Effect of phenylalanine and its metabolites on the proliferation and viability of neuronal and astroglial cells: Possible relevance in maternal phenylketonuria

Phenylketonuria is a genetic defect that, without strict dietary control, r esults in the accumulation of phenylalanine (Phe) in body fluids. If a low- Phe diet is not maintained during pregnancy, the offspring of phenylketonur ic women are born with mental retardation and microcephaly. Primary culture s of rat cerebellar granule cells, rat cortical astrocytes, human fetal ast rocytes, and human neuroblastoma (SY5Y) cells and human astrocytoma (1321N1 ) cells were used to test the hypothesis that the microencephaly may be a r esult of neuronal cell death and reduced astrocyte proliferation. Exposure to Phe or to six Phe metabolites [phenylacetic acid (PAA), phenyllactic aci d, hydroxyphenylacetic acid, phenylpyruvic acid, phenylethylamine (PEA), an d mandelic acid] did not result in astroglial or neuronal cell cytotoxicity . Treatment of 1321N1 cells, human fetal astrocytes, or rat astrocytes with 5 mM Phe for 24 h decreased DNA synthesis 19 +/- 4, 30 +/- 4, and 60 +/- 6 %, respectively. This effect was concentration dependent, and flow cytometr y revealed that Phe treatment resulted in the accumulation of cells in the G(0)/G(1) phase of the cell cycle. In addition, in 1321N1 cells, exposure t o 5 mM PAA, and in rat astrocytes, exposure to 0.5 mM PEA inhibited cell pr oliferation 42 +/- 4 and 55 +/- 4%, respectively. These metabolites also re sulted in the accumulation of cells in the G(0)/G(1) phase of the cell cycl e. In human fetal astrocytes, 0.5 mM PEA and 0.5 mM PAA resulted in a 41 +/ - 12 and 52 +/- 11% reduction proliferation, respectively.