Department of Pharmaceutical Sciences, Northeastern University, Boston, MA
02115, USA.

Methylation events play a critical role in the ability of growth factors
to promote normal development. Neurodevelopmental toxins, such as ethanol
and heavy metals, interrupt growth factor signaling, raising the
possibility that they might exert adverse effects on methylation. We found
that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated
methionine synthase (MS) activity and folate-dependent methylation of
phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and
MAP-kinase-dependent mechanism. The stimulation of this pathway increased
DNA methylation, while its inhibition increased methylation-sensitive gene
expression. Ethanol potently interfered with IGF-1 activation of MS and
blocked its effect on DNA methylation, whereas it did not inhibit the
effects of dopamine. Metal ions potently affected IGF-1 and
dopamine-stimulated MS activity, as well as folate-dependent phospholipid
methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+),
Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing
preservative thimerosal inhibited both IGF-1- and dopamine-stimulated
methylation with an IC(50) of 1 nM and eliminated MS activity. Our
findings outline a novel growth factor signaling pathway that regulates MS
activity and thereby modulates methylation reactions, including DNA
methylation. The potent inhibition of this pathway by ethanol, lead,
mercury, aluminum and thimerosal suggests that it may be an important
target of neurodevelopmental toxins.


Donna