We have reported the protein-reactive, chromogenic and neurotoxic properties of the aromatic and aliphatic gamma-diketone solvent metabolites 1, 2-diacetylbenzene (1, 2-DAB) and 2, 5-hexanedione (2, 5-HD), respectively; by contrast their corresponding non-chromogenic isomers, 1, 3-DAB and amp; 2, 4-HD, respectively, fail to induce murine neuropathy, the hallmark of which is proximal (1, 2-DAB) or distal (2, 5-HD) axonal swellings (with distal atrophy) filled with maloriented neurofilaments (NF). We asked whether 1, 2, 4-triethylbenzene (1, 2, 4-TEB), the probable precursor of 1, 2, 4-triacetylbenzene (1, 2, 4-TAB) shows comparable structure-dependent chromogenic and neurotoxic properties. Twelve week-old male C57BL/6 mice were dosed orally with 300 mg/kg (n=3), 600 mg/kg (n=3) or 900 mg/kg (n=3) body weight of 1, 2, 4-TEB, equivalent doses of 1, 3, 5-TEB (which lacks the 1, 2-diacetyl moiety), or an equal volume of the TEB Vehicle (olive oil), for 3 evenly spaced days/week for up to 12 weeks. Mice treated with 1, 2, 4- TEB excreted greenish urine after 5 (900 mg/kg), 14 (600 mg/kg) and 49 (300 mg/kg) days and, thereafter, developed muscle spasm and hind-limb weakness. Blue-greenish tissue from the central nervous system (frontal cortex, hippocampus, basal ganglia, cerebellum, medulla oblongata, lumbar and cervical spinal cord) and the peripheral nervous system (lumbar spinal ventral roots, dorsal spinal roots and ganglia, sciatic nerves) were sampled for light and electron microscopy. Mice treated with 1, 2, 4-TEB showed a dose-dependent 1, 2-DAB-like pattern of intramedullary, intraspinal and spinal root NF-filled axonal swellings presumably arising from proximal blockade of NF anterograde transport. Mice treated with 1, 3, 5-TEB or Vehicle lacked urine and tissue discoloration, hindlimb weakness, and neuropathology. These results show that 1, 2-spaced ethyl moieties on a benzene ring are required to induce a 1, 2-DAB-like pattern of murine CNS-PNS proximal axonopathy.
