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. 2001 Sep;109(9):943–947. doi: 10.1289/ehp.01109943

Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat.

D J Liao 1, A Blanck 1, P Eneroth 1, J A Gustafsson 1, I P Hällström 1
PMCID: PMC1240445  PMID: 11673124

Abstract

The acute toxicity of diethylnitrosamine (DEN) to the liver has been well documented in the literature, but whether DEN also affects the endocrine parameters has been addressed in only a few studies. We thus investigated the effects of DEN on pituitary, serum hormone levels, and certain sex-differentiated liver enzymes in this study. Adult male Wister rats were intraperitoneally injected with DEN at a single dose of 200 mg/kg and were sacrificed at 1, 3, 7, and 35 days after injection; DEN-treated females were included as controls at days 7 and 35. Electron microscopic observation showed that during the first week after injection, all types of granular cells of the anterior pituitary in male animals exhibited cellular damage, including disrupted organelles and cellular structure, as well as pyknotic or lytic nuclei. Many undamaged secretory cells exhibited dilated endoplasmic reticula, hypertrophic Golgi complexes, and peripheral location of secretory granules, which usually are morphologic features of increased cellular activities. In male rats, the serum level of total testosterone decreased and the corticosterone increased 1 day after DEN treatment. The serum level of growth hormone (GH) decreased and the prolactin level increased on day 3. The hepatic expression of the male-specific cytochrome P450 2C11 (CYP2C11) decreased to 1-5% of the normal levels during the first week and was still 50% lower than the normal level on day 35, whereas the female-specific CYP2C12 expression increased only slightly. Activities of the male predominant 16alpha, 16beta, and 6beta hydroxylation of androstenedione by microsome decreased in an in vitro assay, whereas the non-sex-differentiated 7alpha hydroxylation and the female-predominant 5alpha reduction of androstenedione were unaffected. In female rats, decreased serum GH level was observed on day 7. The CYP2C12 expression in females was decreased to about 1% and 80% of the normal levels on day 7 and day 35, respectively, but the CYP2C11 expression was unchanged. These data suggest that in male rats, DEN treatment may cause pituitary damage, disturb serum hormone levels, and induce long-lasting reduction of sexual dimorphism in certain liver functions.

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Selected References

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  1. Akintonwa D. A. The derivation of nitrosamines from some therapeutic amines in the human environment. Ecotoxicol Environ Saf. 1985 Feb;9(1):64–70. doi: 10.1016/0147-6513(85)90035-1. [DOI] [PubMed] [Google Scholar]
  2. Andersson K., Fuxe K., Eneroth P., Härfstrand A., Agnati L. F. Involvement of D1 dopamine receptors in the nicotine-induced neuro-endocrine effects and depletion of diencephalic catecholamine stores in the male rat. Neuroendocrinology. 1988 Aug;48(2):188–200. doi: 10.1159/000125007. [DOI] [PubMed] [Google Scholar]
  3. Andersson K., Jansson A., Kuylenstierna F., Eneroth P. Nicotine and its major metabolite cotinine have different effects on aldosterone and prolactin serum levels in the normal male rat. Eur J Pharmacol. 1993 Apr 1;228(5-6):305–312. doi: 10.1016/0926-6917(93)90065-x. [DOI] [PubMed] [Google Scholar]
  4. Blanck A., Assefaw-Redda Y., Eneroth P., Bäckman L. Pronounced effects of cyclosporin A and NVA2-cyclosporin on hepatic steroid metabolism and endocrine parameters in male Sprague-Dawley rats. J Steroid Biochem Mol Biol. 1991 Jul;39(1):33–37. doi: 10.1016/0960-0760(91)90009-t. [DOI] [PubMed] [Google Scholar]
  5. Blanck A., Hansson T., Eriksson L. C., Gustafsson J. A. On mechanisms of sex differences in chemical carcinogenesis: effects of implantation of ectopic pituitary grafts on the early stages of liver carcinogenesis in the rat. Carcinogenesis. 1984 Oct;5(10):1257–1262. doi: 10.1093/carcin/5.10.1257. [DOI] [PubMed] [Google Scholar]
  6. Blanck A., Hansson T., Gustafsson J. A., Eriksson L. C. Pituitary grafts modify sex differences in liver tumor formation in the rat following initiation with diethylnitrosamine and different promotion regimens. Carcinogenesis. 1986 Jun;7(6):981–985. doi: 10.1093/carcin/7.6.981. [DOI] [PubMed] [Google Scholar]
  7. Blanck A., Hällström I. P., Eriksson L. C. Loss of sexual differentiation of metabolism of steroids and xenobiotics in nodular hepatic tissue from male and female Wistar rats treated according to the resistant hepatocyte model. Carcinogenesis. 1990 Jul;11(7):1067–1073. doi: 10.1093/carcin/11.7.1067. [DOI] [PubMed] [Google Scholar]
  8. Blanck A., Hällström I. P., Svensson D., Mode A., Eriksson L. C., Gustafsson J. A. Increased expression of the female-predominant cytochrome P4502C12 in liver nodules from male Wistar rats. Carcinogenesis. 1993 Apr;14(4):755–759. doi: 10.1093/carcin/14.4.755. [DOI] [PubMed] [Google Scholar]
  9. Carr B. I., Roitman A., Hwang D. L., Barseghian G., Lev-Ran A. Effects of diethylnitrosamine on hepatic receptor binding and autophosphorylation of epidermal growth factor and insulin in rats. J Natl Cancer Inst. 1986 Jul;77(1):219–225. [PubMed] [Google Scholar]
  10. Durnam D. M., Palmiter R. D. A practical approach for quantitating specific mRNAs by solution hybridization. Anal Biochem. 1983 Jun;131(2):385–393. doi: 10.1016/0003-2697(83)90188-4. [DOI] [PubMed] [Google Scholar]
  11. Eriksson L. C., Andersson G. N. Membrane biochemistry and chemical hepatocarcinogenesis. Crit Rev Biochem Mol Biol. 1992;27(1-2):1–55. doi: 10.3109/10409239209082558. [DOI] [PubMed] [Google Scholar]
  12. Everett R. Factors affecting spontaneous tumor incidence rates in mice: a literature review. Crit Rev Toxicol. 1984;13(3):235–251. doi: 10.3109/10408448409003374. [DOI] [PubMed] [Google Scholar]
  13. Farber E. Clonal adaptation as an important phase of hepatocarcinogenesis. Cancer Biochem Biophys. 1991 Nov;12(3):157–165. [PubMed] [Google Scholar]
  14. GLENN E. M., LYSTER S. C., BOWMAN B. J., RICHARDSON S. L. Potentiation of biological activities of steroids by carcinogenic hydrocarbons. Endocrinology. 1959 Mar;64(3):419–430. doi: 10.1210/endo-64-3-419. [DOI] [PubMed] [Google Scholar]
  15. Goldsworthy T. L., Hanigan M. H., Pitot H. C. Models of hepatocarcinogenesis in the rat--contrasts and comparisons. Crit Rev Toxicol. 1986;17(1):61–89. doi: 10.3109/10408448609037071. [DOI] [PubMed] [Google Scholar]
  16. Gustafsson J. A., Stenberg A. On the obligatory role of the hypophysis in sexual differentiation hepatic metabolism in rats. Proc Natl Acad Sci U S A. 1976 May;73(5):1462–1465. doi: 10.1073/pnas.73.5.1462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hartman M. L., Veldhuis J. D., Thorner M. O. Normal control of growth hormone secretion. Horm Res. 1993;40(1-3):37–47. doi: 10.1159/000183766. [DOI] [PubMed] [Google Scholar]
  18. Hirano N., Shiino M. Changes in prolactin cells caused by partial hepatectomy in the rat. Acta Anat (Basel) 1991;141(2):170–173. doi: 10.1159/000147118. [DOI] [PubMed] [Google Scholar]
  19. Ingleton P. M., Hancock M. P. Pituitary growth hormone and somatotrophs in rats bearing chemically induced hepatomas. Virchows Arch B Cell Pathol. 1976 Apr 29;20(3):253–260. doi: 10.1007/BF02890344. [DOI] [PubMed] [Google Scholar]
  20. Jansson J. O., Edén S., Isaksson O. Sexual dimorphism in the control of growth hormone secretion. Endocr Rev. 1985 Spring;6(2):128–150. doi: 10.1210/edrv-6-2-128. [DOI] [PubMed] [Google Scholar]
  21. Kelly P. A., Djiane J., Postel-Vinay M. C., Edery M. The prolactin/growth hormone receptor family. Endocr Rev. 1991 Aug;12(3):235–251. doi: 10.1210/edrv-12-3-235. [DOI] [PubMed] [Google Scholar]
  22. Kovács K., Virágh S., Tiboldi T. Electron microscopie study of anterior pituitary necrosis caused by hexadimethrine bromide in rats. Virchows Arch Pathol Anat Physiol Klin Med. 1966 Dec 14;341(4):271–279. doi: 10.1007/BF00956867. [DOI] [PubMed] [Google Scholar]
  23. Lafaurie M., Aussel C., Castelli D., Krebs B., Stora C. Sex steroid hormones levels and testicular activity during hepatocarcinogenesis by N-2-fluorenylacetamide. Res Commun Chem Pathol Pharmacol. 1982 Jul;37(1):49–63. [PubMed] [Google Scholar]
  24. Liao D., Porsch-Hällström I., Gustafsson J. A., Blanck A. Sex differences at the initiation stage of rat liver carcinogenesis--influence of growth hormone. Carcinogenesis. 1993 Oct;14(10):2045–2049. doi: 10.1093/carcin/14.10.2045. [DOI] [PubMed] [Google Scholar]
  25. Mode A., Wiersma-Larsson E., Gustafsson J. A. Transcriptional and posttranscriptional regulation of sexually differentiated rat liver cytochrome P-450 by growth hormone. Mol Endocrinol. 1989 Jul;3(7):1142–1147. doi: 10.1210/mend-3-7-1142. [DOI] [PubMed] [Google Scholar]
  26. Nagasue N., Kohno H. Hepatocellular carcinoma and sex hormones. HPB Surg. 1992;6(1):1–6. doi: 10.1155/1992/72761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ogawa K., Medline A., Farber E. Sequential analysis of hepatic carcinogenesis: a comparative study of the ultrastructure of preneoplastic, malignant, prenatal, postnatal, and regenerating liver. Lab Invest. 1979 Jul;41(1):22–35. [PubMed] [Google Scholar]
  28. Poirier M. C., Beland F. A. DNA adduct measurements and tumor incidence during chronic carcinogen exposure in rodents. Environ Health Perspect. 1994 Oct;102 (Suppl 6):161–165. doi: 10.1289/ehp.94102s6161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Roitman A., Lev-Ran A., Carr B. I., Hwang D. L., Barseghian G. Binding of growth hormone to rat liver during experimental chemical hepatocarcinogenesis. Endocrinology. 1986 May;118(5):1869–1871. doi: 10.1210/endo-118-5-1869. [DOI] [PubMed] [Google Scholar]
  30. Saeger W. Effect of drugs on pituitary ultrastructure. Microsc Res Tech. 1992 Jan 15;20(2):162–176. doi: 10.1002/jemt.1070200205. [DOI] [PubMed] [Google Scholar]
  31. Schüller H. M. Nitrosamine-induced lung carcinogenesis and Ca2+/calmodulin antagonists. Cancer Res. 1992 May 1;52(9 Suppl):2723s–2726s. [PubMed] [Google Scholar]
  32. Shapiro B. H., Agrawal A. K., Pampori N. A. Gender differences in drug metabolism regulated by growth hormone. Int J Biochem Cell Biol. 1995 Jan;27(1):9–20. doi: 10.1016/1357-2725(94)00056-5. [DOI] [PubMed] [Google Scholar]
  33. Shiino M., Rennels E. G. Ultrastructural observaitons of growth hormone (STH) cells of anterior pituitary glands of partially hepatectomized rats. Cell Tissue Res. 1975 Nov 12;163(3):343–351. doi: 10.1007/BF00219468. [DOI] [PubMed] [Google Scholar]
  34. Solleveld H. A., Haseman J. K., McConnell E. E. Natural history of body weight gain, survival, and neoplasia in the F344 rat. J Natl Cancer Inst. 1984 Apr;72(4):929–940. [PubMed] [Google Scholar]
  35. Solt D. B., Medline A., Farber E. Rapid emergence of carcinogen-induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis. Am J Pathol. 1977 Sep;88(3):595–618. [PMC free article] [PubMed] [Google Scholar]
  36. To Y. C. Physiological and biochemical reviews of sex differences and carcinogenesis with particular reference to the liver. Adv Cancer Res. 1973;18:155–209. [PubMed] [Google Scholar]
  37. Tsukamoto T., Inada K., Fukami H., Yamamoto M., Tanaka H., Kusakabe M., Bishop C. E., Tatematsu M. Mouse strain susceptibility to diethylnitrosamine induced hepatocarcinogenesis is cell autonomous whereas sex-susceptibility Is due to the micro-environment: analysis with C3H <--> BALB / c sexually chimeric mice. Jpn J Cancer Res. 2000 Jul;91(7):665–673. doi: 10.1111/j.1349-7006.2000.tb00997.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Varey S. N., Ingleton P. M. Ultrastructure of pituitary somatotrophs of male rats during liver carcinogenesis by 3'-methyl-4-dimethylaminoazobenzene. Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;46(1-2):21–32. doi: 10.1007/BF02890292. [DOI] [PubMed] [Google Scholar]
  39. Verna L., Whysner J., Williams G. M. N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther. 1996;71(1-2):57–81. doi: 10.1016/0163-7258(96)00062-9. [DOI] [PubMed] [Google Scholar]
  40. Zaphiropoulos P. G., Mode A., Norstedt G., Gustafsson J. A. Regulation of sexual differentiation in drug and steroid metabolism. Trends Pharmacol Sci. 1989 Apr;10(4):149–153. doi: 10.1016/0165-6147(89)90167-3. [DOI] [PubMed] [Google Scholar]

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