Relation between toxicity and carcinogenesis in the kidney: an heuristic hypothesis
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B F Trump1, T W Jones, K A Elliget
1Department of Pathology, University of Maryland School of Medicine, Baltimore.
Abstract:
Cellular toxicity and cellular carcinogenesis are closely linked. In the kidney, this relationship has been emphasized by the recent discovery of a number of putatively non-mutagenic chemicals that result in acute and chronic toxicity and ultimately in carcinogenesis, especially in the male rat. Many, but not all such compounds, result in renal PTE phagolysosomal overload. At the same time, known metabolites of other carcinogens, e.g., HCBD and FBPA, result in acute renal injury and/or necrosis, followed by chronic tubular disease, interstitial nephritis, and ultimately carcinogenesis. A series of cell mechanisms have been suggested that lead from acute cell injury to altered control of cell division. These mechanisms appear to involve ion deregulation, (especially [Ca2+]i) resulting from a variety of continued injuries, (e.g., oxidative stress from inflammatory cells) and ultimately leading to altered gene expression.
Insights
Cellular toxicity can lead to kidney cancer, particularly in male rats, through mechanisms involving cell injury, ion deregulation, and altered gene expression. Non-mutagenic chemicals highlight this critical link.
Area of Science:
- Toxicology
- Carcinogenesis
- Renal Cell Biology
Background:
- Cellular toxicity and carcinogenesis are closely linked, particularly in kidney studies.
- Non-mutagenic chemicals can induce acute and chronic toxicity, leading to carcinogenesis, especially in male rats.
- Renal toxicity mechanisms include phagolysosomal overload and acute injury from carcinogen metabolites.
Purpose of the Study:
- To explore the relationship between cellular toxicity and carcinogenesis in the kidney.
- To elucidate the mechanisms linking acute cell injury to altered cell division and gene expression.
- To highlight the role of specific chemicals and cellular processes in renal carcinogenesis.
Main Methods:
- Review of studies on non-mutagenic chemicals and their renal effects.
- Analysis of cellular mechanisms, including phagolysosomal overload and ion deregulation.
- Investigation of pathways from acute renal injury to chronic disease and cancer.
Main Results:
- Several non-mutagenic chemicals induce renal toxicity and carcinogenesis, particularly in male rats.
- Phagolysosomal overload is a common finding in toxicity-induced carcinogenesis.
- Carcinogen metabolites cause acute renal injury, progressing to chronic disease and cancer.
- Cellular mechanisms involve ion deregulation (e.g., intracellular calcium) and altered gene expression.
Conclusions:
- Acute and chronic kidney injury can progress to carcinogenesis through specific cellular pathways.
- Ion deregulation and altered gene expression are key mechanisms linking cell injury to cancer.
- Understanding these pathways is crucial for identifying and mitigating chemical carcinogenesis risks.