Animal models of peripheral neuropathy due to environmental toxicants

Abstract

Despite the progress in our understanding of pathogeneses and the identification of etiologies of peripheral neuropathy, idiopathic neuropathy remains common. Typically, attention to peripheral neuropathies resulting from exposure to environmental agents is limited relative to more commonly diagnosed causes of peripheral neuropathy (diabetes and chemotherapeutic agents). Given that there are more than 80,000 chemicals in commerce registered with the Environmental Protection Agency and that at least 1000 chemicals are known to have neurotoxic potential, very few chemicals have been established to affect the peripheral nervous system (mainly after occupational exposures). A wide spectrum of exposures, including pesticides, metals, solvents, nutritional sources, and pharmaceutical agents, has been related, both historically and recently, to environmental toxicant-induced peripheral neuropathy. A review of the literature shows that the toxicity and pathogeneses of chemicals adversely affecting the peripheral nervous system have been studied using animal models. This article includes an overview of five prototypical environmental agents known to cause peripheral neuropathy--namely, organophosphates, carbon disulfide, pyridoxine (Vitamin B6), acrylamide, and hexacarbons (mainly n-hexane, 2,5-hexanedione, methyl n-butyl ketone). Also included is a brief introduction to the structural components of the peripheral nervous system and pointers on common methodologies for histopathologic evaluation of the peripheral nerves.

Keywords: acrylamide; carbon disulfide; environmental toxicant; hexacarbon; organophosphate; peripheral neuropathy; pyridoxine; vitamin B6.

Figure 1

Tangential section of perfusion-fixed sciatic nerve embedded in epoxy resin of a chicken exposed to a neurotoxic dose (2.5 mg/kg) of phenyl saligenin phosphate (intramuscular) 15 days before it was killed. Several stages of myelinated fiber degeneration are seen, including a swollen pale stained axon (black arrow) and a fiber undergoing degradation (Wallerian-type) within a phagocyte (white arrow). Toluidine blue and safranin stain.

Figure 2

Muscular branch of the posterior tibial nerve (perfusion fixed and embedded in epoxy resin) with multiple swollen axons (arrow head and arrow) within a nerve fascicle from a rat exposed to 800 ppm of carbon disulfide (by inhalation) for 13 weeks (6 hours/day for 5 days/week). Note the thinning of the myelin sheath in a swollen axon (arrow). Toluidine blue stain.

Figure 3

Muscular branch of the posterior tibial nerve (perfusion fixed and embedded in epoxy resin) illustrating axonal degeneration (arrows) within a nerve fascicle from a rat exposed to 800 ppm of carbon disulfide (by inhalation) for 13 weeks (6 hours/day for 5 days/week). Toluidine blue stain.

Figure 4

Dorsal root ganglion of a rat (perfusion fixed and embedded in epoxy resin) exposed to a toxic dose (600 mg/kg) of pyridoxine administered intraperitoneally twice a day for 4 days and killed 2 days after the last exposure. Degradative change is seen in the soma of a neuron (black arrow), which progresses to necrosis manifest by satellite cell phagocytosis of an affected neuron cell body (neuronophagia) (arrowhead). There also is axonal degeneration of a myelinated dorsal root fiber within the ganglion (white arrow). Toluidine blue and safranin stain.