Brain Disrupting Actions of Prenatal Diethylstilbestrol Exposure in Mice - Behavioral, Neurochemical and Electrophysiological Studies

Abstract

In addition to effects on the reproductive system, endocrine disruptors are thought to have brain-disrupting actions based on epidemiological and animal studies. In this review, we discuss the current state of studies on the brain-disrupting actions of diethylstilbestrol (DES), which is a prototype endocrine disruptor that has potent estrogen-like action, focusing on our own findings. The major findings concerning the brain-disrupting action of DES are as follows: Exposure to a minute amount of DES during the late stage of gestation, but not the late stage of the lactation period, caused neurobehavioral changes such as impairment of the passive avoidance response in mice offspring. There is a difference in effect between male and female offspring of DES exposure on dendritic arbolization of hippocampal pyramidal neurons. In 6-week-old male offspring, prenatal DES exposure did not affect the responsiveness of N-methyl-d-aspartate (NMDA)- or GABAA-receptors in the hippocampal pyramidal neurons, but drastically increased the level of phosphorylated Ca2+/calmodulin-dependent protein kinase II in the hippocampus. These findings suggest that, in mice, DES has brain-disrupting actions, with a critical period of exposure. Further studies are needed to clarify the primary site and mechanism of these actions, using various methods and animal models such as estrogen-receptor `knock-out' and/or `knock-in' mice.