Revealing a Pre-neoplastic Renal Tubular Lesion by p-S6 Protein Immunohistochemistry after Rat Exposure to Aristolochic Acid.
Aristolochic acid (AA) has, in the last decade, become widely promoted as the cause of the Balkan endemic nephropathy and associated renal or urothelial tumours, although without substantial focal evidence of the quantitative dietary exposure via bread in specific households in hyperendemic villages. Occasional ethnobotanical use ofAristolochia clematitismight be a source of AA, and Pliocene lignite contamination of well-water is also a putative health risk factor. The aim of this study was two-fold: to verify if extracts ofA. clematitisand Pliocene, or AA by itself, could induce the development of renal or urothelial tumours, and to test the utility of the ribosomal protein p-S6 to identify preneoplastic transformation. Rats were given extracts ofA. clematitisin drinking water or AA I, by gavage. After seven months, renal morphology was studied using conventional haematoxylin and eosin and immunohistochemistry for ribosomal p-S6 protein. Plant extracts (cumulative AA approximately 1.8 g/kg b.w.) were tolerated and caused no gross pathology or renal histopathological change, with only faint diffuse p-S6 protein (except in the papilla) as in controls. Cumulative AA I (150 mg/kg b.w. given over 3 days) was also tolerated for seven months by all recipients, without gross pathology or kidney tumours. However, p-S6 protein over-expression was consistent particularly within the renal papilla. In one case given AA I, intense p-S6 protein staining of a proximal tubule fragment crucially matched the pre-neoplastic histology in an adjacent kidney section. We briefly discuss these findings, which compound uncertainty concerning the cause of the renal or upper urinary tract tumours of the Balkan endemic nephropathy.
Pathology Department, County Hospital Timisoara, Timisoara 300736, Romania; Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK; Department of Biology, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania; Centre for Environmental Policy, Imperial College London, London SW7 2AZ, UK.
Alexandra
A
Gruia
Pathology Department, County Hospital Timisoara, Timisoara 300736, Romania; Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK; Department of Biology, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania; Centre for Environmental Policy, Imperial College London, London SW7 2AZ, UK.
Patrycja
P
Gazinska
Pathology Department, County Hospital Timisoara, Timisoara 300736, Romania; Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK; Department of Biology, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania; Centre for Environmental Policy, Imperial College London, London SW7 2AZ, UK.
Diana
D
Herman
Pathology Department, County Hospital Timisoara, Timisoara 300736, Romania; Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK; Department of Biology, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania; Centre for Environmental Policy, Imperial College London, London SW7 2AZ, UK.
Valentin
V
Ordodi
Pathology Department, County Hospital Timisoara, Timisoara 300736, Romania; Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK; Department of Biology, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania; Centre for Environmental Policy, Imperial College London, London SW7 2AZ, UK.
Calin
C
Tatu
Pathology Department, County Hospital Timisoara, Timisoara 300736, Romania; Breakthrough Breast Cancer Research Unit, Guy's Hospital, King's Health Partners AHSC, King's College London School of Medicine, London SE1 9RT, UK; Department of Biology, University of Medicine and Pharmacy "Victor Babes", Timisoara, Romania; Centre for Environmental Policy, Imperial College London, London SW7 2AZ, UK.
Peter
P
Mantle