Structural and functional alterations in the rat retina after long term exposure to two n-hexane metabolites
Author: Bäckström, Birgitta
Date: 1999-12-10
Location: Föreläsningssalen, Fysiologiska institutionen, Karolinska Institutet
Time: 9.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
Abstract
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 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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
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
Pubmed
Issue date: 1999-11-19
Publication year: 1999
ISBN: 91-7045-533-3
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