Biochemistry & Biophysics

Stephen H. Safe

safe Distinguished Professor of Veterinary Physiology and Pharmacology and of
Biochemistry and Biophysics
Syd Kyle Chair in Veterinary Medicine
Associate Director, Center for Encironmental and Rural Health
Faculty of Toxicology

Phone: (979) 845-5988
Email: ssafe@cvm.tamu.edu

B.S. Queens University (1962)
D.Phil. Oxford University (1966)
Postdoc. Oxford and Harvard Universities (1966-68)

Joined Texas A&M faculty in 1981

Molecular Biology of Endocrine Disruption Chemicals
The aryl hydrocarbon receptor (AhR) is a nuclear helix-loop-helix transcription factor which forms a ligand-induced nuclear heterodimer with the AhR nuclear translocator (Arnt) protein. Research in this laboratory is focused on the molecular mechanism of crosstalk between the AhR and estrogen receptor (ER) signaling pathways in which the AhR inhibits estrogen-induced gene expression. The antiestrogenic activities of some AhR agonists are also being developed as drugs for clinical treatment of breast and endometrial cancers in women. Research on estrogen-dependent gene expression in various cancer cell lines is focused on analysis of several gene promoters to determine the mechanisms of ERa and ERb action. This includes several genes that are activated through interactions of the ER with Sp1 protein and other DNA-bound transcription factors.

Recent Publications
  1. Reddivari L, Vanamala J, Chintharlapalli S, Safe SH & Miller JC Jr (2007) Anthocyanin fraction from potato extracts is cytotoxic to prostate cancer cells through activation of caspase-dependent and caspase-independent pathways. Carcinogenesis 28: 2227-35
  2. Konopleva M, Zhang W, Shi YX, McQueen T, Tsao T, Abdelrahim M, Munsell MF, Johansen M, Yu D, Madden T, Safe SH, Hung MC & Andreeff M (2006) Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells. Mol Cancer Ther 5: 317-28
  3. Zhang S, Li X, Burghardt R, Smith R 3rd & Safe SH (2005) Role of estrogen receptor (ER) alpha in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells. J Mol Endocrinol 35: 433-47
  4. Fleming JG, Spencer TE, Safe SH & Bazer FW (2006) Estrogen regulates transcription of the ovine oxytocin receptor gene through GC-rich SP1 promoter elements. Endocrinology 147: 899-911
  5. Calabrò P, Samudio I, Safe SH, Willerson JT & Yeh ET (2005) Inhibition of tumor-necrosis-factor-alpha induced endothelial cell activation by a new class of PPAR-gamma agonists. An in vitro study showing receptor-independent effects. J Vasc Res 42: 509-16
  6. Contractor R, Samudio IJ, Estrov Z, Harris D, McCubrey JA, Safe SH, Andreeff M & Konopleva M (2005) A novel ring-substituted diindolylmethane,1,1-bis[3'-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane, inhibits extracellular signal-regulated kinase activation and induces apoptosis in acute myelogenous leukemia. Cancer Res 65: 2890-8
  7. Cizmas L, Zhou GD, Safe SH, McDonald TJ, Zhu L & Donnelly KC (2004) Comparative in vitro and in vivo genotoxicities of 7H-benzo[c]fluorene, manufactured gas plant residue (MGP), and MGP fractions. Environ Mol Mutagen 43: 159-68
  8. Zhang S, Qin C & Safe SH (2003) Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect 111: 1877-82
  9. Safe SH, Pallaroni L, Yoon K, Gaido K, Ross S & McDonnell D (2002) Problems for risk assessment of endocrine-active estrogenic compounds. Environ Health Perspect 110 Suppl 6: 925-9
  10. Barhoumi R, Mouneimne Y, Awooda I, Safe SH, Donnelly KC & Burghardt RC (2002) Characterization of calcium oscillations in normal and benzo[a]pyrene-treated clone 9 cells. Toxicol Sci 68: 444-50
  11. Safe SH, Pallaroni L, Yoon K, Gaido K, Ross S, Saville B & McDonnellc D (2001) Toxicology of environmental estrogens. Reprod Fertil Dev 13: 307-15
  12. McDougal A, Gupta MS, Morrow D, Ramamoorthy K, Lee JE & Safe SH (2001) Methyl-substituted diindolylmethanes as inhibitors of estrogen-induced growth of T47D cells and mammary tumors in rats. Breast Cancer Res Treat 66: 147-57
  13. Stewart DM, Johnson GA, Vyhlidal CA, Burghardt RC, Safe SH, Yu-Lee LY, Bazer FW & Spencer TE (2001) Interferon-tau activates multiple signal transducer and activator of transcription proteins and has complex effects on interferon-responsive gene transcription in ovine endometrial epithelial cells. Endocrinology 142: 98-107
  14. Safe SH (2000) Endocrine disruptors and human health--is there a problem? An update. Environ Health Perspect 108: 487-93
  15. Wang F, Duan R, Chirgwin J & Safe SH (2000) Transcriptional activation of cathepsin D gene expression by growth factors. J Mol Endocrinol 24: 193-202
  16. McDougal A, Sethi Gupta M, Ramamoorthy K, Sun G & Safe SH (2000) Inhibition of carcinogen-induced rat mammary tumor growth and other estrogen-dependent responses by symmetrical dihalo-substituted analogs of diindolylmethane. Cancer Lett 151: 169-79
  17. Barhoumi R, Mouneimne Y, Ramos KS, Safe SH, Phillips TD, Centonze VE, Ainley C, Gupta MS & Burghardt RC (2000) Analysis of benzo[a]pyrene partitioning and cellular homeostasis in a rat liver cell line. Toxicol Sci 53: 264-70
  18. Fernandez P, Wilson C, Hoivik D & Safe SH (1998) Altered phenotypic characteristics of T47d human breast cancer cells after prolonged growth in estrogen-deficient medium. Cell Biol Int 22: 623-33
  19. Ramamoorthy K, Gupta MS, Sun G, McDougal A & Safe SH (1999) 3,3'4,4'-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary cells and in human breast cancer cells. Carcinogenesis 20: 115-23
  20. Safe SH (1998) Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach. Environ Health Perspect 106 Suppl 4: 1051-8
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