Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we applied our fly genetic model of galactosemia to ask whether oxidative stress contributes to the acute galactose-sensitivity of GALT-null animals. Our first approach tested the impact of pro- and anti-oxidant food supplements on the survival of GALT-null vs. control larvae. We observed a clear pattern: each of two oxidants, paraquat and DMSO, had a negative impact on the survival of mutant but not control animals exposed to galactose, and each of two anti-oxidants, vitamin C and α-mangostin, had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested, but interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose-sensitivity of GALT-null Drosophila, and by extension, suggest that reactive oxygen species may also contribute to the acute pathophysiology in classic galactosemia.
- Received May 3, 2012.
- Accepted June 24, 2012.
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