IRON OVERLOAD AND BIRTH DEFECTS

Large, intravenous doses of iron-dextran are teratogenic in a number of laboratory species (M Phil). To elucidate the mechanism, studies were performed in rats and rabbits to identify possible maternal, placental and foetal sites of action. Maternal toxicity, manifested by bodyweight depression, abortion and total litter loss, was evident in the rat (>700 mg Fe kg‘\ Day 8 of gestation) and in the rabbit (>50 mg Fe kg ’. Day 16 of gestation). A marked hypotensive effect, accompanied by disturbance of ECG, was evident in the rat immediately on dosing (250 mg Fe kg ’) probably due, in part, to loosely bound iron. In the rabbit, maternal ascorbate was significantly reduced (40%) and plasma calcium significantly increased (36%) for up to two days following 100 mg Fe kg’. Increases in hepatic malondialdehyde (107%), decreases in reduced glutathione (20%) and an increased susceptibility of erythrocytes to lysis induced by hydrogen peroxide in vitro (seven-fold), provided evidence of lipid peroxidation in maternal tissues. Rabbit amniotic fluid volume was increased (11%) within 4 hours and this persisted for 24 hours whilst iron levels rose four-fold. Embryonic weight and foetal liver GSH level were reduced over this period whilst the foetus sequestered up to 2% of the administered dose of iron (estimated at term). Direct iron-dextran instillation into amniotic and yolk sac cavities at dose levels producing equivalent foetal liver iron concentration to intravenous administration (up to 2.5 mg Fe) did not affect foetal growth, survival or the incidence of malformation. Administration of vitamin E (100 mg kg ’. Days 15 to 18) ameliorated the adverse effects of iron-dextran with improvement in foetal survival, pup weight and incidence of malformation. Vitamin C co-administration (40 mg kg ’. Days 15 to 18) exacerbated adverse effects whilst increasing the rate of disappearance of iron from the plasma. The relative importance of maternal, placental and foetal mechanisms in iron-dextran teratogenicity is discussed.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

De Montfort University

Year dc:date.issued

1993

Author dc:creator

• SMITH, DAVID

Licence

• https://dora.dmu.ac.uk/bitstreams/d5ef06bd-bbef-4d53-b150-385b486707df/download