Abstract
BackgroundLead is a metal with many recognized adverse health side effects, and yet the molecular processes underlying lead toxicity are still poorly understood. Quantifying the injurious effects of lead is also difficult because of the diagnostic limitations that exist when analyzing human blood and urine specimens for lead toxicity.ResultsWe analyzed the deleterious impact of lead on human cells by measuring its effects on cytokine production and gene expression in peripheral blood mononuclear cells. Lead activates the secretion of the chemokine IL-8 and impacts mitogen-dependent activation by increasing the secretion of the proinflammatory cytokines IL-6 and TNF-α and of the chemokines IL-8 and MIP1-α in the presence of phytohemagglutinin. The recorded changes in gene expression affected major cellular functions, including metallothionein expression, and the expression of cellular metabolic enzymes and protein kinase activity. The expression of 31 genes remained elevated after the removal of lead from the testing medium thereby allowing for the measurement of adverse health effects of lead poisoning. These included thirteen metallothionein transcripts, three endothelial receptor B transcripts and a number of transcripts which encode cellular metabolic enzymes. Cellular responses to lead correlated with blood lead levels and were significantly altered in individuals with higher lead content resultantly affecting the nervous system, the negative regulation of transcription and the induction of apoptosis. In addition, we identified changes in gene expression in individuals with elevated zinc protoporphyrin blood levels and found that genes regulating the transmission of nerve impulses were affected in these individuals. The affected pathways were G-protein mediated signaling, gap junction signaling, synaptic long-term potentiation, neuropathic pain signaling as well as CREB signaling in neurons. Cellular responses to lead were altered in subjects with high zinc protoporphyrin blood levels.ConclusionsThe results of our study defined specific changes in gene and protein expression in response to lead challenges and determined the injurious effects of exposures to lead on a cellular level. This information can be used for documenting the health effects of exposures to lead which will facilitate identifying and monitoring efficacious treatments for lead-related maladies.
Highlights
Lead is a metal with many recognized adverse health side effects, and yet the molecular processes underlying lead toxicity are still poorly understood
The majority of the cytokines were below the lower detection limit and only chemokines IL-8, MIP-1β, MCP-1, Eotaxin, MIP-1α and RANTES were detected in the peripheral blood mononuclear cells (PBMC) culture supernatants
The highest increase of cytokine levels was at 50 μM lead acetate and some effect was detected at 10 μM. These results demonstrated that lead increases mitogenic activation of PBMC, which is in agreement with the lead-dependent stimulation of lymphocyte and leukocyte proliferation and function observed in earlier studies [24,25,26,27]
Summary
Lead is a metal with many recognized adverse health side effects, and yet the molecular processes underlying lead toxicity are still poorly understood. Lead (Pb) is a widely distributed industrial metal and it is naturally present in the environment. It is an environmentally persistent element and a major global environmental hazard. 99 percent of lead is retained in the blood for approximately 30-35 days and over the following 4-6 weeks it is dispersed and accumulated in other tissues – liver, renal cortex, aorta, brain, lungs, spleen, teeth and bones [3]. The half-life of lead in brain tissue is about two years and in bones it persists for 20-30 years [4]. Liver tissue is the largest repository of lead (33%) followed by the kidney cortex and medulla [5]
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