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 sho wn to result in a long-lasting depression of cellular and humoral immu ne responses in the offspring. Considerable alterations in mitogen-sti mulated cytokine production in rats exposed to diazepam prenatally hav e now been observed: TNF-alpha liberation by splenocytes of diazepam-e xposed rats was reduced at 2 wk of age and increased above control val ues 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 p eriods in male offspring but only in adult life in female offspring. I n contrast, T-cell derived IL-2 was decreased during the postnatal per iod and normalized in adulthood. Prostaglandin E(2) (PGE(2)), which is known to down-regulate tumour necrosis factor-alpha (TNF-alpha) was i ncreased and interferon-gamma (IFN-gamma), which stimulates TNF-alpha release, was depressed in 2-wk-old offspring that had been treated pre natally. Release of PGE(2) and IFN-gamma was still altered in young ad ulthood. 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 [H-3]PK 11195 binding to macrophage membra nes of 8-wk-old offspring and an increased Kd of spleen cell membranes of 2-wk-old offspring).