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If glycolysis is inhibited in distal axonopathy, there should be a concomitant inhibition of lipogenesis from glucose. To investigate this possibility, lipogenesis from [14C]glucose and [3H]acetate was studied in sciatic nerves incubated with iodoacetate, a known inhibitor of glycolysis, in sciatic nerves incubated with 2,5-hexanedione, a putative inhibitor of glycolysis, and in sciatic nerves from rats exhibiting clinical signs of peripheral neuropathy induced by 2,5-hexanedione. Nerves incubated with 1.0 mm iodoacetate, in comparison with untreated nerves, exhibited decreased incorporation of [14C]glucose into sterols + diacylglycerols (33-fold), free fatty acids (14-fold), triacylglycerols (27-fold), and phospholipids (21-fold). In addition, these nerves exhibited decreased incorporation of [3H]acetate into sterols + diacylglycerols (30-fold), free fatty acids (2-fold), triacylglycerols (23-fold), and phospholipids (12-fold). In contrast, the incorporation of [14C]glucose into sterols + diacylglycerols, free fatty acids, and triacylglycerols was not affected by 1.0 mm 2,5-hexanedione. Compared to untreated nerves, nerves incubated with 1.0 mm 2,5-hexanedione exhibited a small decrease (15%) in the incorporation of [14C]glucose into phospholipids. Nerves from rats given 1% 2,5-hexanedione in the drinking water for 6 weeks, in comparison with those from pair-fed control rats, exhibited decreased (45%) incorporation of [14C]glucose and [3H]acetate into digitonin-precipitable sterols. Nerves from 2,5-hexanedione-treated and pair-fed control rats exhibited similar incorporation of [14C]glucose and [3C]acetate into free fatty acids, triacylglycerols, and phospholipids. The data indicate that while sterologenesis is inhibited in distal axonopathy, glycolysis is not.

The chronic administration of 2,5-hexanedione (2,5-HD) to experimental animals can cause azoospermia and morphologic changes in central nervous system (CNS) areas related to visual and motor function. The present experiments were designed to determine the degree of CNS involvement in the testicular lesions seen after 2,5-HD administration. Additionally, activity measurements were made of some enzymes found in specific cell types in the testes. The 2,5-HD was administered as a 1% solution in the drinking water to adult male F-344 rats. Treated rats, pair fed controls, and ad libitum controls were killed after 1, 3, and 6 weeks of 2,5-HD treatment. The circulating levels of testosterone and the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were not depressed at any time measured. After 6 weeks, the testes were azoospermic; this coincided with a rise in LH and FSH. After 3 weeks of 2,5-HD treatment, when the testes were morphologically normal, testicular activity of the Sertoli-cell-specific enzymes, β-glucuronidase and γ-glutamyl transpeptidase, were decreased. The testicular enzyme profile after 6 weeks was similar to that seen in the azoospermic, cryptorchid testis. Activities of hepatic β-glucuronidase and acid phosphatase were decreased at all time points. The data indicate that 2,5-HD does not act via the central gonadotropin control systems to induce azoospermia, and that demonstrable changes in Sertoli cell biochemistry occur prior to visible morphologic changes in the testis.

Distal axonopathy induced by n-hexane and methyl n-butyl ketone has been attributed to a common metabolite, 2,5-hexanedione. Since altered lipid metabolism is frequently associated with neuropathy, the effects of 2,5-hexanedione on lipid biosynthesis from [1-14C]acetate in sciatic nerve and brain of rats given 1% 2,5-hexanedione in drinking water have been studied, in vitro. Clinical signs of neuropathy appeared after 6 weeks. Loss of body weight induced by 2,5-hexanedione was similar to that observed in pair-fed control rats. Compared to nerves from pair-fed controls, nerves from rats fed 2,5-hexanedione exhibited decreased incorporation of [1-14C]acetate into triacylglycerols (32%), total sterols + diacylglycerols (54%), digitonin-precipitable sterols (55%), squalene (55%), and ubiquinone (43%). Incorporation of [1-14C]acetate into phospholipids, fatty acids, and cholesteryl esters was similar in nerves of 2,5-hexanedione-treated rats and pair-fed controls. In brain, incorporation of [1-14C]acetate into lipids was similar in 2,5-hexanedione-treated and pair-fed control rats, except into the fatty acid fraction which was significantly decreased by 11%. The data support the hypothesis that lipid metabolism, in particular sterol metabolism, is altered in hexacarbon-induced distal axonopathy.