MECHANISMS OF OCCUPATIONAL DISTAL AXONOPATHY

Monomeric acrylamide is an industrially important agent which produces
central-peripheral distal axonopathy in humans and laboratory animals
following repeated exposure. Acrylamide is one of several chemically
unrelated environmental toxins which induce occupational and environmental
polyneuropathy and is a useful tool for creating and studying models of
axonal degeneration seen in human neuronal degenerative disease of unknown
etiology. Preliminary data have demonstrated that single and repeated
doses of acrylamide cause dramatic reductions in the rate of retrograde
axoplasmic transport, the means by which neuron cell bodies are informed of
the need to repair axon damage. In addition, single doses of acrylamide
markedly attenuate perikaryal markers of repair-associated gene expression
following axotomy of peripheral nerve. This study will investigate the
hypothesis that acrylamide-induced axonopathy is the result of a diminished
capacity to repair non-specific axon damage resulting from covalent binding
of acrylamide. (1) Perikaryl responses to axotomy will be utilized as a
model system to study the effects of both single and repeated doses of
acrylamide (and equimolar N,N'-methylene-bis-acrylamide) on perikaryal
repair processes. This will include measurement of a marker of gene
expression (ornithine decarboxylase), RNA synthesis, mRNA synthesis, and
synthesis of repair-specific proteins. (2) The effect of single and
repeated doses of acrylamide (and equimolar N,N'-methylene-bis-acrylamide)
on capacity for regeneration will be studied in detail using biochemical
and morphologic techniques. (3) To examine the role of altered repair
processes in acrylamide-induced axonopathy, repair processes in peripheral
segments of bipolar afferent neurons will be stimulted by central-process
transection. If decreased repair capacity is involved in the etiology of
acrylamide-induced axonopathy, stimulation of repair will markedly delay or
attenuate the pathogenesis of axonopathy. (4) In the converse of
experiment (3) above, the hypothesis that altered repair is involved in the
etiology of acrylamide-induced axonopathy will be tested by determining if
pharmacologic blockade of repair responses renders non-neurotoxic
N,N'-methylene-bis-acrylamide neurotoxic. Diminished perikaryal repair
capacity, in the presence of low-level axon damage, represents a novel
mechanism by which toxic agents may alter neuronal function or structure.
Additionally, these studies will provide detailed data regarding the means
by which neuronal repair responses are initiated and regulated. It is
expected that these studies will substantially further our understanding of
how neurotoxic agents alter normal neuronal processes to produce axonopathy.