Common and divergent features of galactose-1-phosphate and fructose-1-phosphate toxicity in yeast.

Metabolic dysregulation leading to sugar-phosphate accumulation is toxic in organisms ranging from bacteria to humans. By comparing two models of sugar-phosphate toxicity in Saccharomyces cerevisiae, we demonstrate that toxicity occurs, at least in part, through multiple, isomer-specific mechanisms, rather than a single general mechanism.

Galactose and its Metabolites Deteriorate Metaphase II Mouse Oocyte Quality and Subsequent Embryo Development by Disrupting the Spindle Structure.

Premature ovarian insufficiency (POI) is a frequent long-term complication of classic galactosemia. The majority of women with this disorder develop POI, however rare spontaneous pregnancies have been reported. Here, we evaluate the effect of D-galactose and its metabolites, galactitol and galactose 1-phosphate, on oocyte quality as well as embryo development to elucidate the mechanism through which these compounds mediate oocyte deterioration. Metaphase II mouse oocytes (n = 240), with and without cumulus cells (CCs), were exposed for 4 hours to D-galactose (2 µM), galactitol (11 µM) and galactose 1-phosphate (0.1 mM), (corresponding to plasma concentrations in patients on galactose-restricted diet) and compared to controls. The treated oocytes showed decreased quality as a function of significant enhancement in production of reactive oxygen species (ROS) when compared to controls. The presence of CCs offered no protection, as elevated ROS was accompanied by increased apoptosis of CCs. Our results suggested that D-galactose and its metabolites disturbed the spindle structure and chromosomal alignment, which was associated with significant decline in oocyte cleavage and blastocyst development after in-vitro fertilization. The results provide insight into prevention and treatment strategies that may be used to extend the window of fertility in these patients.

Galactose toxicity in animals.

In most organisms, productive utilization of galactose requires the highly conserved Leloir pathway of galactose metabolism. Yet, if this metabolic pathway is perturbed due to congenital deficiencies of the three associated enzymes, or an overwhelming presence of galactose, this monosaccharide which is abundantly present in milk and many non-dairy foodstuffs, will become highly toxic to humans and animals. Despite more than four decades of intense research, little is known about the molecular mechanisms of galactose toxicity in human patients and animal models. In this contemporary review, we take a unique approach to present an overview of galactose toxicity resulting from the three known congenital disorders of galactose metabolism and from experimental hypergalactosemia. Additionally, we update the reader about research progress on animal models, as well as advances in clinical management and therapies of these disorders.

Galactosemia: how does long-term treatment change the outcome?

In galactosemic subjects, treatment prevents liver and kidney failure, brain damage and cataracts, but total exclusion of galactose from the diet does not ensure the absence of all pathology. Early and well-treated children show satisfactory general health and growth, make reasonable though suboptimal intellectual progress, are prone to speech defects, and commonly experience visual perceptual difficulties and some social maladjustment. Two different metabolites are potentially toxic: galactitol is responsible for the cataracts while galactose-1-phosphate causes the rest of the pathology. As both metabolites are present in the fetus and in postnatal life, pathological changes may develop at any time in life, even when treatment is strict. Owing to UDP-galactose 4'-epimerase, man can generate galactose from glucose from early embryonic life on. Therefore, transferase-deficient individuals can form galactose-1-phosphate in the absence of exogenous galactose, a process for which UDP-glucose pyrophosphorylase is essential. Biosynthesis of galactose from glucose in well-treated galactosemics constitutes a mechanism of self-intoxication, not only in utero but also in adult life. The prognosis for some treated galactosemics may depend on their own ability to limit this process. Galactosemic girls, whether well-treated or not, run a considerable risk of developing ovarian dysfunction. Hypergonadotropinism has been diagnosed from 2 years of age to the third decade. Prenatal ovarian failure is not excluded but the observed facts suggest that ovarian failure is acquired after ovarian differentiation and initiation of folliculogenesis, at an individual rate and possibly through continuous self-intoxication with galactose-1-phosphate. Up to now, mild hypergonadotropinism has been documented in only 2 galactosemic males, but the male cohort of galactosemics studied for gonadal dysfunction is yet small.