Increases in mouse uterine heat shock protein levels are a sensitive and specific response to uterotrophic agents

There is increasing consensus that the uterotrophic estrogenicity assay should be coupled with other morphometric or molecular end points that might enhance its sensitivity. We have previously shown that bisphenol A (BPA), similarly to 17beta-estradiol (E-2), increases levels of uterine heat shock proteins (hsps), mainly hsp90alpha and glucose-regulated protein (grp) 94. In this study we investigated whether increases in uterine lisp levels are a specific response of estrogens or estrogen mimics. We therefore examined the ability of a) E-2 diethylstilbestrol (DES), and tamoxifien (TAM); b) the xenoestrogens coumestrol (CM), methoxychlor (MXC), BPA, and dibutyl phthalate (DBP); c) the progestin medroxyprogesterone (MED); d) the glucocorticoid dexamethasone (DEX); and e) phytol (PHY), a precursor to a retinoid X and peroxisome proliferator-activating receptor agonist, to increase uterine weights and alter uterine morphology and lisp levels. We showed that DES, TAM, CM, MXC, and BPA significantly increased uterine weights and uterine hsp90alpha and grp94 levels. Even though the doses of CM, MXC, and BPA used were much higher than the E-2 dose, those treatments resulted in lower increases in uterine weight. On the other hand, increases in grp94 levels were equal to those induced by E-2 treatment. Treatments with MED, DEX, DBP, or PHY did not significantly alter uterine weight or morphology and had no significant effects on uterine hsp levels. The results of this study suggest that only the estrogens increase uterine hsp90alpha and grp94 levels, and that this lisp effect is a more sensitive uterotrophic response than uterine weight increase.