Prenatal exposure to diazepam: late postnatal teratogenic effect.

Abstract

During the last 5 days of gestation, pregnant Sprague-Dawley rats were treated daily with SC diazepam (DZ) injections (average dose 6 mg/kg of body weight). The control pregnant rats were treated with corresponding volumes of the vehicle. The progenies were examined for the occurrence of neoplastic and non-neoplastic lesions for up to 20 months. Although there were no early postnatal effects of DZ, 13 neoplasms developed in the 52 DZ-exposed rats (12 mammary fibroadenomas and one uterine sarcoma), while there were not such lesions in 44 control rats (p less than 0.001, Fisher's exact test). The non-neoplastic lesions in the DZ-exposed group, such as infections, arteriosclerosis etc., were also significantly greater in magnitude and incidence, compared to control animals (p = 0.007, Wilcoxon Rank Sum test). Also, the DZ-exposed rats had a significantly lower titre of the plasma immunoglobulin G (IgG), higher levels of white blood cells and lower hematocrit values than the control animals. DZ is known to bind with high affinity to both central nervous system and non-neuronal receptors present in peripheral organs and blood cells, such as monocytes. The monocyte receptors appear to be critical for chemotaxis induced by many agents affecting the normal function of the immune system including antineoplastic defense. We have previously shown that prenatal DZ suppresses ontogenesis of brain benzodiazepine receptors as tested in adult 12 months old cat and rat progenies. If the ontogenesis of "peripheral" receptors is also suppressed, this would provide a plausible explanation for teratogenic effect of DZ.