Acrylamide

MECHANISMS OF ACTION

Since acrylamide is water soluable and diffuses easily, it is readily absorbed through the intestinal tract, the skin, the lungs and the placental barrier. Acrylamide’s mechanism of action is greatly enhanced through its wide distribution in body fluids and fairly even distribution throughout body organs. (46) Despite acrylamide’s rapid metabolism and excretion following exposure, its high reactivity with proteins could be the reason it is hazardous to workers.

BIOTRANSFORMATION
Acrylamide biotransformation is thought to occur through glutathione conjugation and decarboxylation.

METABOLITES
Four urinary metabolites have been found in rat urine along with N-acetyl-S-cystein accounting for 48% of oral doses, 2% unmetabolized acrylamide, and three non-sulfur-containing metabolites 14%.

Acrylamide and its metabolites can accumulate in the body if they are bound to protein in nervous system tissues or hemoglobin in blood.

In the body, acrylamide is transformed to glycinamide (Figure 4), a more toxic molecule, by enzymes known as microsomal oxidases. Glycidamide can bind directly to DNA, but its mutagenic potential has been poorly studied. If acrylamide or glycinamide is conjugated to glutathione it is excreted from the body.


Figure 4. Acrylamide and metabolite, glycidamide. (45)

GENOTOXIC
It is thought that although acrylamide has gene interactions it affects chromosomal aberrations or clastogenicity rather than DNA mutations. However, there is no evidence that acrylamide does not produce detectable gene mutations. Regardless of the specific mechanism of interacting with genes, acrylamide has been classified as being genotoxic. Because glycidamide also binds to DNA, it has been hypothesized to be the actual agent of toxicity.
The genotoxic effects in rodents affect mainly germinal tissue and do not affect somatic cells in the same way. The positive gene test that acrylamide tested positive are the dominant lethal test, mammalian spot test, heritable translocation assay, and the specific locus test. Acrylamide is inactive in tests for gene mutations such as the CHO/HGPRT test. (51)

CARCINOGENAITY
In 1988, studies were done that found that acrylamide is an initiator in conjunction with tumor-promoting agents such as 12-O-tetradecanoylphorbol-13-acetate, which causes acceleration of the appearance of skin tumors and lung tumors in various strains. The mode of action of tumors is thought to involve binding acrylamide to dopamine receptors. When acrylamide is present the appearance of background tumors in rats and mice accelerates. Cell proliferation in the skin and lung is believed to be cause by either the partial dopamine agonist activity of acrylamide or modulation of hormone levels.

REPRODUCTI VE TOXICITY
It has also been demonstrated that acrylamide accumulates in the liver and kidney as well as in the male reproductive system. There are two mechanisms of action in reproductive toxicity . The first is that acrylamide or glycidamide cause dominant lethality and effects sperm morphology by binding to spermatid protamines. The second is that acrylamide affects the mating process where rats have hindlimb weakness and are unable to mount, the sperm cannot move or intromission. This involves acrylamide binding to motor proteins, causing distal axonopthy. Based on reproductive studies, glycidamide mutations are not the bases of reproductive effects. (47)

NEUROTOXICITY
It is probable that acrylamide enters the neuron at the neuromuscular junction by pinocytosis and then binds to tubulin sulfhydryl groups in the axon resulting in disassembly of microtubules and consequent disruption of retrograde transport. Another theory is that water and altered neuronal calcium homeostasis interferes with calmodulin-dependent enzymes and phosphorylation of cytoskeleton proteins. Other mechanistic theories include deregulation of axonal and or Schwann cell elements. Acrylamide may also alter neurotransmitter concentration and function thereby mediating some of its CNS effects. (49)
Acrylamide and glycidamide have been shown to bind to dopamine receptors and spermatid protamines. They inhibit the activity of kinesin and dyneine, which are involved in trans-axonal transport. As a result they interference with neuronal intracellular transport, transport of nerve growth factor from the distal axon, the transport of organelles and nutrients from the cell body to the distal axon and sperm motility. The cell is unable to function and the dying back of nerves result.