Year-end Sale % OFF 
Abstract
The risks of methylmercury (MeHg) toxicity are greatest during early life where it has long been appreciated that the developing nervous system is an especially sensitive target. Yet, understanding the discrete mechanisms of MeHg toxicity have been obscured by the wide variation in the nature and severity of developmental outcomes that are typically seen across individuals in MeHg exposed populations. Some insight has come from studies aimed at identifying a role for genetic background as a modifier of MeHg toxicity, which have predominantly focused on factors influencing MeHg toxicokinetics, notably, polymorphisms in genes related to glutathione (GSH) metabolism. For example, variants in genes encoding the catalytic and modifier subunits of glutamyl-cysteine ligase (GCLc and GCLm), the rate limiting enzyme for GSH synthesis, have been reported to associate with Hg body burden (Hg levels in blood or hair) in humans. However, GSH can facilitate both toxicokinetics and toxicodynamics of MeHg by forming MeHg-GSH conjugates, which are readily transported and excreted, and by acting indirectly as an anti-oxidant. In this study, we refine a model to distinguish kinetic and dynamic traits of MeHg toxicity using a paradigm of Drosophotoxicolgy. First, we identify that the pupal stage is selectively sensitive to MeHg toxicity. Using a protocol of larval feeding, measurements of Hg body burden, and assays of development to adulthood (pupal eclosion), we identify strain-dependent variation in MeHg elimination as a potential kinetic determinant of differential tolerance to MeHg. We also find that global upregulation of GSH levels, with GCLc trans-gene expression, can induce MeHg tolerance and reduce Hg body burden. However, we demonstrate that MeHg tolerance can also be achieved independently of reducing Hg body burden, in both wild-derived strains and with targeted expression of GCLc in developing neuronal and muscle tissue, pointing to a robust toxicodynamic mechanism. Our findings have important implications for understanding variation in MeHg toxic potential on an individual basis and for informing the process of relating a measurement of Hg body burden to the potential for adverse developmental outcome.
Highlights
Methylmercury (MeHg) is an environmental toxicant and contaminant of seafood that arises from both natural and anthropogenic sources
Using the standard Canton S laboratory strain, we examined a variety of development endpoints subsequent to exposure to MeHg food at three distinct life stages: embryonic, larval, and adult (Figure 1A)
With MeHg exposure initiated at the first instar larval stage (L1) a dose-dependent delay in time to pupariation was seen with approximately a 1-day delay seen on 10 μM MeHg food and a 2-day delay on 20 μM MeHg food relative to untreated larvae (Figure 1C)
Summary
Methylmercury (MeHg) is an environmental toxicant and contaminant of seafood that arises from both natural and anthropogenic sources. A number of studies have demonstrated a wide variation in neurological outcomes associated with prenatal and early life MeHg exposure, ranging from none at all to measurable motor and cognitive deficits that can be persistent in children through adolescence (Grandjean et al, 1997; Murata et al, 2004; Davidson et al, 2006; Davidson et al, 2008). This wide variation of outcomes seen in humans has hampered the process of risk assessment for MeHg and has called for greater understanding of MeHg toxicity mechanisms. Variability in toxicity can stem from toxicodynamic mechanisms at the site of action, e.g., affinity for tissue-specific targets and secondary response, such as generation of reactive oxygen species (ROS), both having the potential to vary with genetic background and developmental timing
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
