The aims of the present study are to compare effects of estrogen depletion (OVX) and estradiol (E2) supplementation on the tissue effects of exposure to the endocrine disrupting organochlorine 3,3',4,4',5-pentachlorobiphenyl (PCB126). For this purpose two highly estrogen-dependent tissues, bone and uterus, were studied. Forty rats exposed to PCB126 (ip) for 3 months (total dose 384 microg/kg body weight (bw)) were randomized in to OVX/sham operation or E2 supplementation (ip, 23 microg/kg, 3 days weekly) per vehicle (corn oil) groups in a 2 x 2 factorial design. Sham operated rats were treated with vehicle, PCB or PCB plus E2 (sham, sham + PCB and sham + PCB + E2, n=10 per group) whereas ovariectomized were treated with vehicle, PCB or PCB plus E2(OVX, OVX + PCB and OVX + PCB + E2, n=10 per group). As control groups served OVX or sham, and OVX + E2 (n=10 in each group). In OVX rats PCB126 + E2 treatment increased trabecular bone volume (TBV) (P<0.01), whilst the opposite was found in sham-operated rats (P<0.01). In OVX animals exposed to PCB126, E2 supplementation decreased the uterine weight and increased the uterine ERbeta mRNA level, whilst no difference was found between the PCB126 and PCB126 + E2 exposed groups in the sham-operated animals. In conclusion, estrogen modulates PCB126 induced effects on trabecular bone, as well as several uterine parameters. These results further support an important role of estrogen on the toxic effects of PCB126 on bone and uterus.