Abstract
Methylmercury (MeHg) is a persistent environmental toxin present in seafood that can compromise the developing nervous system in humans. The effects of MeHg toxicity varies among individuals, despite similar levels of exposure, indicating that genetic differences contribute to MeHg susceptibility. To examine how genetic variation impacts MeHg tolerance, we assessed developmental tolerance to MeHg using the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP). We found significant genetic variation in the effects of MeHg on development, measured by eclosion rate, giving a broad sense heritability of 0.86. To investigate the influence of dietary factors, we measured MeHg toxicity with caffeine supplementation in the DGRP lines. We found that caffeine counteracts the deleterious effects of MeHg in the majority of lines, and there is significant genetic variance in the magnitude of this effect, with a broad sense heritability of 0.80. We performed genome-wide association (GWA) analysis for both traits, and identified candidate genes that fall into several gene ontology categories, with enrichment for genes involved in muscle and neuromuscular development. Overexpression of glutamate-cysteine ligase, a MeHg protective enzyme, in a muscle-specific manner leads to a robust rescue of eclosion of flies reared on MeHg food. Conversely, mutations in kirre, a pivotal myogenic gene identified in our GWA analyses, modulate tolerance to MeHg during development in accordance with kirre expression levels. Finally, we observe disruptions of indirect flight muscle morphogenesis in MeHg-exposed pupae. Since the pathways for muscle development are evolutionarily conserved, it is likely that the effects of MeHg observed in Drosophila can be generalized across phyla, implicating muscle as an additional hitherto unrecognized target for MeHg toxicity. Furthermore, our observations that caffeine can ameliorate the toxic effects of MeHg show that nutritional factors and dietary manipulations may offer protection against the deleterious effects of MeHg exposure.
Highlights
Methylmercury (MeHg) is a potent environmental neurotoxin that presents a risk to human health
Quantitative genetic analysis of natural variation in tolerance to MeHg during development To characterize natural genetic variation in tolerance and susceptibility to MeHg during development, we examined 176 Drosophila melanogaster Genetic Reference Panel (DGRP) lines in an eclosion assay on four concentrations ([MeHg] = 0, 5, 10, 15 mM, Table S3) of MeHg-containing food
Functional assessment of sensitivity of muscle development to MeHg toxicity To functionally assay developing muscle tissue as a sensitive MeHg target, we examined flies that carry a gene known to affect MeHg tolerance expressed under the muscle specific enhancer myocyte enhancing factor 2 (Mef2) [40]
Summary
Methylmercury (MeHg) is a potent environmental neurotoxin that presents a risk to human health. Clinical cases of Minamata disease, and limited samples of human fetal brain histopathology associated with them, have consolidated the notion that the developing nervous system is a target tissue for MeHg toxicity [4,5,6]. Large-scale epidemiologic studies that have investigated outcomes of prenatal MeHg exposure through seafood diets have yielded incongruent results with respect to neurological deficits [7,8]. Recent population studies have identified MeHg effects on cardiovascular factors (e.g., heart rate variability and blood pressure) [12,13] and the immune system [14,15]. There is evidence that overall fetal and infant growth rates are inversely related to prenatal MeHg exposure [16,17]. Given the prevailing focus on neural-specific mechanisms, the extent to which other developing organ systems are affected by MeHg during development has not been fully explored
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