Mechanistic studies of the halogenated aromatic hydrocarbons- antagonism and antiestrogenicity

Abstract

Two polychlorinated biphenyl congeners, namely 2,2',4,4',5,5',-hexa- and 2,2',5,5'-tetrachlorobiphenyl and MCDF antagonized 2,3,7,8-TCDD-induced deft palate in C57BL/6 mice. Administration of [³H]-2,3,7,8-TCDD to C57BL/6 mice showed that there was a rapid uptake of radiolabel into the fetal palate. Cotreatment with [³H]-2,3,7,8-TCDD plus 2,2',4,4',5,5',-hexachlorobiphenyl or MCDF resulted in decreased uptake of radiolabel into the fetal palate tissue. These studies suggest that the protective effects of these compounds may be due to modulation of 2,3,7,8-TCDD reaching the palate in the co-treated animals. The effects of 2,3,7,8-TCDD and MCDF on the 17B-estradiol-induced growth and protein secretion in estrogen-responsive MCF-7 and estrogennonresponsive MDA-MB-231 human breast cancer cells was determined. 2,3,7,8-TCDD and MCDF inhibited MCF-7 cell growth of untreated cells and inhibited 17B-estradiol-induced proliferation in MCF-7 cells, but did not effect the growth of MDA-MB-231 cells. Treatment of MCF-7 cells with 17Bestradiol resulted in a significant induction of the secretion of the 34-kDa, 52- kDa and 160-kDa proteins, where as treatment with 2,3,7,8-TCDD, MCDF and 17B-estradiol plus 2,3,7,8-TCDD or MCDF resulted in protein secretion levels not significantly different from the values observed for the control cells. These treatments had no effect on MDA-MB-231 cells. These results clearly confirm the antiestrogenic effects caused by 2,3,7,8-TCDD and MCDF in estrogen-responsive MCF-7 cells. IGF-I was found to significantly induced MCF-7 cell proliferation and treatment with IGF-I plus 2,3,7,8-TCDD resulted in significant inhibition this cell proliferation. Neither compound altered the proliferation of MDA-MB-231 cells. IGF-I also induced the secretion of the 34-, 5 2 -and 160-kDA proteins in MCF-7 cells. 2,3,7,8-TCDD inhibited the IGF-I induced protein secretion. These results extend the range of antiestrogenic properties of 2,3,7,8-TCDD and suggest that 2,3,7,8-TCDD may effect both the autocrine and paracrine regulatory pathways of estrogen-responsive human breast cancer cells.