Lead, mercury, thimerosal, aluminum all inhibit methionine synthase and methylation

[Guest guest]

Activation of methionine synthase by insulin-like growth factor-1 and dopamine:

a target for neurodevelopmental toxins and thimerosal,

Waly M , Olteanu H , Banerjee R , Choi SW , Mason JB , BS , Sukumar S ,

Shim S , Sharma A , Benzecry JM , Power-Charnitsky VA , Deth RC .       Mol

Psychiatry. 2004 Apr;9(4):358-70

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.