Growth retardation is a feature of several diseases associated with chronic hemolysis (i.e., uremia and the hemoglobinopathies). Although the growth failure is undoubtedly multifactorial, circulating hemoglobin (Hb) may inhibit cartilage growth directly. We tested this hypothesis using the hypophysectomized rat costal cartilage sulfation bioassay and the embryonic chicken pelvic rudiment bioassay, both very sensitive to growth factors and growth inhibitors. In the rat bioassay, Hb produced a dose-dependent inhibition of both basal and normal rat serum (NRS)-stimulated 35SO4 uptake. In the chick bioassay, NRS stimulated cartilage growth as expected, but Hb severely inhibited both basal and NRS-stimulated growth. However, after the cartilages were preincubated with Hb for 2 days, subsequent exposure to NRS allowed them to resume growth at the same rate as cartilage exposed to NRS for the entire 5 days. The growth inhibition could be accounted for by the heme contained in Hb. We conclude that Hb produces a dose-dependent and reversible inhibition of cartilage growth and may contribute to the growth retardation associated with chronic hemolytic conditions.
ABSTRACT. The increased morbidity during pregnancies complicated by hematologic or liver disease has generally been attributed to the metabolic abnormalities of the illness itself. Because tetrapyrrole concentrations are elevated in these conditions, we introduced bilirubin or heme (prepared as 10 mM solutions) into the air sac of fertilized chicken eggs to study their effect on the growth of normal chicken embryos. In 9-d eggs, the injection of 0.06 mL heme resulted in significant embryo growth inhibition as indicated by overall wt (91 2 3% versus control), tibia length (84 f 2%), tibia wt (81 + 3%), femur length (88 + I%), and femur wt (78 + 3%); doses greater than 0.10 mL resulted in substantial fetal losses. The injection of 0.06 mL bilirubin into the same-age eggs also resulted in less than normal tibia length (87 2 2% versus control), tibia wt (75 2 4%), femur length (91 + 2%), and femur wt (81 2 3%); larger doses resulted in more pronounced growth inhibition, but fetal losses were less common than with heme. Older chick embryos (12-d) appeared more resistant to the effects of bilirubin: 0.15 mL bilirubin inhibited only tibia and femur wt; larger doses were required to significantly suppress the other growth parameters. The sameage chicken embryos, however, remained exquisitely sensitive to heme; 0.05 mL resulted in less than normal whole embryo wt (88 + 2% versus control), tibia length (80 2 I%), tibia wt (76 +. I%), femur length (78 + I%), and femur wt (77 + 1%). Substantial fetal loss occurred with heme doses above 0.10 mL as well as among the less mature chicks. Significant inhibition of the growth of long bones (tibia and femur) also occurred when we added 0.05 mM bilirubin or 0.025 mM Hb to bones maintained in organ culture in vitro for 5 d. We conclude that several heme compounds and bilirubin inhibit the growth and survival of normal chick embryos in ovo and in vitro.We suggest that prenatal exposure to high levels of these compounds may have a previously underestimated negative influence on fetal development (Pediatr Res 27: 617-621, 1990) In pregnancies complicated by maternal hematologic or liver diseases, the risk of adverse fetal outcome is higher than normal. How these maternal illnesses harm the fetus remains poorly understood (1-3). Although maternal hematologic or liver diseases are systemic disorders with multiple metabolic abnormalities that could affect fetal outcome, one feature they share is sustained elevation of circulating tetrapyrroles (heme compounds and/or bilirubin), which may affect fetal metabolism directly. Supported by NIH Grant AR 37326. 6That exposure to heme compounds or bilirubin may exert a direct negative influence on fetal growth and development has not received attention, but our recent studies prompt us to examine this possibility carefully. We have demonstrated that several tetrapyrroles can profoundly inhibit the growth of embryonic chicken cartilage in organ culture in vitro (4-7), the growth of normal, growing rats in vivo (8), and the proliferation of chon...
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