"Three samples [were] collected at different times: 1998, 2002, 2007. The total sample consisted of 825 children between 11 and 14 years of age living in different municipalities of Sardinia (Italy). [We measured] the lead concentration in hair (PbH).
The mean PbH is much higher in 1998 (5.84 μg/g) than in 2002 (1.49 μg/g) and 2007 (0.78 μg/g). [There is an] impact of lead on growth that differs according to the mean lead concentration in the hair. For 1998, the relationships between all three anthropometric variables[height, sitting height, and estimate leg length] and logPbH are significantly negative. For 2002, there are significant negative associations between height and estimated leg length and logPbH but not between sitting height and logPbH. For 2007, there are not significant associations between logPbH and anthropometric variables."
Why would the effects of lead change over the years?
"Lead is widespread in the environment, with several anthropogenic sources such as traffic, lead battery production, lead-containing plastics and paint, solder, ceramic table and kitchen ware, combustion of fossil fuels, metallurgy, smelting processes, [and] direct ingestion of dust"
According to the study, the mean amount of lead in hair also lowered greatly throughout the years. So maybe lead only has negative impacts at very high quantities?
1998 Mean Lead 7.40 Decrease Height(More lead in hair correlates with height decrease)
2002 Mean Lead 1.17 Decrease Height
2007 Mean Lead 0.76 Increase Height(more lead in hair correlates with height increase)
So likely lead has an equilibrium level to maximize height. Of course the study had other issues as lead levels in the hair are not a perfect correlate to lead levels in serum.
They found a positive relationship between upper arm muscle area and height. This could be myostatin related.
"The negative effects of lead on growth are due to the fact that this heavy metal, a calcium antagonist, has a high affinity for bone tissue; many of the circulating ions are deposited in bone, inhibiting development of the long bones and flat bones via activation of chondrocytic inflammation which slows or inhibits cell division. The stunting effect of blood lead on linear growth indicates a dose-related reduction in stature by about 1 to 3 cm for each 10 μg/dL increase in blood lead level."
"[The] greater influence of lead on chondrocyte proliferation, hypertrophy, and matrix calcification at long bone growth plates is a leading cause of reduced growth in leg and arm lengths, while a secondary cause of reduced height is probably reduced osteoblast activity and bone remodeling. Growth plates of the lower extremities, and to a lesser extent of the upper extremities, [may be] more susceptible to lead levels because they grow more rapidly early in life when children are prone to having higher blood lead levels"
The 2007 group had the shortest mean height. The 2002 group had the highest mean height. The 2002 group were likely closest to the equilibrium value of lead.
Thus obtaining an equilibrium quantity of lead may increase height.
Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations.
"Skeletal growth is stunted in lead-exposed children.
Pb [influences] chondrogenesis in murine limb bud mesenchymal cells (MSCs). The effects of Pb on transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling was studied. [We studied] cyclic adenosine monophosphate response element binding protein (CREB), beta-catenin, AP-1, and nuclear factor-kappa B (NF-kappaB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo.
Pb-exposed MSCs showed enhanced basal and TGF-beta/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. Chondrogenesis [was enhanced] during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-beta but inhibited BMP-2 signaling as measured by analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/beta-catenin pathway activity, it induced NFkappaB signaling and inhibited AP-1 signaling.{all things that affect chondrogenesis}
The in vitro and in vivo induction of chondrogenesis by Pb [may involve the signaling pathways] TGF-beta, BMP, AP-1, and NFkappaB."
"Prostaglandin E2, through protein kinase A signaling also induces chondrogenesis, whereas retinoic acid is considered an inhibitor of chondrogenic commitment possibly via down-regulation of TGF-β/Smad signaling"
Pb may also "[induce] ERK1/2 (extracellular signal regulated kinase 1 and 2) and p38 (mitogen-activated protein kinase; MAPK) phosphorylation"
"Although the effect of BMP-2 was slightly greater (3.2-fold) than that of TGF-β (1.7-fold), the induction of chondrogenesis by both growth factors was enhanced by Pb. In the presence of 10 μM Pb, BMP-2 induced chondrogenesis 5-fold and TGF-β induced a 3-fold increase"
"Pb dose-dependently enhanced the expression of these genes, with 10-μM Pb inducing a 2-fold increase in Sox9, a 5-fold increase in col2, and a 2.5-fold increase in aggrecan compared with untreated cultures"<-doses above 10 were not tried so we can't see the equilibrium point.
"Pb affects neither basal BMP-2 nor TGF-β signaling; thus it is unlikely that the effect of Pb on chondrogenesis is related to a direct alteration of these signaling pathways. Moreover, although Pb enhanced the effect of BMP-2 on chondrogenesis, it acted as an inhibitor of Smad1/5/8 signaling."
"although neither Pb nor TGF-β alone affected the expression of BMP-6, in combination they induced its expression 3-fold"
"signaling on the NFκB pathway has been shown to destabilize Sox9 mRNA and inhibit chondrogenesis"
Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling.
Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations.
"Skeletal growth is stunted in lead-exposed children.
Pb [influences] chondrogenesis in murine limb bud mesenchymal cells (MSCs). The effects of Pb on transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling was studied. [We studied] cyclic adenosine monophosphate response element binding protein (CREB), beta-catenin, AP-1, and nuclear factor-kappa B (NF-kappaB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo.
Pb-exposed MSCs showed enhanced basal and TGF-beta/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. Chondrogenesis [was enhanced] during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-beta but inhibited BMP-2 signaling as measured by analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/beta-catenin pathway activity, it induced NFkappaB signaling and inhibited AP-1 signaling.{all things that affect chondrogenesis}
The in vitro and in vivo induction of chondrogenesis by Pb [may involve the signaling pathways] TGF-beta, BMP, AP-1, and NFkappaB."
"Prostaglandin E2, through protein kinase A signaling also induces chondrogenesis, whereas retinoic acid is considered an inhibitor of chondrogenic commitment possibly via down-regulation of TGF-β/Smad signaling"
Pb may also "[induce] ERK1/2 (extracellular signal regulated kinase 1 and 2) and p38 (mitogen-activated protein kinase; MAPK) phosphorylation"
"Although the effect of BMP-2 was slightly greater (3.2-fold) than that of TGF-β (1.7-fold), the induction of chondrogenesis by both growth factors was enhanced by Pb. In the presence of 10 μM Pb, BMP-2 induced chondrogenesis 5-fold and TGF-β induced a 3-fold increase"
"Pb dose-dependently enhanced the expression of these genes, with 10-μM Pb inducing a 2-fold increase in Sox9, a 5-fold increase in col2, and a 2.5-fold increase in aggrecan compared with untreated cultures"<-doses above 10 were not tried so we can't see the equilibrium point.
"Pb affects neither basal BMP-2 nor TGF-β signaling; thus it is unlikely that the effect of Pb on chondrogenesis is related to a direct alteration of these signaling pathways. Moreover, although Pb enhanced the effect of BMP-2 on chondrogenesis, it acted as an inhibitor of Smad1/5/8 signaling."
"although neither Pb nor TGF-β alone affected the expression of BMP-6, in combination they induced its expression 3-fold"
"signaling on the NFκB pathway has been shown to destabilize Sox9 mRNA and inhibit chondrogenesis"
Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-β signaling.
"As lead is concentrated in articular cartilage, we hypothesize that it can disrupt normal chondrocyte phenotype through suppression of TGF-β signaling. [We] examine the effects of lead exposure in vivo and in vitro at biologically relevant levels, from 1 nM to 10 µM on viability, collagen levels, matrix degrading enzyme activity, TGF-β signaling, and articular surface morphology. [Chondrocyte] viability was unchanged at levels ≤100 µM Pb, but low and high level lead in vivo exposure resulted in fibrillation and degeneration of the articular surface. Lead treatment also decreased levels of type II collagen and increased type X collagen, in vivo and in vitro. MMP13 activity increased in a dose-dependent manner. Active caspase 3 and 8 were dose-dependently elevated, and treatment with 10 µM Pb resulted in increases of 30% and 500%, respectively. Increasing lead treatment resulted in a corresponding reduction in TGF-β reporter activity, with a 95% reduction at 10µM. Levels of phosphoSmad2 and 3 were suppressed in vitro and in vivo and lead dose-dependently increased Smurf2."
Smurf2 degrades Smad2/3.
Developmental exposure to As, Cd and Pb-mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.
"We studied the effect of metal mixture (MM), comprising of As[Arsenic], Cd[Cadmium] and Pb[Lead], in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e. As: 0.38ppm, Pb: 0.22 ppm and Cd: 0.098 ppm {so enough concentrations to influence water are present in some drinking waters} or 10× of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative- and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary- and secondary spongiosa, and hypomineralized osteoids - a major characteristic of osteomalacia. In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone."
Lead contamination has been found in drinking water in the United States.
"During development, skeletal tissue assimilates heavy metals to which they are exposed. The incorporated metals are eliminated by resorption" Several years are required to eliminate these metals.
The reduction in tibial lengths by the Metal Mixture was dose dependent.
Developmental exposure to As, Cd and Pb-mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.
"We studied the effect of metal mixture (MM), comprising of As[Arsenic], Cd[Cadmium] and Pb[Lead], in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e. As: 0.38ppm, Pb: 0.22 ppm and Cd: 0.098 ppm {so enough concentrations to influence water are present in some drinking waters} or 10× of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative- and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary- and secondary spongiosa, and hypomineralized osteoids - a major characteristic of osteomalacia. In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone."
Lead contamination has been found in drinking water in the United States.
"During development, skeletal tissue assimilates heavy metals to which they are exposed. The incorporated metals are eliminated by resorption" Several years are required to eliminate these metals.
The reduction in tibial lengths by the Metal Mixture was dose dependent.
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