Lack of evidence for neonatal misoprostol neurodevelopmental toxicity in C57BL6/J mice

Abstract

Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 µg/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth.

Figure 1. Neurodevelopmental composite score (sensory and motor development) for the four treatment groups.

No group differences were statistically significant.

Figure 2. Number of bouts of ultrasonic vocalizations (USV) on postnatal days 9, 11 13 & 17.

No group differences were statistically significant.

Figure 3. Mean escape latency in the Morris water maze for the four treatment groups.

No group differences were statistically significant.

Figure 4. Number of hippocampal CA1 pyramidal neurons across treatment groups and sex.

Four treatment groups (i.e. vehicle, 0.4, 4.0 & 40 µg/kg misoprostol, s.c.) were analyzed for male mice, and two treatment groups, the vehicle and high 40 µg/kg dose group, were analyzed for females. No significant treatment effects, sex differences or sex by treatment interaction were found.