Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

Abstract

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 methylationsensitive 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 þ promoted enzyme activity and methylation, while Cu þ , Pb 2 þ , Hg 2 þ and Al 3 þ 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.

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…In neural cells lines IGF-1 also regulates the activity of methionine synthase, an enzyme that converts homocysteine to methyionine, which may serve as a methyl donor [159]. Moreover, in the same study by Waly et al [159] IGF-1 was able to increase global methylation in the neural cell line. Thus, IGF-1 has the capacity to activate DNA methylation and/or acetylation in neural tissues, and changes in the expression or level of IGF-1 protein would affect its ability to modify epigenetic processes.…”

“…Interestingly, IGF-1 can stimulate histone H3 and H4 acetylation in the nervous system, and a causal relationship was established between overexpression of IGF-1 in cortex and hippocampus (hypothalamus was not studied) and this epigenetic process [151]. In neural cells lines IGF-1 also regulates the activity of methionine synthase, an enzyme that converts homocysteine to methyionine, which may serve as a methyl donor [159]. Moreover, in the same study by Waly et al [159] IGF-1 was able to increase global methylation in the neural cell line.…”

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

“…Further, immune response genes may be linked to other heritable factors mediating toxin-induced CNS damage, such as systems regulating antioxidant 45 or DNA methylation 46 status, apoptosis pathways, 47 glutamatergic transmission or excitotoxicity, 48 metallothionein isoforms, 49 or proinflammatory cytokine responses. 50 As a central role is implicated for the Th1-type cytokine, interferon-g (IFN-g), in mercuryinduced autoimmunity 51 and general autoimmune disease susceptibility, 52 we included C57 mice in our strain comparison; similar to SJL mice, C57 mice show a Th1-type cytokine predominance, including increased levels of IFN-g gene expression at baseline, 53 yet are less sensitive than SJL mice to autoimmune sequelae following mercury or other Th1-dependent, autoimmunity-provoking challenges.…”

Monocyte Differentiation, Activation, and Mycobacterial Killing Are Linked to Transsulfuration-dependent Redox Metabolism

“…The reaction was terminated, cells were harvested, and phospholipids were isolated by following a procedure described previously (22). Radioactivity recorded as disintegrations/min was normalized to the protein concentration in each sample.…”