Lindane induces nephropathy and renal accumulation of α2u-globulin in male but not in female Fischer 344 rats or male NBR rats

Abstract

Lindane, the y-isomer of 1,2,3,4,5,6-hexachlorocyclohexane, is a widely used organochlorine pesticide. The application of lindane in soil, foliar, and seed treatment for a large variety of fruit and vegetable crops, its application on livestock, pets, and on agricultural premises, in pharmaceutical prepa itions, as well as in public health pest control, could lead to the exposure of humans to low concentrations of this compound. Various experiments were carried out in order to assess the toxicity and carcinogenicity of lindane [ 1,2]. In some of these experiments, male rat specific renal toxicity was observed. This toxicity was characterized by an exacerbated formation of hyaline droplets, enlargement of lysosomes in the proximal tubules, and necrosis of proximal tubule epithelial cells [3,4]. The male rat specific occurrence of hyaline droplet formation and necrosis of proximal tubule epithelial cells are characteristic lesions for the chemically induced male rat renal disease, a2u-globulin nephropathy. This disease occurs only in male rats of strains other than the NBR, the only strain that does not synthesize the androgendependent form of a2u-globulin [5]. It is induced by the reversible binding of chemicals or their metabolites, such as 2,2,4_trimethylpentane, d-limonene, 1,4-dichlorobenzene, unleaded gasoline, and isophorone to the low-molecular-weight protein a2u-globulin, which leads to the accumulation of this a2u-globulin-chemical complex in the lysosomes of the proximal tubule epithelial cells [6]. This results in lysosomal overload, which leads to degeneration and necrosis of epithelial cells, followed by compensatory regeneration [7].