Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2000 Oct;108(10):973–977. doi: 10.1289/ehp.00108973

Environmentally relevant xenoestrogen tissue concentrations correlated to biological responses in mice.

E M Ulrich 1, A Caperell-Grant 1, S H Jung 1, R A Hites 1, R M Bigsby 1
PMCID: PMC1240131  PMID: 11049819

Abstract

The effects of xenoestrogens have been extensively studied in rodents, generally under single, high-dose conditions. Using a continuous-release, low-dose system in ovariectomized mice, we correlated the estrogenic end points of uterine epithelial height (UEH) and vaginal epithelial thickness (VET) with concentrations of two organochlorine pesticide isomers in fat and blood. Silastic capsules containing a range of doses of either ss-hexachlorocyclohexane (ss-HCH) or o, p'-dichlorodiphenyltrichloroethane (o,p'-DDT) were implanted subcutaneously, and animals were killed after 1 week. Average blood levels achieved by the various doses were 4.2-620 ng/mL for o,p'-DDT and 5.0-300 ng/mL for ss-HCH. Fat concentrations of o,p'-DDT and ss-HCH correlated linearly to blood levels (o,p'-DDT, r(2) = 0.94; ss-HCH, r(2) = 0.83). Fat concentrations (nanograms per gram of tissue) were higher than blood concentrations (nanograms per milliliter) by 90 +/- 5- and 120 +/- 9-fold (mean +/- SE) for o, p'-DDT and ss-HCH, respectively. The VET ranged from 12 +/- 0.9 microm in controls to 114 +/- 8 microm in treated animals, and was correlated to blood levels of either treatment compound. The UEH ranged from an average of 7.7 +/- 0.3 microm in controls to 26 +/- 2 microm in high-dose o,p'-DDT-treated animals. The UEH was also correlated with ss-HCH concentration, but it plateaued at approximately 11 microm at the highest doses. The lowest blood concentrations that produced statistically significant increases in VET or UEH were 18 +/- 2 ng/mL o,p'-DDT and 42 +/- 4 ng/mL ss-HCH. These values are within the same order of magnitude of blood concentrations found in some human subjects from the general population, suggesting that human blood concentrations of these organochlorines may reach estrogenic levels.

Full Text

The Full Text of this article is available as a PDF (105.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adami H. O., Lipworth L., Titus-Ernstoff L., Hsieh C. C., Hanberg A., Ahlborg U., Baron J., Trichopoulos D. Organochlorine compounds and estrogen-related cancers in women. Cancer Causes Control. 1995 Nov;6(6):551–566. doi: 10.1007/BF00054165. [DOI] [PubMed] [Google Scholar]
  2. Bigsby R. M., Caperell-Grant A., Madhukar B. V. Xenobiotics released from fat during fasting produce estrogenic effects in ovariectomized mice. Cancer Res. 1997 Mar 1;57(5):865–869. [PubMed] [Google Scholar]
  3. Clitheroe H. J., Bonnycastle D. D., Kukla L. Effects of clomiphene citrate on the mouse uterus. Proc Soc Exp Biol Med. 1966 May;122(1):70–73. doi: 10.3181/00379727-122-31052. [DOI] [PubMed] [Google Scholar]
  4. Coosen R., van Velsen F. L. Effects of the beta-isomer of hexachlorocyclohexane on estrogen-sensitive human mammary tumor cells. Toxicol Appl Pharmacol. 1989 Nov;101(2):310–318. doi: 10.1016/0041-008x(89)90279-2. [DOI] [PubMed] [Google Scholar]
  5. Cunha G. R., Taguchi O., Namikawa R., Nishizuka Y., Robboy S. J. Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract. Hum Pathol. 1987 Nov;18(11):1132–1143. doi: 10.1016/s0046-8177(87)80381-7. [DOI] [PubMed] [Google Scholar]
  6. DALE W. E., GAINES T. B., HAYES W. J., Jr Storage and excretion of DDT in starved rats. Toxicol Appl Pharmacol. 1962 Jan;4:89–106. doi: 10.1016/0041-008x(62)90078-9. [DOI] [PubMed] [Google Scholar]
  7. Dewailly E., Dodin S., Verreault R., Ayotte P., Sauvé L., Morin J., Brisson J. High organochlorine body burden in women with estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1994 Feb 2;86(3):232–234. doi: 10.1093/jnci/86.3.232. [DOI] [PubMed] [Google Scholar]
  8. Dua V. K., Pant C. S., Sharma V. P., Pathak G. K. Determination of HCH and DDT in finger-prick whole blood dried on filter paper and its field application for monitoring concentrations in blood. Bull Environ Contam Toxicol. 1996 Jan;56(1):50–57. doi: 10.1007/s001289900008. [DOI] [PubMed] [Google Scholar]
  9. Fornander T., Rutqvist L. E., Wilking N. Effects of tamoxifen on the female genital tract. Ann N Y Acad Sci. 1991;622:469–476. doi: 10.1111/j.1749-6632.1991.tb37890.x. [DOI] [PubMed] [Google Scholar]
  10. Fry D. M. Reproductive effects in birds exposed to pesticides and industrial chemicals. Environ Health Perspect. 1995 Oct;103 (Suppl 7):165–171. doi: 10.1289/ehp.95103s7165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Harper M. J., Walpole A. L. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil. 1967 Feb;13(1):101–119. doi: 10.1530/jrf.0.0130101. [DOI] [PubMed] [Google Scholar]
  12. Hoffman W. Organochlorine compounds: Risk of non-Hodgkin's lymphoma and breast cancer? Arch Environ Health. 1996 May-Jun;51(3):189–192. doi: 10.1080/00039896.1996.9936015. [DOI] [PubMed] [Google Scholar]
  13. Hunter D. J., Hankinson S. E., Laden F., Colditz G. A., Manson J. E., Willett W. C., Speizer F. E., Wolff M. S. Plasma organochlorine levels and the risk of breast cancer. N Engl J Med. 1997 Oct 30;337(18):1253–1258. doi: 10.1056/NEJM199710303371801. [DOI] [PubMed] [Google Scholar]
  14. Høyer A. P., Grandjean P., Jørgensen T., Brock J. W., Hartvig H. B. Organochlorine exposure and risk of breast cancer. Lancet. 1998 Dec 5;352(9143):1816–1820. doi: 10.1016/S0140-6736(98)04504-8. [DOI] [PubMed] [Google Scholar]
  15. Kedar R. P., Bourne T. H., Powles T. J., Collins W. P., Ashley S. E., Cosgrove D. O., Campbell S. Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet. 1994 May 28;343(8909):1318–1321. doi: 10.1016/s0140-6736(94)92466-x. [DOI] [PubMed] [Google Scholar]
  16. Krieger N., Wolff M. S., Hiatt R. A., Rivera M., Vogelman J., Orentreich N. Breast cancer and serum organochlorines: a prospective study among white, black, and Asian women. J Natl Cancer Inst. 1994 Apr 20;86(8):589–599. doi: 10.1093/jnci/86.8.589. [DOI] [PubMed] [Google Scholar]
  17. Kupfer D., Bulger W. H. Interaction of o, p'DDT with the estrogen-binding protein (EBP) in human mammary and uterine tumors. Res Commun Chem Pathol Pharmacol. 1977 Mar;16(3):451–462. [PubMed] [Google Scholar]
  18. Lakshmanan F. L., Pommer A., Patterson O. Chlorinated hydrocarbon insecticide residues in tissues of rats before and after reduction of body fat by dietary restriction. J Agric Food Chem. 1979 Jul-Aug;27(4):720–725. doi: 10.1021/jf60224a011. [DOI] [PubMed] [Google Scholar]
  19. Long X., Steinmetz R., Ben-Jonathan N., Caperell-Grant A., Young P. C., Nephew K. P., Bigsby R. M. Strain differences in vaginal responses to the xenoestrogen bisphenol A. Environ Health Perspect. 2000 Mar;108(3):243–247. doi: 10.1289/ehp.00108243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. López-Carrillo L., Torres-Arreola L., Torres-Sánchez L., Espinosa-Torres F., Jiménez C., Cebrián M., Waliszewski S., Saldate O. Is DDT use a public health problem in Mexico? Environ Health Perspect. 1996 Jun;104(6):584–588. doi: 10.1289/ehp.104-1469381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. MacMahon B. Pesticide residues and breast cancer? J Natl Cancer Inst. 1994 Apr 20;86(8):572–573. doi: 10.1093/jnci/86.8.572. [DOI] [PubMed] [Google Scholar]
  22. McBlain W. A., Lewin V. Differing estrogenic activities for the enantiomers of o, p'-DDT in immature female rats. Can J Physiol Pharmacol. 1976 Aug;54(4):629–632. doi: 10.1139/y76-088. [DOI] [PubMed] [Google Scholar]
  23. McLachlan J. A., Newbold R. R. Estrogens and development. Environ Health Perspect. 1987 Nov;75:25–27. doi: 10.1289/ehp.877525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mes J. Organochlorine residues in human blood and biopsy fat and their relationship. Bull Environ Contam Toxicol. 1992 Jun;48(6):815–820. doi: 10.1007/BF00201140. [DOI] [PubMed] [Google Scholar]
  25. Moysich K. B., Ambrosone C. B., Vena J. E., Shields P. G., Mendola P., Kostyniak P., Greizerstein H., Graham S., Marshall J. R., Schisterman E. F. Environmental organochlorine exposure and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1998 Mar;7(3):181–188. [PubMed] [Google Scholar]
  26. Newbold R. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. Environ Health Perspect. 1995 Oct;103 (Suppl 7):83–87. doi: 10.1289/ehp.95103s783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nishino Y., Neumann F. 8 alpha-Estra-1,3,5(10)-triene-1,3, 17 beta-triol as a special type of estrogen having a high vaginotrophic activity and a low uterotrophic activity in castrated mice. Steroids. 1977 Aug;30(2):179–192. doi: 10.1016/0039-128x(77)90080-0. [DOI] [PubMed] [Google Scholar]
  28. O'Connor J. C., Cook J. C., Craven S. C., Van Pelt C. S., Obourn J. D. An in vivo battery for identifying endocrine modulators that are estrogenic or dopamine regulators. Fundam Appl Toxicol. 1996 Oct;33(2):182–195. [PubMed] [Google Scholar]
  29. Olaya-Contreras P., Rodríguez-Villamil J., Posso-Valencia H. J., Cortez J. E. Organochlorine exposure and breast cancer risk in Colombian women. Cad Saude Publica. 1998;14 (Suppl 3):125–132. doi: 10.1590/s0102-311x1998000700013. [DOI] [PubMed] [Google Scholar]
  30. Perlmutter D. Organochlorines, breast cancer, and GATT. JAMA. 1994 Apr 20;271(15):1160–1161. [PubMed] [Google Scholar]
  31. Radomski J. L., Astolfi E., Deichmann W. B., Rey A. A. Blood levels of organochlorine pesticides in Argentina: occupationally and nonoccupationally exposed adults, children and newborn infants. Toxicol Appl Pharmacol. 1971 Oct;20(2):186–193. doi: 10.1016/0041-008x(71)90044-5. [DOI] [PubMed] [Google Scholar]
  32. Radomski J. L., Deichmann W. B., Rey A. A., Merkin T. Human pesticide blood levels as a measure of body burden and pesticide exposure. Toxicol Appl Pharmacol. 1971 Oct;20(2):175–185. doi: 10.1016/0041-008x(71)90043-3. [DOI] [PubMed] [Google Scholar]
  33. Ramachandran M., Banerjee B. D., Gulati M., Grover A., Zaidi S. S., Hussain Q. Z. DDT & HCH residues in the body fat & blood samples from some Delhi hospitals. Indian J Med Res. 1984 Nov;80:590–593. [PubMed] [Google Scholar]
  34. Robison A. K., Schmidt W. A., Stancel G. M. Estrogenic activity of DDT: estrogen-receptor profiles and the responses of individual uterine cell types following o,p'-DDT administration. J Toxicol Environ Health. 1985;16(3-4):493–508. doi: 10.1080/15287398509530758. [DOI] [PubMed] [Google Scholar]
  35. Robison A. K., Sirbasku D. A., Stancel G. M. DDT supports the growth of an estrogen-responsive tumor. Toxicol Lett. 1985 Sep;27(1-3):109–113. doi: 10.1016/0378-4274(85)90127-4. [DOI] [PubMed] [Google Scholar]
  36. Sasaki K., Ishizaka T., Suzuki T., Takeda M., Uchiyama M. Accumulation levels of organochlorine pesticides in human adipose tissue and blood. Bull Environ Contam Toxicol. 1991 May;46(5):662–669. doi: 10.1007/BF01689949. [DOI] [PubMed] [Google Scholar]
  37. Simonich S. L., Hites R. A. Global distribution of persistent organochlorine compounds. Science. 1995 Sep 29;269(5232):1851–1854. doi: 10.1126/science.7569923. [DOI] [PubMed] [Google Scholar]
  38. Soto A. M., Sonnenschein C., Chung K. L., Fernandez M. F., Olea N., Serrano F. O. The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environ Health Perspect. 1995 Oct;103 (Suppl 7):113–122. doi: 10.1289/ehp.95103s7113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Spearow J. L., Doemeny P., Sera R., Leffler R., Barkley M. Genetic variation in susceptibility to endocrine disruption by estrogen in mice. Science. 1999 Aug 20;285(5431):1259–1261. doi: 10.1126/science.285.5431.1259. [DOI] [PubMed] [Google Scholar]
  40. Steinmetz R., Young P. C., Caperell-Grant A., Gize E. A., Madhukar B. V., Ben-Jonathan N., Bigsby R. M. Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells. Cancer Res. 1996 Dec 1;56(23):5403–5409. [PubMed] [Google Scholar]
  41. Toppari J., Larsen J. C., Christiansen P., Giwercman A., Grandjean P., Guillette L. J., Jr, Jégou B., Jensen T. K., Jouannet P., Keiding N. Male reproductive health and environmental xenoestrogens. Environ Health Perspect. 1996 Aug;104 (Suppl 4):741–803. doi: 10.1289/ehp.96104s4741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wassermann M., Nogueira D. P., Tomatis L., Mirra A. P., Shibata H., Arie G., Cucos S., Wassermann D. Organochlorine compounds in neoplastic and adjacent apparently normal breast tissue. Bull Environ Contam Toxicol. 1976 Apr;15(4):478–484. doi: 10.1007/BF01685076. [DOI] [PubMed] [Google Scholar]
  43. Wolff M. S., Toniolo P. G., Lee E. W., Rivera M., Dubin N. Blood levels of organochlorine residues and risk of breast cancer. J Natl Cancer Inst. 1993 Apr 21;85(8):648–652. doi: 10.1093/jnci/85.8.648. [DOI] [PubMed] [Google Scholar]
  44. Yeh C. Y., Kuo P. H., Tsai S. T., Wang G. Y., Wang Y. T. A study on pesticide residues in umbilical cord blood and maternal milk. Taiwan Yi Xue Hui Za Zhi. 1976 Aug;75(8):463–470. [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES