BIOGRAPHICAL SKETCH

		Rex A. Hess
		Professor of Reproductive Biology and Toxicology
		B.S., University of Missouri-Columbia M.S., University of Missouri-Columbia  Ph.D., Clemson University
		email: rexhess@uiuc.edu
Biographical Information and HomePage

Research Interests

Studies in the Hess laboratory have a major focus on male reproductive pathology, endocrinology and toxicology. Specific interests include testicular growth and development, estrogen regulation of the male reproductive tract and spermatogonial stem cell regulation. Recent studies have focused on the presence and function of estrogen receptors in the male reproductive tract and Sertoli cell regulation of stem cell self-renewal. Efferent ductules of the male were found to express estrogen receptors 3.5 fold greater than female tissue. Using the ERalpha knockout mice and antiestrogen treatment, the Hess laboratory discovered the first known function for estrogen in the male reproductive tract. Estrogen was found to regulate fluid reabsorption by the efferent ductule epithelium, a function that is now considered to be essential for fertility. Using this new discovery, current research is attempting to develop a novel male contraceptive by targeting estrogen receptor in the male tract. Our stem cell research came about through a discovery at the Washington University School of Medicine. Scientists at Wash U found that knocking out a transcription factor, ERM (from the PEA-3 family), led to male infertility and through a collaboration we were able to demonstrate that this factor was specific for the Sertoli cell and that it was responsible for stem cell renewal. This study was recently published in Nature 436:1030. We are currently collaborating with Paul Cooke and Marie-Claude Hofmann to develop this animal model for the study of stem cell niche regulation. Through both basic and applied research, we seek a better understanding of structure and function of the male reproductive tract and improvements in reproductive and endocrine health.

Estrogen in the male. My laboratory conducts research in the areas of male reproductive biology, endocrinology and toxicology, with the following specific interests: spermatogenesis, testicular growth and development, structure and function of the epididymis and the role of estrogens in male reproduction. A major discovery was published in Nature (1997) 390, 509-512, showing for the first time an important function for estrogen in the male reproductive tract. Estrogen is considered the "female" hormone, whereas testosterone is considered the "male" hormone. Both hormones, however, are present in both sexes. Thus, sexual distinctions are not qualitative differences, but rather due to quantitative divergence in hormone concentrations and differential expressions of steroid hormone receptors. In males, oestrogen is present in low concentrations in blood, but can be extraordinarily high in semen and as high as 250 pg/ml in rete testis fluids, which is higher than serum estradiol in the female. It is well known that male reproductive tissues express oestrogen receptors; yet, the role of oestrogen in male reproduction had remained an open question until now. In this paper, we were able to show that estrogen regulates reabsorption of luminal fluid in the head of the epididymis. This was the first demonstration of a physiological function for oestrogen in male reproductive organs. Disruption of this essential function causes sperm to enter the epididymis diluted, rather than concentrated, resulting in infertility.

Molecular mechanism of estrogen function in the male. We have now determined that estrogen regulates expression of the Na+/H+ exchanger-3 (NHE3) and the rate of (22)Na+ transport, sensitive to a NHE3 inhibitor. Immunohistochemical staining for NHE3, carbonic anhydrase II (CAII) and aquaporin-I (AQP1) was decreased in ERa knockout (aERKO) efferent ductules. Targeted gene deficient mice were compared to aERKO and the NHE3 knockout and CAII deficient mice showed aERKO-like fluid accumulation, but only the NHE3 knockout and aERKO mice were infertile. Northern blot analysis showed decreases in mRNA for NHE3 in aERKO and antiestrogen-treated mice. The changes in AQP1 and CAII in aERKO appeared to be secondary, due to the disruption of apical cytoarchitecture. Ductal epithelial ultrastructure was abnormal only in aERKO mice. Thus, in the male, estrogen regulates one of the most important epithelial ion transporters and maintains epithelial morphological differentiation in efferent ductules of the male, independent of its regulation of Na+ transport. Finally, these data raise the possibility of targeting ERa in developing a contraceptive for the male. Proc. Natl. Acad. Sci. USA (2001) 98:

References

All references to efferent ductules and/or estrogen

• Estrogen receptors in the male
  
  An understanding of estrogen's function in the male reproductive tract is limited and estrogen receptor (ER) localization in the reproductive tract of the adult male rat has not been described. In the Nov/Dec issue of J. of Andrology, we present data showing the location of ERalpha by immunohistochemistry using ER21 antibody, which recognizes only ERalpha. Strongest immunoreactivity was seen in epithelia of ductuli efferentes and of the initial segment of the epididymis. Nuclei of both ciliated and nonciliated cells were positive. The epithelium of the rete testis, caput, corpus and cauda epididymides stained less intensely for ERalpha. The vas deferens epithelium was ERalpha negative. Stromal tissue in the excurrent ducts was also ERalpha positive. Using 3H-estradiol autoradiography, specific binding of estradiol was seen in nuclei of ductuli efferentes. ERalpha mRNA expression was greatly enhanced in ductuli efferentes compared to other regions of the male tract and was 3.5 times greater than in uterus. For comparison, the presence of ERß was determined using reverse transcription-polymerase chain reaction (RT-PCR) amplification. ERß mRNA was expressed throughout the male tract and in prostate. These results indicate that all organs in the male excurrent ductal system of the rat express ERa and are potential targets of estrogen. However, the ductuli efferentes are the site of most intense ERa expression. The role of ERß remains to be determined, but its expression appears ubiguitous in the male tract. References
  
• Toxicant effects of benomyl on male reproduction
  
  Testicular and efferent ductule effects of carbendazim (methyl 2-benzimidazole carbamate), a metabolite of the fungicide benomyl, were determined in the adult rat after a single exposure. Effects were first seen beginning at 8 h post-exposure as an increase in testis weight; then decreases in testicular spermatid numbers, epididymal sperm reserves, and in the percentage of morphologically normal cauda sperm. Significant testicular and efferent ductal alterations occurred in animals treated with dosages of 100 mg/kg or greater. A dose-dependent increase in testicular weight at 2 days post-treatment was accompanied by increases in seminiferous tubular diameter, and excessive loss of immature germ cells in a stage-dependent manner. There was also a dose dependent increased incidence of occlusions in the efferent ductules. The occluded ductules were characterized by severe inflammation and epithelium disorganization. At 70 days post treatment, there were dose-dependent decreases in mean testis weight and mean seminiferous tubular diameter. Only minimal long-term effects were seen at 50 mg/kg. In testes exhibiting greater than 25% seminiferous tubular atrophy (100 mg/kg or greater dosages), 100% of the testes were associated with efferent ductules containing occlusions and the caput sperm numbers were significantly reduced. Occlusions, abnormal ductules, fibrosis, spermatic granulomas and mineralizations were observed in the ductuli efferentes. Long-term effects of carbendazim on the testis were induced primarily by the ductal occlusions. Carbendazim effects on the male reproductive system were found to be more severe than those produced by the fungicide benomyl.
  
  Ilio and Hess, 1994. Structure and Function of the Ductuli Efferentes: A Review. Microscopy Res. and Technique 29:432-467.
  
  Benomyl References

Publications (last 5 years)

2003

97. Witzmann FA, Bobb A, Briggs GB, Coppage HN, Hess RA, Li J, Pedrick NM, Ritchie GD, Rossi J, Still KR, 2003. Analysis of rat testicular protein expression following 91-day exposure to JP-8 jet fuel vapor. Proteomics 3:1016-1027.
98. Frasor, J., Barnett, D.H., Danes, J.M., Hess, R., Parlow, A.F. and Katzenellenbogen, B.S. 2003. Response-Specific and Ligand Dose-Dependent Modulation of Estrogen Receptor (ER) alpha Activity by ERbeta in the Uterus. Endocrinology. 144, 3159-3166.
99. Cho HW, Carnes K, Nie R, Zhou Q, Sharief NAQ, Hess RA, 2003. The antiestrogen ICI 182,780 induces early effects on the adult male mouse reproductive tract and long-term decreased fertility without testicular atrophy. Reprod Biol Endocrinol. 1, 57.
100. Oliveira C, Nie R, Carnes K, Franca LR, Prins GS, Saunders PTK, Hess RA. 2003. The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules. Reprod Biol Endocrinol. 1, 75. 2004
101. DuTeaux SB, Berger T, Hess RA, Sartini BL and Miller MG. 2004. Male Reproductive Toxicity of Trichloroethylene: Sperm Protein Oxidation and Decreased Fertilizing Ability. Biol Reprod 70:1518-1526.
102. Kuster CE, Hess RA and Althouse GC. 2004. Immunofluorescence reveals ubiquitination of retained distal cytoplasmic droplets on ejaculated porcine spermatozoa. J Androl 25:340-347.
103. Oliveira CA, Mahecha GA, Carnes K, Prins GS, Saunders PT, Franca LR, Hess RA. 2004. Differential hormonal regulation of estrogen receptors ERalpha and ERbeta and androgen receptor expression in rat efferent ductules. Reproduction 128:73-86. 2005
104. Oliveira CA, Carnes K, França LR, Hermo L, Hess RA. 2005. Aquaporin-1 and -9 are differentially regulated by estrogen in the efferent ductule epithelium and initial segment of the epididymis. Biology of the Cell 97:385-895.
105. Chen C, Ouyang W, Grigura V, Zhou Q, Carnes K, Lim H, Zhao G-Q, Arber S, Kurpios N, Murphy TL, Cheng AM, Hassell JA, Chandrashekar V, Hofmann M-C, Hess RA, Murphy KM. 2005. ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436:1030-1034.
106. Holsberger DR, Buchold GM, Leal MC, Kiesewetter SE, O'Brien D A, Hess RA, Franca LR, Kiyokawa H, Cooke PS (2005) Cell-cycle inhibitors p27Kip1 and p21Cip1 regulate murine Sertoli cell proliferation. Biol Reprod 72:1429-36. 2006
107. Ruz R, Gregory M, Smith CE, Cyr DG, Lubahn DB, Hess RA, Hermo L. 2006. Expression of aquaporins in the efferent ductules, sperm counts, and sperm motility in estrogen receptor-alpha deficient mice fed lab chow versus casein. Mol Reprod Dev. 73:226-237.
108. Khor B, Bredemeyer AL, Huang CY, Turnbull IR, Evans R, Maggi LB, Jr., White JM, Walker LM, Carnes K, Hess RA, Sleckman BP. 2006. Proteasome activator PA200 is required for normal spermatogenesis. Mol Cell Biol 26:2999-3007.
109. Surace, EI, Strickland, AM, Hess, RA, Gutmann, DH and Naughton, CK. 2006. Tslc1 (nectin-like molecule-2) is essential for spermatozoa motility and male fertility. J Androl 27: 816-825.
110. Cooke PS, Hess RA, Simon L, Schlesser HN, Carnes K, Tyagi G, Hofmann M-C and Murphy KM. 2006. The transcription factor Ets-related molecule (ERM) is essential for spermatogonial stem cell maintenance and self-renewal. Anim Reprod 3(2): 98-107.
111. Picciarelli-Lima P, Oliveira AG, Reis AM, Kalapothakis E, Mahecha GA, Hess RA and Oliveira CA. 2006. Effects of 3-beta-diol, an androgen metabolite with intrinsic estrogen-like effects, in modulating the aquaporin-9 expression in the rat efferent ductules. Reprod Biol Endocrinol 4(1): 51.

2007
112. Gist, DH, Bradshaw, S, Morrow, CM, Congdon, JD and Hess, RA. 2007. Estrogen response system in the reproductive tract of the male turtle: An immunocytochemical study. Gen Comp Endocrinol 151(1): 27-33.
113. Hild, SA, Marshall, GR, Attardi, BJ, Hess, RA, Schlatt, S, Simorangkir, DR, Ramaswamy, S, Koduri, S, Reel, JR and Plant, TM. 2007. Development of l-cdb-4022 as a nonsteroidal male oral contraceptive: Induction and recovery from severe oligospermia in the adult male cynomolgus monkey (macaca fascicularis). Endocrinology 148(4): 1784-1796.
114. Simon, L, Ekman, GC, Tyagi, G, Hess, RA, Murphy, KM and Cooke, PS. 2007. Common and distinct factors regulate expression of mRNA for ETV5 and GDNF, Sertoli cell proteins essential for spermatogonial stem cell maintenance. Exp Cell Res 313(14): 3090-3099.
115. Oliveira, AG, Telles, LF, Hess, RA, Mahecha, GA and Oliveira, CA. 2007. Effects of the herbicide roundup on the epididymal region of drakes Anas platyrhynchos. Reprod Toxicol 23(2): 182-191.
116. Oliveira, AG, Coelho, PH, Guedes, FD, Mahecha, GA, Hess, RA and Oliveira, CA. 2007. 5alpha-androstane-3beta,17beta-diol (3beta-diol), an estrogenic metabolite of 5alpha-dihydrotestosterone, is a potent modulator of estrogen receptor ERbeta expression in the ventral prostrate of adult rats. Steroids 72(14): 914-922. 117. Martin, LJ, Chen, H, Liao, X, Allayee, H, Shih, DM, Lee, GS, Hovland, DN, Jr., Robbins, WA, Carnes, K, Hess, RA, Lusis, AJ and Collins, MD. 2007. Fk506, a calcineurin inhibitor, prevents cadmium-induced testicular toxicity in mice. Toxicol Sci 100(2): 474-485.
118. Dornas, RA, Oliveira, AG, Kalapothakis, E, Hess, RA, Mahecha, GA and Oliveira, CA. 2007. Distribution of vitamin D3 receptor in the epididymal region of roosters (gallus domesticus) is cell and segment specific. Gen Comp Endocrinol 150(3): 414-418.
119. Dass, B, Tardif, S, Park, JY, Tian, B, Weitlauf, HM, Hess, RA, Carnes, K, Griswold, MD, Small, CL and Macdonald, CC. 2007. Loss of polyadenylation protein tauCstF-64 causes spermatogenic defects and male infertility. Proc Natl Acad Sci U S A 104(51): 20374-20379.
120. Morrow, C, Hostetler, C, Griswold, M, Hofmann, MC, Murphy, K, Cooke, PS and Hess, RA. 2007. ETV5 is required for continuous spermatogenesis in adult mice and may mediate blood-testes barrier function and testicular immune privilege. Ann N Y Acad Sci 1120: 144-151.

2008
121. Zhou Q, Nie R, Li Y, Friel P, Mitchell D, Hess RA, Small C and Griswold MD. 2008. Expression of Stimulated by Retinoic Acid Gene 8 (Stra8) in Spermatogenic Cells Induced by Retinoic Acid: an in vivo Study in Vitamin A Sufficient Postnatal Murine Testes. Biol Reprod. 79:35-42.
122. Schlesser HN, Simon L, Hofmann MC, Murphy KM, Murphy T, Hess RA, Cooke PS. 2008. Effects of ETV5 (Ets Variant Gene 5) on testis and body growth, time course of spermatogonial stem cell loss, and fertility in mice. Biol Reprod. 78:483-489.
123. Stutler, SA, Johnson, EW, Still, KR, Schaeffer, DJ, Hess, RA and Arfsten, AD. 2008. Effect of method of euthanasia on sperm motility of mature sprague-dawley rats. J Am Assoc Lab Anim Sci 46(2): 13-20.
124. Oliveira, AG, Dornas, RA, Kalapothakis, E, Hess, RA, Mahecha, GA and Oliveira, CA. 2008. Vitamin D3 and androgen receptors in testis and epididymal region of roosters (gallus domesticus) as affected by epididymal lithiasis. Anim Reprod Sci.(in press).
125. Netzel-Arnett S, Bugge TH, Hess RA, Carnes K, Stringer BW, Scarman AL, Hooper JD, Tonks ID, Kay GF and Antalis TM. (2008) The glycosylphosphatidylinositol (GPI)-anchored serine protease Testisin directs epididymal sperm cell maturation and fertilizing ability (submitted)
126. Morrow C, Gaurav T, Simon L, Carnes K, Murphy T, Murphy K, Cooke PS, Hofmann MC and Hess, RA. 2008.Murine Sertoli cell Claudin-5 expression depends upon the presence of germ cells and Sertoli cell Ets-Variant Gene 5 (ETV5) and contributes to blood-testis barrier function. (submitted).

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