Short stature, one of the classic stigmata of childhood lead (Pb) poisoning, has received almost no contemporary consideration. Analysis of the National Health and Nutrition Examination Survey (NHANES II) of 1976-1980 data on 2695 children ages 6 months - 7 years showed a significant, independent, negative correlation of blood lead (PbB) with height, weight and chest circumference. The typical explanation which associates nutritional deficiency and high lead exposure in children at socioeconomic risk, was not statistically verified. There are several plausible biologic mechanisms for growth retardation by lead, with strong evidence for neuroendocrine toxicity. Clinical endocrine studies of two children with lead toxicity demonstrated an impaired thyroid stimulation hormone (TSH) response to thyrotropin releasing hormone (TRH), similar to that reported in adult lead workers. This prompted preliminary in vitro studies of possible mechanisms of toxicity. Rat pituitary cells incubated in the presence of 0.1- 100uM Pb++ showed a dose related inhibition of TRH-induced TSH release. Additional kinetic analysis of calcium distribution in anterior pituitary slices after incubation with Pb++ implicates a Pb/Ca interaction.
The specific aims of the proposed study are: 1) Define the endocrine toxicity of low level PbB in children 2-5 years old with PbB 25-55 ug/d1 by cross sectional and longitudinal and studies of the basal and stimulated responses of thyroid stimulating hormone (TSH) to TRH, and growth hormone (GH) and basal TSH, GH, prolactin, FSH and LH T3, T4, free T4, Cortisol and ACTH and correlate endocrine function and growth with indices of acute and chronic body burden of lead. 2) Test, in pituitary cells of immature and mature rats, the effect of lead on the response to TRH, GnRH and GHRH as measured by hormone release and morphology. 3) Examine the mechanisms by which Pb might inhibit TRH induced TSH release by studying, in thyrotrophs of immature rats, the effect of Pb on: a) 3H-TRH binding to membrane receptors, b) voltage and receptor-mediated calcium channels, c) intracellular distribution of calcium, and d) the activation of intracellular calcium receptors such as calmodulin and protein kinase C.
| Huseman, C A; Varma, M M; Angle, C R (1992) Neuroendocrine effects of toxic and low blood lead levels in children. Pediatrics 90:186-9 |
| Thomas, D J; Angle, C R; Swanson, S A (1990) Effect of 5-azacytidine on metallothionein inducibility and sensitivity to lethality of cadmium in rat osteosarcoma (ROS 17/2.8) cells. Toxicology 65:169-78 |
| Angle, C R; Thomas, D J; Swanson, S A (1990) Toxicity of cadmium to rat osteosarcoma cells (ROS 17/2.8): protective effect of 1 alpha,25-dihydroxyvitamin D3. Toxicol Appl Pharmacol 103:113-20 |
| Angle, C R; Thomas, D J; Swanson, S A (1990) Lead inhibits the basal and stimulated responses of a rat osteoblast-like cell line ROS 17/2.8 to 1 alpha,25-dihydroxyvitamin D3 and IGF-I. Toxicol Appl Pharmacol 103:281-7 |
| Angle, C R; Kuntzelman, D R (1989) Increased erythrocyte protoporphyrins and blood lead--a pilot study of childhood growth patterns. J Toxicol Environ Health 26:149-56 |
