Distinguishing between maternally-mediated and directly embryotoxic modes-of-action for postimplantation loss induced in rats by 2-amino-2-methylpropanol

In rats, 2-amino-2-methylpropanol (AMP) caused an increase in postimplantation loss in an oral reproductive/developmental toxicity screening assay but not in a dermal developmental toxicity assay. Studies were performed to characterize the mode of action and determine whether the postimplantation loss was a result of direct embryotoxicity or a maternally mediated effect. The studies identified that the postimplantation loss occurs shortly after implantation, has a steep dose response with a clear threshold, requires exposure to AMP for a period of approximately 2-3 weeks prior to gestation and does not involve direct embryo toxicity. The uterine histopathology and gene array analysis of decidual swellings suggested AMP acts via a maternally mediated mechanism affecting the ability of the uterus to support an implanted embryo. Since the postimplantation loss occurs only at maternally toxic doses, the implications for human risk assessment are discussed.