Sex Differences in the Rat Brain: A Procedure for Estimating Developmental Toxicity

The sexually dimorphic nucleus of the preoptic area (SDN‐POA) and the anteroventral periventricular nucleus of the preoptic area (AVPvN‐POA) are sexually dimorphic regions in the rat brain. These regions are sensitive to reproductive function‐related drugs, and thus applied for aromatase inhibitor evaluation in the present study. Effects of NKS01 (an aromatase inhibitor) and tamoxifen on the SDN‐POA and AVPvN‐POA were examined. Five mg of NKS01 or its vehicle was injected to SD male and female rats from days 1 to 14 (the day of birth = day 0). Other 10 males and 10 females received a single injection of 100 μg tamoxifen on day 1. Rats in each group were sacrificed at day 30 or 60. The SDN‐POA was examined at days 30 and 60, and the AVPvN‐POA at day 60. When NKS01 was given to male rats for the first 14 days of life, a significant reduction of SDN‐POA size was observed on day 60. When tamoxifen was given, SDN‐POA reduction in size was also observed at days 30 and 60 in male rats. As for the AVPvN‐POA, tamoxifen markedly reduced volume in female rats, resulting in polycystic ovaries at day 60. This may be due to an estrogenic property of tamoxifen. On the other hand, NKS01 was not significantly effective in the AVPvN‐POA, although the volume of the nucleus in NKS01 males was inclined to increase. From these results, as well as the SDN‐POA, the AVPvN‐POA may be useful to evaluate the side effect of reproductive function‐related drug.