testes, ovarian hypoplasia , and Leydig cell hyperplasia in the testes . Recently, we analyzed these morphological changes induced by the prenatal exposure to EE2 by qT-RT-PCR methods and found the up regulation of aromatase mRNA in the uterus and ovaries of the mice .
Since, uterine and ovarian cancers are known to express transcripts for Epo, EpoR, aromatase, and VEGF, we measured these mRNA levels in surgically resected normal and malignant samples of patients by real-time quantitative RT-PCR analysis. No significant differences were detected between the malignant and normal samples of the average expression of these transcripts. However, the ratios of mRNA levels of aromatase to Epo, EpoR and VEGF between the malignant to normal origins showed higher levels, especially in uterine cancers (Table 1).
|Average transcriptional levels*|
|Epo mRNA||EpoR mRNA||Aromatase mRNA||VEGF mRNA|
|Uterus||Normal||0.39 ± 0.07 (12)||1.78 ± 0.16 (12)||0.41 ± 0.14 (12)||15.55 ± 2.35 (12)|
|Malignant||0.10 ± 0.02 (21)||1.48 ± 0.16 (21)||0.81 ± 0.30 (21)||7.74 ± 1.27 (21)|
|Ovaries||Normal||3.22 ± 1.76 (5)||1.66 ± 0.50 (5)||3.21 ± 0.94 (5)||20.84 ± 8.02 (5)|
|Malignant||0.12 ± 0.03 (10)||0.82 ± 0.10 (10)||0.52 ± 0.12 (10)||5.58 ± 0.86 (10)|
|Aromatase/Epo mRNA||Aromatase/EpoR mRNA||-||Aromatase/VEGF mRNA|
|Respective ratio||Malignant to normal||Respective ratio||Malignant to normal||Respective ratio||Malignant to normal|
|Uterus||Normal||1.10 (12)||7.30||0.23 (10)||2.40||0.03 (10)||3.30|
|Malignant||8.10 (21)||0.55 (21)||0.101 (21)|
|Ovaries||Normal||1.00 (5)||4.73||1.96 (5)||0.32||0.15 (5)||0.06|
|Malignant||4.73 (10)||0.63 (10)||0.01 (10)|
Table 1: Average mRNA levels and their expression ratio in normal and malignant uterus and ovaries
The number in parentheses indicates the number of samples examined.
* Relative content of each mRNA to 18S rRNA mRNA.
The environmental chemicals have been reported to be important factors affecting the fertility of men and women exposed to them during their prenatal and/or neonatal period.
Exposure to p,p’-dichloro diphenyl trichloroethane (DDT) has been reported to induce precocious puberty  ; polycystic aromatic hydrocarbons (PAHs) that are present in tobacco smoke binds to aromatic hydrocarbons receptor (Ah receptor) in the ovary leading to apoptotic death of the fetal germ cells due to the accumulation of Bax protein in them [19,20]; polychlorinated dibenzo-p-dioxin(PCDD, PCDF, TCDD) by binding to the Ah receptor induces reduced sperm counts in adult ; polychlorinated biphenyl(PBS) and polyhalogenated hydrocarbons (PHAs) suppress activity of the enzyme, estrogen sulphotransferase (SULTIEI) leading to high activity of estrogen .
Taking into consideration the data that prenatal exposure to EE2 induces significantly higher aromatase expression in fetal and adult mouse testes as well as in the mature mouse uterus and ovaries, unrecognizable exposure and/or prescription of oral contraceptives (EE2) may cause uterine and ovarian cancer in females and sterility in males. Furthermore, another unrecognizable exposure to the environmental chemicals such as DDT, PAH, dioxin, PCB, and PHA, during prenatal period are reported to cause sterility in men and women due to the disruption of hormonal balance to differentiate into male and female reproductive organs.
- Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M, et al. (1998) Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol. Chem. 273: 25381-25387. [Ref.]
- Yasuda Y, Fujita Y, Musha T, Tanaka H, Shiokawa S, et al. (2001) Expression of erythropoietin in human female reproductive organs. Ital J Anat Embryol 106: 215-222. [Ref.]
- Yasuda Y, Musha T, Tanaka H, Fujita Y, Fujita H, et al. (2001) Inhibition of erythropoietin signaling destroys xenografts of ovarian and uterine cancers in nude mice. Br J Cancer 84: 836-843. [Ref.]
- Yasuda Y, Fujita Y, Masuda S, Musha, T, Ueda K, et al. (2002) Erythropoietin is involved in growth and angiogenesis in malignant tumors of female reproductive organs. Carcinogenesis 23: 1791-1805. [Ref.]
- Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, et al. (2003) Erythropoietin regulates tumor growth of human malignancies. Carcinogenesis 24: 1021-1029. [Ref.]
- Arcasoy MO, Amin K, Karayal AF, Chou SC, Raleigh JA, et al. (2002) Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest 82: 911-918. [Ref.]
- Acs G, Zhang PJ, Rebbeck TR, Acs P, Verma A (2002) Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer 95: 965-981. [Ref.]
- Feldman L, Wang Y, Rhim JS, Bharttacharya N, Loda M, et al. (2006) Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells. Prostate 66: 135-145. [Ref.]
- Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW (2007) Erythropoietin biology in cancer. Clin Cancer res 12: 332-339. [Ref.]
- Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the vagina-Association of maternal stilbestrol therapy with tumor appearance in young. New Engl Jof Med 284: 878-881. [Ref.]
- Yasuda Y, Kihara T, Nishimura H (1977) Effect of prenatal treatment with ethinyl estradiol on the mouse uterus and ovary. Am J Obstet Gynecol 127: 832-836. [Ref.]
- Yasuda Y, Kihara T, Takeda T (1978) Ethynyl estradiol may lead to malignancy. Am J Obstet Gynecol 130: 506-508.
- Yasuda Y, Ohara I, Konishi H, Tanimura T (1988) Long-term effects on male reproductive organs of prenatal exposure to ethinyl estradiol. Am J Obstet Gynecol 159: 1246-1250. [Ref.]
- Yasuda Y, Kihara T and Nishimura H (1981) Effect of ethinyl estradiol on development of mouse fetuses. Teratology 23: 233-239. [Ref.]
- Yasuda Y, Kihara T, Tanimura T, Nishimura H (1985) Gonadal dysgenesis induced by prenatal exposure to ethinyl estradiol in mice. Teratology 32: 219-227. [Ref.]
- Yasuda Y, Konishi H and Tanimura T (1986) Leydig cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol. Teratology 33: 281-288. [Ref.]
- Koike E, Yasuda Y, Shiota M, Shimaoka M, Tsuritani M, et al. (2013) Exposure to ethinyl estradiol prenatally and/or after sexual maturity induces endometriotic and precancerous lesions in uteri and ovaries of mice. Congenit Anom (Kyoto) 53: 9-17. [Ref.]
- Krstevska-Konstantinova M, Charlier C, Craen M, Du Caju M, Heinrichs C, et al., (2001) Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Hum Reprod 16: 1020-1026. [Ref.]
- Matikainen TM, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, et al. (2001) Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nature Genet 28: 355-360. [Ref.]
- Matikainen TM, Moriyama T, Morita Y, Perez GI, Korsmeyer SJ et al. (2002) Ligand activation of the aromatic hydrocarbon receptor transcription factor drives Bax-dependent apoptosis in developing fetal ovarian germ cells. Endocrinology 143: 615-620. [Ref.]
- Mably TA, Bjerke DL, Moore RW, Gendron-Fitzpatrick A, Peterson RE (1992) In utero and lactational exposure of male rats to 2,3,7,8-tetra chlorodivenzo-p-dioxin. 3. Effects on spermatogenesis and reproductive capability. Toxicol Appl Pharmacol 114: 118-126. [Ref.]
- Kester MH, Bulduk S, Tibboel D, Meinl W, Glatt H et al. (2000) Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs. Endocrinology 141: 1897-1900. [Ref.]
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Article Type: Short Communication
Citation: Yasuda Y (2017) Erythropoietin Concomitantly with Ethinyl Estradiol can Cause Uterine and Ovarian Cancers. J Epidemiol Public Health Rev 2(4): doi http://dx.doi.org/10.16966/2471-8211.149
Copyright: © 2017 Yasuda Y. This is an openaccess article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.