ABERRANT REPRODUCTIVE PHENOTYPES EVIDENT IN TRANSGENIC MICE EXPRESSING THE WILD-TYPE MOUSE ESTROGEN-RECEPTOR

The estrogen receptor (ER) acts as a transcription factor to regulate multiple cellular functions involved in normal physiology, differentia tion, and reproduction. To date, there is no known animal model for st udying aberrant ER expression. Therefore, we created transgenic mice e xpressing the wild-type mouse ER under the control of the mouse metall othionein-I (MT) promoter to determine whether overexpression of the E R would disrupt normal reproductive processes. Five male and one femal e founder mice were produced, and all were fertile. The progeny from t hese mice were screened for MT-mER expression by the ribonuclease prot ection assay. Mice in all six lines were found to express the transgen e in a variety of tissues, although generally at low levels. The highe st level of expression was observed in the female reproductive tract o f line E. Females in all six lines demonstrated aberrant reproductive phenotypes involving processes at parturition and, with some of the li nes, a tendency toward reduced fertility. Gestational length was prolo nged up to 4 days beyond the normal gestation of 19 days, providing ev idence of delayed parturition. In addition, prolonged labor (up to 3 d ays in length to deliver all pups) and labors requiring cesarean secti ons for maternal survival demonstrated the occurrence of dystocia in t he MT-mER females. As maternal age increased, the incidence of stillbo rn litters, delayed parturition, and dystocia approached 100% in the t ransgenic dams. Difficulties at parturition were not observed in nontr ansgenic control females. These phenotypes suggest that the mechanisms regulating parturition may be perturbed by improper expression of the ER. The MT-mER transgenic mice may provide a novel approach for study ing the estrogen-regulated signals involved in parturition and fertili ty as well as a unique animal model for the human reproductive phenoty pes of delayed parturition and dystocia.