ATLA::Alternatives to Laboratory Animals

Volume 24, Number 3

In vitro studies of acrylamide neurotoxicity in rat pheochromocytoma (PC12) cells.

ATLA 24, 359-366, May/June 1996

Weiquan W. Lin,¹ Larry R. Johnson,² Marvin A. Friedman² and Mohamed B. Abou-Donia²

Laboratory of Neurotoxicology, Department of Pharmacology, Duke University Medical Centre, P.O. Box 3813, Durham, NC 27710; ²Cytec Industries, 5 Garret Mountain Plaza, West Paterson, NJ 07424

SUMMARY

This review discusses our studies on molecular mechanisms of acrylamide neurotoxicity by using the rat pheochromocytoma (PC12) cell line. The results showed that: a) acrylamide altered the gross morphology of PC12 cells; b) acrylamide induced neurofilament accumulation in PC12 cells; c) the effects of acrylamide on PC12 cells are consistent with its neurotoxicity in vivo; d) acrylamide stimulated neurofilament protein synthesis in PC12 cells; e) acrylamide did not act via nerve growth factor (NGF) receptor gpl40trk to regulate neurofilament synthesis in PC12 cells; f) dexamethasone antagonized NGF and/or acrylamide induced neurofilament protein synthesis and expression; and g) acrylamide differentially regulated the mRNA levels of three neurofilament subunit genes in PC12 cells. These molecular studies provide the first evidence that: a) there are distinctive and convergent signalling pathways for NGF-regulated and acrylamide-regulated neurofilament expression; b) acrylamide may differentially regulate the expression of each subunit, resulting in aberrant accumulation of neurofilament proteins, and c) there is a dexamethasone-sensitive signalling step common to NGF and acrylamide. These results could partially explain the mechanisms of neurofilament accumulation in distal axonal swellings, a pathognomonic feature of acrylamide neurotoxicity.

Keywords: acrylamide, dexamethasone, in vitro, neurofilament proteins, neurotoxicity, pheochromocytoma (PC12) cells