Delayed developmental immunotoxicity of prenatal benzodiazepines

Treatment of pregnant rats with low doses of classical benzodiazepines (BDZ, e.g. 1.25 mg diazepam/kg body weight) or a peripheral type BDZ receptor (PBR) agonist between gestational days 14 and 20 has been shown to result in a long-lasting depression of cellular and humoral immune responses in the offspring. Considerable alterations in mitogen-stimulated cytokine production in rats exposed to diazepam prenatally have now been observed: TNF-alpha liberation by splenocytes of diazepam-exposed rats was reduced at 2 wk of age and increased above control values at 8 wk, and interleukin (IL)-6 was depressed in the offspring at 2 and 8 wk of age. IL-1 was diminished during post-weaning and adult periods in male offspring but only in adult life in female offspring. In contrast, T-cell derived IL-2 was decreased during the postnatal period and normalized in adulthood. Prostaglandin E(2) (PGE(2)), which is known to down-regulate tumour necrosis factor-alpha (TNF-alpha) was increased and interferon-gamma (IFN-gamma), which stimulates TNF-alpha release, was depressed in 2-wk-old offspring that had been treated prenatally. Release of PGE(2) and IFN-gamma was still altered in young adulthood. While the initial action on the foetal immune system remains unknown, an interaction of the drugs with the PBR is suggested by the effectiveness of the PBR agonist and by altered characteristics of PBR (i.e. a decreased B(max) of [(3)H]PK 11195 binding to macrophage membranes of 8-wk-old offspring and an increased Kd of spleen cell membranes of 2-wk-old offspring).