Suppression of erythropoietin induction by diethylstilbestrol in rats
Diethylstilbestrol is an estrogenic endocrine disrupter that has diverse health effects in humans. Bisphenol A is another estrogen-like chemical with possible similar effects to diethylstilbestrol, which has been increasingly used for industry to lead to globally widespread human exposure to it. Hematopoiesis is another of their possible targets, since estrogen suppresses erythropoietin induction to induce anemia. The aim of this study was to clarify the effects of diethylstilbestrol and bisphenol A on erythropoietin induction in rats. We observed the effects of one-shot subcutaneous injection of diethylstilbestrol or bisphenol A on hypoxia-, bleeding-, and cobalt-stimulated erythropoietin induction within 24 h and the hematological outcomes after repeated subcutaneous injection of diethylstilbestrol three times a week for 1 month in rats. Diethylstilbestrol at 10–1,000 μg/kg suppressed stimulus-elevated levels of plasma erythropoietin and its renal mRNA induction. In contrast, bisphenol A at 1,000 μg/kg did not suppress plasma erythropoietin elevated by any stimuli. Repeated injection of diethylstilbestrol at 1,000 μg/kg to rats for 1 month induced an anemic trend due to decelerated erythropoiesis through the insufficient production of erythropoietin, mimicking the effects of estradiol. In conclusion, diethylstilbestrol has a suppressive effect on erythropoietin induction, leading to deceleration of erythropoiesis and the development of anemia.
KeywordsAnemia Bisphenol A Diethylstilbestrol Estrogen Erythropoietin Rat
This research was supported by research grants from CREST-JST and Grant-in-Aid for the Encouragement of Young Scientists (A) (no. 12770179) from the Ministry of Education, Science, and Culture of Japan. The authors gratefully acknowledge that this publication was subsidized by JKA through its promotion funds from KEIRIN RACE.
Conflict of interest
The authors declare that they have no conflict of interest.
- Frye CA, Bo E, Calamandrei G, Calzà L, Dessì-Fulgheri F, Fernández M, Fusani L, Kah O, Kajta M, Le Page Y, Patisaul HB, Venerosi A, Wojtowicz AK, Panzica GC (2012) Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. J Neuroendocrinol 24:144–159PubMedCentralPubMedCrossRefGoogle Scholar
- Hoover RN, Hyer M, Pfeiffer RM, Adam E, Bond B, Cheville AL, Colton T, Hartge P, Hatch EE, Herbst AL, Karlan BY, Kaufman R, Noller KL, Palmer JR, Robboy SJ, Saal RC, Strohsnitter W, Titus-Ernstoff L, Troisi R (2011) Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365:1304–1314PubMedCrossRefGoogle Scholar
- International Committee for Standardization in Haematology (ICSH) (1978) Recommendations for reference method for haemoglobinometry in human blood (ICSH Standard EP 6/2: 1977) and specifications for international haemiglobincyanide reference preparation (ICSH Standard EP 6/3: 1977). J Clin Pathol 31:139–143CrossRefGoogle Scholar
- Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472PubMedCrossRefGoogle Scholar
- Kazi AA, Jones JM, Koos RD (2005) Chromatin immunoprecipitation analysis of gene expression in the rat uterus in vivo: estrogen-induced recruitment of both estrogen receptor alpha and hypoxia-inducible factor 1 to the vascular endothelial growth factor promoter. Mol Endocrinol 19:2006–2019PubMedCrossRefGoogle Scholar
- Kubo T, Maezawa N, Osada M, Katsumura S, Funae Y, Imaoka S (2004) Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1α (HIF-1α): structural requirement of bisphenol A for degradation of HIF-1α. Biochem Biophys Res Commun 318:1006–1011PubMedCrossRefGoogle Scholar
- Melzer D, Gates P, Osborne NJ, Henley WE, Cipelli R, Young A, Money C, McCormack P, Schofield P, Mosedale D, Grainger D, Galloway TS (2012) Urinary bisphenol A concentration and angiography-defined coronary artery stenosis. PLoS One 7:e43378. doi: 10.1371/journal.pone.0043378 PubMedCentralPubMedCrossRefGoogle Scholar
- Perkins SL (1999) Examination on the blood and bone marrow. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM (eds) Wintrobe’s clinical hematology, 10th edn. Williams & Wilkins, Baltimore, pp 9–35Google Scholar