Xenobiotics released from fat during fasting produce estrogenic effects in ovariectomized mice

Abstract

The pesticide residues 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2,2-trichloroethane (o,p'-DDT) and beta-hexachlorocyclohexane (beta-HCH) act as weak estrogens, producing uterotrophic responses in ovariectomized rodents and stimulating human breast cancer cells in culture. Such activity suggests that these compounds may act as tumor promoters in estrogen-responsive tissues. Organochlorine compounds such as o,p'-DDT and beta-HCH are concentrated in body fat. The present report tests whether sufficient compound can be released from fat depots to produce estrogenic effects in uteri of ovariectomized mice. Adult animals were "loaded" with test compound by three daily injections of vehicle (DMSO), 17beta-estradiol (E2), beta-HCH, or o,p'-DDT. Uterotrophic effects were assessed at 24 h after the last loading dose of test compound and at 2 weeks after the loading regimen, with or without a prior 2-day period of fasting. The initial 3-day treatment with either beta-HCH or o,p'-DDT doubled the relative dry weight of the uterus: 102 +/- 8.6 mg/kg body weight (BW) and 104 +/- 4.4 mg/kg BW for beta-HCH and o,p'-DDT, respectively, compared to 49 +/- 1.9 mg/kg BW for vehicle-treated animals. E2-treated animals had uterine dry weights of 228 +/- 11 mg/kg BW. After 2 weeks without further treatment, a 2-day fast produced a decrease in body mass of 4.1 g/animal (fasted, 25.9 +/- 1.89 g versus fed, 30.0 +/- 2.82 g). Animals that had been loaded with beta-HCH and fasted had uterine weights (88 +/- 12 mg/kg BW) significantly greater (P < 0.05) than those of vehicle-loaded, fasted animals (51 +/- 2.9 mg/kg BW) or of beta-HCH-loaded, fed animals (59 +/- 4.6 mg/kg BW). The uterine weights of the fasted and fed o,p'-DDT-loaded or E2-loaded animals were not different from those of control weights. The difference between wet and dry weights showed that fasting of beta-HCH-loaded animals also increased water imbibition in the uterus; there was no effect from fasting in the other groups. Generally, epithelial cell height reflected the same responses as uterine weight with the exception that cell heights of beta-HCH-loaded, fed animals were slightly higher (P < 0.05) than corresponding controls, indicating that there may have been some active compound available to the tissues even without fasting. The effects of fasting show that during periods of lipolysis beta-HCH can be released in quantities sufficient to stimulate estrogen target tissues, suggesting a novel mechanism linking obesity and the progression of estrogen-responsive tumors. The lack of effect from fasting in o,p'-DDT-loaded animals indicates that these compounds are differentially mobilized from fat depots.