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, differentiation, and reproduction. To date, there is no known animal model for studying aberrant ER expression. Therefore, we created transgenic mice expressing the wild-type mouse ER under the control of the mouse metallothionein-I (MT) promoter to determine whether overexpression of the ER would disrupt normal reproductive processes. Five male and one female founder mice were produced, and all were fertile. The progeny from these mice were screened for MT-mER expression by the ribonuclease protection assay. Mice in all six lines were found to express the transgene in a variety of tissues, although generally at low levels. The highest level of expression was observed in the female reproductive tract of line E. Females in all six lines demonstrated aberrant reproductive phenotypes involving processes at parturition and, with some of the lines, a tendency toward reduced fertility. Gestational length was prolonged up to 4 days beyond the normal gestation of 19 days, providing evidence of delayed parturition. In addition, prolonged labor (up to 3 days in length to deliver all pups) and labors requiring cesarean sections for maternal survival demonstrated the occurrence of dystocia in the MT-mER females. As maternal age increased, the incidence of stillborn litters, delayed parturition, and dystocia approached 100% in the transgenic dams. Difficulties at parturition were not observed in nontransgenic 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 studying the estrogen-regulated signals involved in parturition and fertility as well as a unique animal model for the human reproductive phenotypes of delayed parturition and dystocia.