Myelin Vacuolation Research Articles

Neurotoxicity of hexachlorophene: New pathological and biochemical observations

Twenty female rats with nursing litters were fed a diet containing 500 p.p.m. of hexachlorophene (HCP). The blood concentrations of hexachlorophene in mother rats were 4.7–6.0 μg/ml and in infant rats 2.0–2.5 μg/ml. Fifty percent of mother rats and 75% of infant rats died. Most of the surviving animals were asymptomatic apart from impaired visual function. Ten adult and 20 infant rats were killed by perfusion. Light- and electron-microscopic studies showed vacuolation of myelin in the central and peripheral nervous system and axonal degeneration which was especially severe in the optic nerves. After withdrawal of HCP hydrocephalus ex vacuo was present in the chronically intoxicated infant rats and the optic nerves showed marked atrophy and gliosis. Studies with liver mitochondria prepared from lactating hexachlorophene-fed rats showed a 50–75% inhibition of respiration with succinate as substrate.

Modification of hexachlorophene toxicity by dieldrin and Aroclor 1254

Hexachlorophene (HCP) was fed singly or paired with either aflatoxin B 1 (AF), Aroclor 1254 (AR), or dieldrin (D) to Fischer-344 rats for 8 weeks beginning at 5 weeks of age. For HCP fed singly, there was no mortality at 400 ppm or less, 80% mortality in males and 73% in females at 600 ppm, and 100% mortality in both sexes at 820 ppm. Paralysis was apparent in one female at 400 ppm and in all animals at 600 ppm. Minimal neuronal degeneration was evident in the brain at 50 ppm, focal necrosis and myelin vacuolization at 400 ppm or higher, and focal hemorrhage at 600 ppm. While addition of AF at 1 ppm did not affect the toxicity of 600 ppm of HCP, addition of AR at 160 ppm reduced mortality to less than 7%, and addition of D at 100 ppm to a diet containing 900 ppm of HCP reduced mortality from 100 to less than 4%. For both the HCP/AR and the HCP/D combinations, no paralysis was observed, although the histologic changes in the brain were still apparent.

An electron microscopic study of the early changes distal to a constriction in sympathetic nerves.

The ultrastructural changes distal to a constriction in unmyelinated postganglionic sympathetic axons have been studied in the cat splenic and hypogastric nerves at intervals up to 24h after operation. Since the immediate postoperative changes were identical with those found proximal to the lesion it was concluded that they were due to the mechanical effects of tying the ligature. Within a few hours of operation there was an accumulation of organelles immediately distal to the constriction. At all times this was greatest within 0.5 mm of the lesion and only rarely extended beyond the first 1 mm even after 24h. The organelles which accumulated included mitochondria, many of which were swollen, pleomorphic myelin figures, multi-vesicular bodies, agranular vesicles and vacuoles of various sizes. Vesicles with an electron dense core, i.e. granular vesicles did not accumulate distal to the constriction. Further from the constriction focal accumulations of some structures, in particular mitochondria and myelin figures, did occur but they were rare. In this part of the nerve there was generally a diminution in the number of organelles, and a marked alteration in the axonal morphology. Alternating swollen and narrow regions were common, and many axons were very irregular as if ‘collapsing’. While filaments and occasionally fine tubules persisted in some of these axons up to 24h after operation, there was a reduction in the endoplasmic reticulum. These findings are compared with those seen proximal to the constriction. Although there were some similarities, the absence of granular vesicles, the decrease in the axonal endoplasmic reticulum and the ‘collapse’ of the axons due to the decrease in their contents were notable differences. It is suggested that there is a differential movement of axoplasm and organelles distal to the constriction. Thus while granular vesicles and some axoplasm continue to move towards the periphery, mitochondria and a part of the axoplasm migrate proximally to the site of axonal injury and the region of maximal degenerative change. The movement of mitochondria is considered to indicate a reaction to injury rather than supporting the view that retrograde axoplasmic flow occurs in normal axons.