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Structural and functional alterations in the rat retina after long term exposure to two n-hexane metabolites
Exposure to the two n-hexane metabolites, 2,5-hexanedione (2,5-HD) and 2,5-hexanediol (2,5-HDol) causes swellings in the distal part of long nerve axons. This phenomenon, centralperipheral distal axonopathy, was studied using an indirect immuno-peroxidase method with monoclonal antibodies to neurofilament protein. The injuries of the axons were simply, distinctly and reproducibly demonstrated; including an observation that the excess material in the axon swellings was formed by neurofilament proteins and not by tubulin. The retinas of rats sacrificed immediately after exposure to 2,5 HD or 2,5-HDol for 5 weeks showed a reduction in thickness of the outer nuclear layer (ONL) and the outer segment (OS) and inner segment (IS) of the photoreceptors. After a post-exposure period of 13 weeks an almost completely loss of photoreceptor cells was found. Swellings of the axons innervating the iris were present in all exposed groups.
The rods were found to be more sensitive to numeric reduction than the cones. After the post exposure period of 13 weeks almost all rods had disappeared while the cones were reduced by about 50%. These findings suggest that rods are more sensitive than cones to 2,5-HD. Most of the rats had a considerably higher proportion of photoreceptors left at ora serrata, an area with limited exposure to light. This observation suggested that n-hexane metabolites might cause increased damages to retina in combination with light energy. Light from ordinary fluorescent light tubes, which contain a considerable amount of energy-rich photons from the violet-blue area of visible spectrum, was used to investigate this hypothesis.
Albino rats exposed to 2,5-HDol in the presence of light for 5-weeks exposure had lost about 30% of their photoreceptors. After a 13-week post-exposure period without 2,5-HDol a further damaging effect of 50 % was observed. There was no similar damage found after exposure to 2,5-HDol alone or to light alone or in total darkness. The results imply an interaction exceeding simple summation after exposure to light and 2,5-HDol in destroying photoreceptors in albino rats. The morphological damage progresses after removal of 2,5-HDol from the diet. Electrophysiological recordings of the electroretinogram and the visual response supported the morphological findings.
Using gaschromatography it was observed that the n-hexane metabolites penetrated blood/aqueous humor, retina barriers. 2.5-HD was accumulated in the aqueous humor, probably due to active transport. An elimination study showed that 2,5-HD in serum, retina, and aqueous humor, reached maximum concentration about I hour after the oral administration. No 2,5-HD was detected after 24 hours.
Atropine and 2,5-HD induced an increased damage to the photoreceptor cells during the postexposure period as compared to exposure to 2,5-HD alone or to atropine alone. This finding further supports that combined exposure to light and 2,5-HD induces a synergistic damage on photoreceptor cells.
The progressing loss of photoreceptors after end of exposure to n-hexane metabolites might depend on toxic products for instance pyrrols being formed in light by 2,5-HD and proteins with [epsilon]-Iysine residues. This investigation shows the influence of light on the chemical capacity of the n-hexane metabolites.
List of scientific papers
I. Bäckström B, Collins VP (1987). Cytoskeletal changes in axons of rats exposed to 2,5-hexanediol, demonstrated using monoclonal antibodies. Neurotoxicology. 8(1):85-96.
https://pubmed.ncbi.nlm.nih.gov/3561899
II. Bäckström B, Dumanski JP, Collins VP (1990). The effects of 2,5-hexanedione on the retina of albino rats. Neurotoxicology. 11(1):47-55.
https://pubmed.ncbi.nlm.nih.gov/2197579
III. Bäckströom B, Collins VP (1992). The effects of 2,5-hexanedione on rods and cones of the retina of albino rats. Neurotoxicology. 13(1):199-202.
https://pubmed.ncbi.nlm.nih.gov/1508419
IV. Bäckström B, Nylén P, Hagman M, Johnson AC, Höglund G, Collins VP (1993). Effect of exposure to 2,5-hexanediol in light or darkness on the retina of albino and pigmented rats. I. Morphology. Arch Toxicol. 67(4):277-283.
https://pubmed.ncbi.nlm.nih.gov/8517784
V. Nylén P, Bäckström B, Hagman M, Johnson AC, Collins VP, Höglund G (1993). Effect of exposure to 2,5-hexanediol in light or darkness on the retina of albino and pigmented rats. II. Electrophysiology. Arch Toxicol. 67(6):435-441.
https://pubmed.ncbi.nlm.nih.gov/8215914
VI. Bäckström B, Shibata E, Nylén P, Collins VP (1998). 2,5-Hexanedione concentrations and morphological changes within the eye of albino rat. Arch Toxicol. 72(9):597-600.
https://pubmed.ncbi.nlm.nih.gov/9806432
History
Defence date
1999-12-10Department
- Department of Physiology and Pharmacology
Publication year
1999Thesis type
- Doctoral thesis
ISBN-10
91-7045-533-3Number of supporting papers
6Language
- eng