Mercury-induced toxicity: Mechanisms, molecular pathways, and gene regulation.

Mercury is a well-known neurotoxicant for humans and wildlife. The epidemic of mercury poisoning in Japan has clearly demonstrated that chronic exposure to methylmercury (MeHg) results in serious neurological damage to the cerebral and cerebellar cortex, leading to the dysfunction of the central nervous system (CNS), especially in infants exposed to MeHg in utero. The occurrences of poisoning have caused a wide public concern regarding the health risk emanating from MeHg exposure; particularly those eating large amounts of fish may experience the low-level and long-term exposure. There is growing evidence that MeHg at environmentally relevant concentrations can affect the health of biota in the ecosystem. Although extensive in vivo and in vitro studies have demonstrated that the disruption of redox homeostasis and microtube assembly is mainly responsible for mercurial toxicity leading to adverse health outcomes, it is still unclear whether we could quantitively determine the occurrence of interaction between mercurial and thiols and/or selenols groups of proteins linked directly to outcomes, especially at very low levels of exposure. Furthermore, intracellular calcium homeostasis, cytoskeleton, mitochondrial function, oxidative stress, neurotransmitter release, and DNA methylation may be the targets of mercury compounds; however, the primary targets associated with the adverse outcomes remain to be elucidated. Considering these knowledge gaps, in this article, we conducted a comprehensive review of mercurial toxicity, focusing mainly on the mechanism, and genes/proteins expression. We speculated that comprehensive analyses of transcriptomics, proteomics, and metabolomics could enhance interpretation of "omics" profiles, which may reveal specific biomarkers obviously correlated with specific pathways that mediate selective neurotoxicity.

Methylmercury induces ectopic expression of complement components and apoptotic cell death in the retina of the zebrafish embryo.

Methylmercury (MeHg) is a well-known neurotoxin of humans and wildlife. Visual impairments, including blindness, are frequently present in human patients with MeHg poisoning and in affected animals. It is widely assumed that MeHg-induced damage to the visual cortex is the sole or primary cause of vision loss. MeHg has been shown to accumulate in the outer segments of photoreceptor cells, and to alter the thickness of the inner nuclear layer of the fish retina. However, it is unclear whether the bioaccumulated MeHg has direct deleterious effects on the retina. Herein we report that the genes encoding complement components 5 (c5), c7a, c7b, and c9 were ectopically expressed in the inner nuclear layer of the retinas of zebrafish embryos exposed to MeHg (6-50 µg/L). The numbers of apoptotic cell deaths scored in the retinas of MeHg-treated embryos significantly increased in a concentration-dependent manner. In comparison with cadmium and arsenic, ectopic expression of c5, c7a, c7b, and c9, and the observed apoptotic cell death in the retina were specific to MeHg exposure. Our data provide evidence supporting the hypothesis that MeHg has deleterious impacts on the retinal cells, especially the inner nuclear layer. We propose that MeHg-induced retinal cell death may trigger the activation of the complement system.

Toxicogenomic signatures associated with methylmercury induced developmental toxicity in the zebrafish embryos.

Methylmercury (MeHg) is a toxicant with adverse effects on embryogenesis from fish to man. The developmental outcomes of MeHg are well understood, but molecular understanding of toxicity is rather limited. We performed here a genome-wide transcriptional analyses of 6, 30, and 50 µg/L MeHg exposed zebrafish embryos from 4 to 72 h post-fertilization (hpf) using RNA-sequencing and microarray, and conducted a systematical comparison of MeHg-induced transcriptomic responses reported in this and our previous studies. We observed MeHg significantly to disrupt expression of 1050, 1931, and 2996 genes, respectively including gene ontologies in terms of visual and sensory perception, phototransduction, ferroptosis, and GABAergic synapse. Significantly altered genes were associated with ontology categorized into metabolism, such as fatty acid, amino acid, and glutathione metabolism across all experiments. Expression of genes involved in Wnt, Shh, and Notch signaling pathways previously demonstrated to be crucial for development was changed at varying levels dependent on exposure concentrations and durations. Our findings show MeHg significantly to affect expression of genes associated with tissue and/or organs developmental processing including eye, lateral line, fins, and brain, especially in embryos exposed to 6 µg/L, which did not cause obviously toxic effects on zebrafish embryos. We obtain 21 genes being significantly altered by MeHg in a concentration and stage independent manner, and might be served as signatures for developmental toxicity and/or teratogenic effects.