GSTHgNDD · Role of GST gene variation in susceptibility to mercury (Hg)-induced neurodevelopmental disorders (NDD) in zebrafish

Role of GST gene variation in susceptibility to mercury (Hg)-induced neurodevelopmental disorders (NDD) in zebrafish

Methylmercury (MeHg), an organic form of the heavy metal mercury, is one of the most neurotoxic environmental pollutants, demonstrated to have high potency for causing developmental neurotoxicity even at low levels. However, the role of prenatal MeHg exposure in the aetiology of neurodevelopmental disorders is controversial. While many epidemiological studies identify associations with ADHD, cognitive reduction, decrease in IQ, and ASDs, other studies attest the contrary finding of no significant association between measured mercury exposure in humans and risk for developmental neurotoxicity. This observed inconsistency is hypothesized to be the result of individual genetic variation in specific genes involved in the process of detoxification. The glutathione system plays a central role in MeHg detoxification, and the glutathione-s-transferase (GST) group of genes are key genes in this system. Recent epidemiological studies revealed that specific polymorphisms and deletions in human GST genes are associated with increased mercury retention in the body at similar exposure levels, and therefore higher risk for susceptibility to toxicity. We proposed to develop a new model for assessing the role of gene:environment interactions (GxE), specifically testing GST-related genetic predisposition for MeHg neurotoxicity, and identify early markers predictive of toxicity and behavioural impairment. We chose to use the zebrafish model, since it is a well-established model for vertebrate developmental biology and neurotoxicity studies and has important advantages over traditional rodent models for this purpose. Such advantages include robustness for conducting large experiments with strong statistical power; an embrynic development period of only 5 days after which behavioural data can be obtained; external development of transparent embryos allowing for direct exposure without maternal transfer and direct observation throughout development. Our approach was to expose wild-type and CRISPR-generated Gst mutant embryos to mercury and test whether there is genetic predisposition to increased risk for toxin-induced behavioural phenotypes. We also measured the transcriptomic effects of mercury exposure on the stress axis, the dopamine pathway and oxidative stress markers.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз