John F. Rosen

Low-level lead-induced neurotoxicity in children : an update on central nervous system effects

The neurotoxicity of low-level long-term exposure to lead has a special relevance in children. An extensive database has provided a direct link between low-level lead exposure and deficits in the neurobehavioral-cognitive performance evidenced in childhood through adolescence. Electrophysiological studies showed that neurosensory processing may be affected by lead, with consequent decrease in auditory sensitivity and visuomotor performance. Lead disrupts the main structural components of the blood-brain barrier by primary injury to astrocytes with a secondary damage to the endothelial microvasculature. Within the brain, lead-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum. Some characteristic clinical features of lead poisoning may be attributed to this specific anatomical pattern. The cellular, intracellular and molecular mechanisms of lead neurotoxicity are numerous, as lead impacts many biological activities at different levels of control: at the voltage-gated channels and on the first, second and third messenger systems. These effects could be related to leads ability to interfere with the regulatory action of calcium in cell functions. Consequently, it may be assumed that lead acts as a chemical stressor and causes breakdown of the homeostatic cellular mechanisms. This is expressed in both the anatomical site and the neurotransmitter systems which are crucial in modulating emotional response, memory and learning. There is no threshold below which lead remains without effect on the central nervous system; thus, symptoms could simply be a clinical reflection of the brain regions preferentially involved. In integrating these physiological and clinical data, it may be suggested that the different mechanisms of low level lead neurotoxicity have a final common functional pathway.

Rickets with alopecia: An inborn error of vitaminD metabolism

Rickets with alopecia, an inborn error of vitamin D metabolism, is described in two sisters. The rachitic disorder began during the first year of life and was refractory to 50,000 IU of vitamin D2/day. Surprisingly, both children had marked elevations in serum concentrations of 1,25-(OH)2D. Although the molecular basis for this disorder is not evident to date, intestinal end-organ unresponsiveness to exceedingly high levels of 1,25-(OH)2D was present, in addition to hyporesponsiveness of bone to these high levels of the hormone, since normocalcemia was maintained despite elevated serum levels of PTH. Therapy with oral 1,25-(OH)2D3 failed to reverse the disorder, but oral phosphorus supplements resulted in significant radiographic and clinical improvement.

Reduction in 1,25-dihydroxyvitamin D in children with increased lead absorption.

STUDIES in laboratory animals have demonstrated that a diet low in calcium increases lead retention and that there are associated biochemical and morphologic manifestations of enhanced lead toxicit...

A Cellular Defect in Hereditary Vitamin-D-Dependent Rickets Type II: Defective Nuclear Uptake of 1,25-Dihydroxyvitamin D in Cultured Skin Fibroblasts

VITAMIN-D-dependent (or pseudo-vitamin-D-deficient) rickets is characterized by clinical and biochemical features of vitamin-D-deficient rickets and by remission of these features during treatment ...

Marrow transplantation for juvenile osteopetrosis

Two children with the juvenile form of osteopetrosis were treated with marrow transplants from their HLA identical siblings. Following transplantation each child exhibited extensive bone reabsorption with a marked augmentation of osteoclastic function attributable to donor osteoclasts, including remodeling of bone with expansion of intramedullary hematopoiesis and correction of associated abnormalities of thymic factor and natural killer cells. Osteopetrosis ultimately recurred in one patient in whom engraftment of donor hematopoietic elements was not achieved. Our studies indicate that marrow transplantation will correct osteopetrosis but that permanent reconstitution necessitates sustained engraftment of marrow precursors of cells with osteoclastic activity.

Adverse health effects of lead at low exposure levels : trends in the management of childhood lead poisoning

An extensive database has provided a direct link between low-level lead exposure during early development and deficits in neurobehavioral-cognitive performance evident late in childhood through adolescence. These consistent studies have demonstrated the presence of a constellation of neurotoxic and other adverse effects of lead at blood lead (BPb) levels at least as low as 10 micrograms/dl). Federal agencies and advisory groups have redefined childhood lead poisoning as a BPb level of 10 micrograms/dl. Before discussing some of these studies in greater detail, the pervasiveness of this entirely preventable disease today in millions of American children must be recognized.

The effect of Pb2+ on the structure and hydroxyapatite binding properties of osteocalcin

Lead toxicity is a major environmental health problem in the United States. Bone is the major reservoir for body lead. Although lead has been shown to impair bone metabolism in animals and at the cellular level, the effect of Pb(2+) at the molecular level is largely unknown. We have used circular dichroism (CD), and a hydroxyapatite binding assay to investigate the effect of Pb(2+) on the structure and mineral binding properties of osteocalcin, a noncollagenous bone protein. The CD data indicate Pb(2+) induces a similar structure in osteocalcin as Ca(2+) but at 2 orders of magnitude lower concentration. These results were explained by the more than 4 orders of magnitude tighter binding of Pb(2+) to osteocalcin (K(d)=0.085 microM) than Ca(2+) (K(d)=1.25 mM). The hydroxyapatite binding assays show that Pb(2+) causes an increased adsorption to hydroxyapatite, similar to Ca(2+), but at 2-3 orders of magnitude lower concentration. Low Pb(2+) levels (1 microM) in addition to physiological Ca(2+) levels (1 mM) caused a significant (40%) increase in the amount of mineral bound osteocalcin as compared to 1 mM Ca(2+) alone. These results suggest a molecular mechanism of Pb(2+) toxicity where low Pb(2+) levels can inappropriately perturb Ca(2+) regulated processes. In-vivo, the increased mineral bound osteocalcin could play a role in the observed low bone formation rates and decreased bone density observed in Pb(2+)-intoxicated animals.

The circadian rhythm of serum osteocalcin concentrations: Effects of 1,25 dihydroxyvitamin D administration

SummaryThe effects of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) administration on serum osteocalcin (Oc) concentrations were determined. 2.0 μg doses of 1,25(OH)2D3 were administered orally and intravenously to four healthy adult males. Blood was sampled hourly for 24 hours on four occasions: once prior to the two treatment days (i.v. and p.o.), on each of the treatment days, and during a second nontreatment day 2 years later. Mean circadian Oc rythms of the four subjects on each study day were compared with each other and with a previously derived mathematical representation of the normative Oc rhythm, the circadian Oc rhythm model. We found overall conservation of the mean Oc pattern across time and 1,25(OH)2D3 treatment. However, 1,25(OH)2D3 administration resulted in a rapid rise (within 6 hours) in Oc concentrations that blunted or eliminated the morning fall in Oc levels. The increased Oc levels were sustained for the remainder of the 24 hour period though pattern shapes converged with those of the nontreatment days and the model. We conclude that serum Oc levels are rapidly responsive to near physiological doses of 1,25(OH)2D3 in healthy adult males and that the effects are maintained for at least 24 hours.

Vitamin D-dependent rickets: actions of parathyroid hormone and 25-hydroxycholecalciferol.

Extract: During active rickets, the increase in 3′,5′-adenosine monophosphate (3′,5′-AMP) excretion after infusion of parathyroid hormone (PTH) can be claimed as a demonstration of PTH responsiveness, at least as far as the kidney is concerned (Table II). In patients with vitamin D-dependent rickets, following 25-HCC therapy, the basal excretion ratios of nanomoles 3′,5′-AMP/milligrams creatinine fall within the normal range, and, although the basal ratios of milligrams phosphate/milligrams creatinine excretion decrease to normal (Tables III, IV, and V), a phosphaturic response to PTH is still not evident. The high basal ratios of nanomoles 3′,5′-AMP/ milligrams creatinine and milligrams phosphate/milligrams creatinine suggest underlying hyperparathyroidism during a phase of this syndrome marked by hypocalcemia and hyperaminoaciduria. During 2-day PTH challenges, while rickets was active, the peak increases in serum calcium above base line were 1.92, 1.80, and 1.86 mg/100 ml. After treatment with 25-hydroxycholecalciferol (25-HCG), no further significant increases in serum calcium above base line could be elicited (Tables VI, VII, VIII). It would seem, therefore, that, while these patients were untreated, small but sufficient amounts of 25-HCC or another metabolite of vitamin D were available to permit the calcium-mobilizing action of PTH on bone. The observed hypocalcemia in vitamin D-dependent rickets, then, is most likely secondary to a defect in gastrointestinal absorption. Mineral balance studies during active rickets revealed an absorptive defect for calcium, phosphorus, and magnesium—a defect completely reversible after 25-HCC treatment.Speculation: We suggest that the small intestine represents the prime target organ site for impaired vitamin D action in this disease by differential failure in the biologic formation of 1,25-dihydroxycholecalciferol from 25-HCC. Similarly, we postulate that a variable hydroxylating deficiency may be present in the transformation of vitamin D3 to 25-HCC. Genetic heterogeneity, therefore, may ultimately explain common responses in these three patients to contrasting doses of dihydrotachysterol (DHT) and 25-HCC.

Cellular Ca2+ homeostasis and Ca2+-mediated cell processes as critical targets for toxicant action: Conceptual and methodological pitfalls

Because of the central role of the calcium messenger system in diverse functions of tissues, organs, and cells, Ca2+ homeostasis and function may prove to be critical cellular and molecular targets for a diverse range of toxicants. Experimental proof of these targets as a specific site of toxicant action is challenging and technically difficult as a result of the complexity of Ca2+ homeostatic and Ca2+-mediated processes. However, as the investigation of normal physiological control of Ca2+ and function will continue to be an active and productive area of basic research for several years to come, it is anticipated that these insights will be increasingly applied to the understanding of the mechanisms of action of toxic agents.