Drugs and Chemicals that Affect the Endocrine System

Abstract

The mammalian endocrine system is very dynamic, and undergoes frequent physiological fluctions due to diurnal variations and cyclical hormonal feedback systems. Both hormonal modulations and chemicall drug perturbations can affect the reproductive systems in males and females. An endocrine disrup-tor, a contemporary term that has been used to define an agent that disrupts the endocrine system, is a hormone or antihormone mimic that can modulate endocrine signaling pathways. Unfortunately, this terminology is confusing and ambiguous and fails to account for the ever-changing endogenous hormonal milieu. The endocrine system can be disrupted or modulated by many physiologic events (e.g., exercise, menstruation, pregnancy), by pharm acologic intervention (e.g., oral contraceptives, antithyroidal medication), and by nutritional states (e.g., iodine deficiencies, vitamin deficiencies and malnutrition). Seasonal changes (e.g., light and temperature) can also modulate endocrine events. Phytoestrogens and xenoestrogens (e.g., chlorinated pesticides) can also affect the dynamics of the endocrine system. Heavy metals and certain anti-cancer agents can interfere with testicular and ovarian function and may cause sterility. Several sites of action can be involved between a drug/chemical and the endocrine system, including the central nervous system, specific target organs or subpopulation of cells, hormone-transporting proteins, and xenobi-otic-m etabolizing enzymes in the liver. At the endocrine target organ level, mechanism(s) of action may involve competition for a cell receptor or affect non-receptor-mediated actions. Some drug!chemicals may act as hormone agonists (i.e., mimic) or conversely act as hormone antagonists (i.e., an antihormone); other agents may act as partial agonists or partial antagonists. Clearly, there are many internal and external factors that can modulate the endocrine system, yet the paracrine and autocrine regulation of specific target organs is finely regulated, and, importantly, is very resilient to drugl chemical perturbation.

Keywords

endocrine disruptors environmental estrogens estrogen = mimics hormone antagonists xenoestrogens

References

Bigazzi, M. , Brandi, M. L. , Bani, G. , and Sacchi, T. B. 1992. Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. Cancer 70(3):639–643.

Birrell, S. N. , Bentel, J. M. , Hickey, T. E. , Ricciardelli, C. , Weger, M. A. , Horsfa II, D. J. , and Tilley, W. D. 1995. Androgens induce divergent prolifer-ative responses in human breast cancer cell lines. J. Steroid Biochem. Mol. Biol. 52 (5):459–467.

Bitman, J. , and Cecil, H. C. 1970. Estrogenic activity of DDT analogues and polychlorinated biphenyls. J. Agric. Food Chem. 18:1108–1112.

Catherino, W. H. , Jeng, M. H. , and Jordan, V. C. 1993. Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism. Br. J. Cancer 67 (5):945–952.

Coldham, N. G. , and James, V. H. 1990. A possible mechanism for increased breast cell proliferation by progestins through increased reductive 17 beta-hydroxysteroid dehyrogenase activity. Int. J. Cancer 45 (1): 174–178.

De Leon, D. D. , Wilson, D. M. , Powers, M. , and Rosenfeld, R. G. 1992. Effects of insulin-like growth factors (IGFs) and IGF receptor antibodies on the proliferation of human breast cancer cells. Growth Factors 6(4):327–336.

El-Tanani, M. K. K. , and Green, C. D. 1996. Insulin/IGF-1 modulation of the expression of two estrogen-induced genes in MCF-7 cells. Mol. Cell. Endocrinol. 121:29-35. Gilfillan, S. C. 1965. Lead poisoning and the fall of Rome. J. Occup. Med. 7:53–60.

Giust, R. M. , Iwamoto, K. , and Hatch, E. E. 1995. Diethylstibestrol revisited: A review of the long-term health effects. Ann. Int. Med. 122:778–788.

Hofland, L. J. , van der Burg, B. , van Eijck, C. H. , Sprij, D. M. , van Koetsveld, P. M. , and Lamberts, S. W. 1995. Role of tumor-derived fibroblasts in the growth of primary cultures of human breast-cancer cells: Effects of epidermal growth factor and the somatostatin analogue octreotide. Int. J. Cancer 60 (1):93–99.

10.

Jeng, M. H. , Langan-Fahey, S. M. , and Jordan, V. C. 1993. Estrogenic actions of RU486 in hormone-responsive MCF-7 human breast cancer cells. Endocrinology 132 (6):2622–2630.

11.

Krishnan, A. V. , Stathis, P. , Permuth, S. F. , Tokes, L. , and Feldman, D. 1993. Bisphenol-A: An estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology 132 (6):2279–2286.

12.

Kubota, T. , Josui, K. , Fukutomi, T. , and Kitajima, M. 1995. Growth regulation by estradiol, progesterone and recombinant human epidermal growth factor of human breast carcinoma xenografts grown serially in nude mice. Anticancer Res. 15 (4): 1275–1278.

13.

Kupfer, D. , Mani, C. , Lee, C. A. , and Rifkind, A. B. 1994. Induction of tamox-ifen-4-hydroxylation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), beta-naphthoflavone (beta NF), and phenobarbital (PB) in avian liver, identification of P450 TCDDAA, a catalyst of 4-hydroxylation induced by TCDD and beta NF. Cancer Res. 54 (12):3140–3144.

14.

Lazier, C. B. , and Bapat, B. V. 1988. Antiestrogen binding sites: General and comparative properties. J. Steroid Biochem. 31 (4B):665–669.

15.

Lien, E. J. , Das, A. , and Lien, L. L. 1996. Immunopharmacological and biochemical bases of Chinese herbal medicine. Prog. Drug Res. 46:263–280.

16.

Mayr, U. , Butsch, A. , and Schneider, S. 1992. Validation of two in vitro tests systems for estrogenic activities with zearalenone, phytoestrogens and cereal abstracts. Toxicology 74:135–149.

17.

Mellanen, P. , Petanen, T. , Lehtimaki, J. , Makela, S. , Bylund, G. , Holmbom, B. , Mannila, E. , Oikari, A. , and Santi, R. 1996. Wood-derived estrogens: Studies in vitro with breast cancer cell lines and in vivo in trout. Toxicol. Appl. Pharmacol. 136:381–388.

18.

Najid, A. , and Habrioux, G. 1990. Biological effects of adrenal androgens on MCF-7 and BT-20 human breast cancer cells. Oncology 47(3):269–274.

19.

O'Connor, J. C. , Cook, J. C. , Craven, S. C. , Van Pelt, C. S. , and Obourn, J. D. 1996. An in vivo battery for identifying endocrine modulators that are estrogenic or dopamine regulators. Fundam. Appl. Toxicol. 33:182–195.

20.

Schutze, N. , Vollmer, G. , Tiemann, I. , Geiger, M. , and Knuppen, R. 1993. Catecholestrogens are MCF-7 cell estrogen receptor agonists. J. Steroid Biochem. Mol. Biol. 46 (6):781–789.

21.

Soto, A. M. , Justicia, H. , Wray, J. W. , and Sonnenschein, C. 1991. p-Nonylphenol: An estrogenic xenobiotic released from “modified” polystyrene. Environ. Health Perspect. 92:167–173.

22.

Soto, A. M. , Lin, T. , Justicia, H. , Silvia, R. M. , and Sonnenschein, C. 1992. An “in culture” bioassay to assess the estrogenicity of xenobiotics (E-Screen). In Chemically-Induced Alterations in Sexual and Functional Development: The Wildlife/ Human Connection, eds. T. Colburn and C. Clement , 295–309. Princeton, NJ: Princeton Scientific.

23.

Taylor, J. A. , Grady, L. H. , Engler, K. S. , and Welshons, W. V. 1995. Relationship of growth stimulated by lithium, estradiol, and EGF to phos-pholipase C activity in MCF-7 human breast cancer cells. Breast Cancer Res. Treat 34 (3):265–277.

24.

Thomas, J. A. 1995. Gonodal-specific metal toxicology. In metal toxicology, eds. R. A. Goyer , C. D. Klaassen , and M. P. Waalkes , pp. 413–446. San Diego, CA: Academic Press.

25.

van den Koedijk Christa, D. M. A. , Blank en stein, M. A. , and Thijssen, J. H. H. 1994. Speculation on the mechanism of action of triphenylethylene antioes-trogens. Biochem. Pharmacol. 47(11): 1927–1937.

26.

Welshons, W. V. , Engler, K. S. , Taylor, J. A. , and Grady, L. H. 1995. Lithium-stimulated proliferation and alteration of phosphoinositide metabolites in MCF-7 human breast cancer cells. J. Cell. Physiol. 165(1): 134–144.

27.

Whorton, D. , Milby, T. H. , Krauss, R. M. , and Stabbs, H. A. 1979. Testicular function in DBCP exposed pesticide workers. J. Occup. Med. 21:161–166.

28.

Yee, D. 1994. The insulin-like growth factor system as a target in breast cancer. [Review]. Breast Cancer Res. Treat. 32 (1):85–95.