An exploratory study of sex differences in thallium-induced nephrotoxicity in rats

Sexual dimorphism is recognized in nephrotoxic acute kidney injury, with females being less susceptible than males. Thallium (Tl), a highly toxic heavy metal, induces severe systemic disorders following exposure, including gastrointestinal and neurological disorders and renal failure. However, sex-related differences in Tl-induced nephrotoxicity remain poorly understood. Previous studies have shown that Tl preferentially accumulates in the outer medulla of the kidney of male rats, resulting in mitochondrial dysfunction and medullary thick ascending limb (mTAL) injury, characterized by calcium deposits and impaired renal function. This study investigated the effects of Tl on the kidneys of female rats and the underlying mechanisms. Tl₂SO₄ (30 mg/kg) was administered to rats. Nephrotoxicity was measured 2, 5, and 14 days after Tl-administration using biochemical assays of blood and urine samples, histopathology of the kidney, and transcriptome analysis using microarrays. As in male rats, female Tl-loaded rats developed severe renal dysfunction with calcium deposits in the outer medulla within 5 days after Tl administration. The pathological features were similar to those of male rats; however, the mitochondrial oxidative stress and calcium deposits in the medulla were less extensive in female rats than in male rats. These preliminary findings suggest sex-dependent differences, which might be derived from the differences in sex-hormones, in Tl-induced renal injury and suggest potential involvement of differential oxidative stress handling, mitochondrial responses, and transporter activity. These new insights could assist with the development of therapeutic strategies for treating Tl intoxication in humans.