Methylmercury Toxicity Research Articles

Development of a sensor to detect methylmercury toxicity

Methylmercury (MeHg) is a well-known neurotoxicant that induces various cellular functions depending on cellular- and developmental-specific vulnerabilities. MeHg has a high affinity for selenol and thiol groups, thus impairing the antioxidant system. Such affinity characteristics of MeHg led us to develop sensor vectors to assess MeHg toxicity. In this study, MeHg-mediated defects in selenocysteine (Sec) incorporation were demonstrated using thioredoxin reductase 1 cDNA fused with the hemagglutinin tag sequence at the C-terminus. Taking advantage of such MeHg-mediated defects in Sec incorporation, a cDNA encoding luciferase with a Sec substituted for cysteine-491 was constructed. This construct showed MeHg-induced decreases in signaling in a dose-dependent manner. To directly detect truncated luciferase under MeHg exposure, we further constructed a new sensor vector fused with a target for proteasomal degradation. However, this construct was inadequate because of the low rate of Sec insertion, even in the absence of MeHg. Finally, a Krab transcriptional suppressor fused with Sec was constructed and assessed to demonstrate MeHg-dependent increases in signal intensity. We confirmed that the vector responded specifically and in a dose-dependent manner to MeHg in cultured cerebellar granule cells. This vector is expected to allow monitoring of MeHg-specific toxicity via spatial and temporal imaging.

JAK2/STAT3 signaling pathway mediates methylmercury toxicity in mouse astrocyte neuronal C8-D1A cell line.

Methylmercury (MeHg) is an environmental pollutant. Consumption of contaminated fish is the main exposure route in humans, leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes disrupting glutamate and calcium homeostasis and increasing oxidative stress. Despite extensive research, the molecular mechanisms underlying MeHg neurotoxicity remain incompletely understood. The induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role activating antioxidant responses during MeHg-induced oxidative injury have garnered significant attention as a potential therapeutic target against MeHg toxicity. However, recent studies indicate that the Nrf2 signaling pathway alone may not be sufficient to mitigate MeHg-induced damage, suggesting the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) plays a crucial role in cell growth and survival. Several studies have also highlighted its involvement in regulating redox homeostasis, thereby preventing oxidative stress through mechanisms that involve modulation of nuclear genes that encode electron transport complexes (ETC) and antioxidant enzymes. These characteristics suggest that STAT3 could serve as a viable mechanism to mitigate MeHg toxicity, either in conjunction with or as an alternative to Nrf2 signaling. Our previous findings demonstrated that MeHg activates the STAT3 signaling pathway in the GT1-7 hypothalamic neuronal cell line, suggesting its potential role in promoting neuroprotection. Here, to elucidate the role of the STAT3 signaling pathway in MeHg neurotoxicity, we pharmacologically inhibited STAT3 using AG490 in the C8D1A astrocytic cell line exposed to 10 µM MeHg. Our data demonstrated that pharmacological inhibition of STAT3 phosphorylation exacerbates MeHg-induced mortality, antioxidant responses, and ROS production, suggesting that STAT3 may contribute to neuroprotection against MeHg exposure in astrocytes.

Exploring developmental MeHg impact on extraembryonic and cardiac vessels and its effect on cardiomyocyte contractility.

The toxicity of methylmercury (MeHg) during embryonic development is a relevant issue that remains unclear and deserves investigation. In this sense, there is evidence that links the intake of contaminated food with cardiovascular pathologies in human adults and children. Thus, this study aimed to verify the impact of MeHg on the structure and integrity of extraembryonic and cardiac blood vessels and the contractile function of cardiomyocytes, also evaluating embryonic weight and the cardiosomatic index (CSI). Thus, chicken embryos, used as an experimental model, were exposed to a single dose of 0.1μg MeHg/50 μl saline at E1.5 and analyzed at E10. After exposure, an increase in the number of extraembryonic blood vessels and the veins of the cardiac tissue was observed. These increases were accompanied by a reduction in the content of VEGF and VCAM proteins related to vessel growth and adhesiveness. Together, these results were related to reduced nitrite (NOx) levels. Furthermore, MeHg reduces the number of sarcomeres and increases the content of cardiac troponin I (cTnI), a protein that regulates contraction. In general, exposure to MeHg affected the integrity of extraembryonic and cardiac vessels and the contractile function of cardiomyocytes, which had a systemic impact evidenced by the reduction in embryonic weight gain and CSI.

Methylmercury Induces Apoptosis in Mouse C17.2 Neural Stem Cells through the Induction of OSGIN1 Expression by NRF2.

Methylmercury is a known environmental pollutant that exhibits severe neurotoxic effects. However, the mechanism by which methylmercury causes neurotoxicity remains unclear. To date, we have found that oxidative stress-induced growth inhibitor 1 (OSGIN1), which is induced by oxidative stress and DNA damage, is also induced by methylmercury. Therefore, in this study, we investigated the relationship between methylmercury toxicity and the induction of OSGIN1 expression using C17.2 cells, which are mouse brain neural stem cells. Methylmercury increased both OSGIN1 mRNA and protein levels in a time- and concentration-dependent manner. Moreover, these increases were almost entirely canceled out by pretreatment with actinomycin D, a transcription inhibitor. Furthermore, similar results were obtained from cells in which expression of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) was suppressed, indicating that methylmercury induces OSGIN1 expression via NRF2. Methylmercury causes neuronal cell death by inducing apoptosis. Therefore, we next investigated the role of OSGIN1 in methylmercury-induced neuronal cell death using the activation of caspase-3, which is involved in apoptosis induction, as an indicator. As a result, the increase in cleaved caspase-3 (activated form) induced by methylmercury exposure was decreased by suppressing OSGIN1, and the overexpression of OSGIN1 further promoted the increase in cleaved caspase-3 caused by methylmercury. These results suggest, for the first time, that OSGIN1 is a novel factor involved in methylmercury toxicity, and methylmercury induces apoptosis in C17.2 cells through the induction of OSGIN1 expression by NRF2.

Concerns for Human Health Relating to Methylmercury (MeHg) Toxicity in Aquatic Environment: A Systematic Literature Review

Mercury poses serious health risks to people, and during the last century, its contamination of the ocean's surface has more than doubled. As a result, authorities and organizations have taken measures to shield people from exposure to this dangerous substance. Mercury pollution mainly comes from many anthropogenic activities, such as burning coal and other industrial processes. In addition to polluting food chains in marine and coastal ecosystems, these operations released mercury into the environment, which subsequently accumulated in fish and was ingested by people. Fish eating from marine, estuarine, and freshwater sources is to blame for more than 90% of MeHg (methylmercury) exposure in the United States and most other regions of the world. This systematic review describes the biotransformation of Hg into MeHg, the entry of MeHg into the aquatic food chain/food web, and the bioaccumulation process of MeHg. This article also describes MeHg toxicity in fish. It focuses on the effects of exposure to MeHg on biochemical, histological, and neurological outcomes in humans, as evident from various epidemiological sources.

P21-19: Reappraisal of binary contradictions in methylmercury toxicity in neurons

P21-19: Reappraisal of binary contradictions in methylmercury toxicity in neurons

Variation in habitat use and its consequences for mercury exposure in two Eastern Ontario bat species, Myotis lucifugus and Eptesicus fuscus.

The St. Lawrence River in Eastern Ontario, Canada, has been a designated an area of concern due to past industrial contamination of sediment in some areas and transport of mercury from tributaries. Previous research using bats as sentinel species identified elevated concentrations of total mercury (THg) in fur of local bats and species-specific variation between little brown bats (Myotis lucifugus) and big brown bats (Eptesicus fuscus). Here, we investigated the mercury exposure pathways for these two species by testing the hypothesis that diet variation, particularly the reliance on aquatic over terrestrial insects, is a determinant of local bat mercury concentrations. We analyzed THg concentration and stable isotope ratios of δ15N and δ13C in fur of little and big brown bats, and in aquatic and terrestrial insects. Big brown bats, especially males, accumulated significantly higher THg concentrations in their fur compared to little brown bats. However, this difference was not related to diet because big brown bats consumed terrestrial insects, which were lower in mercury than aquatic insects, the primary prey for little brown bats. We also evaluated whether fur THg concentrations translate into molecular changes in tissues linked to (methyl)mercury toxicity by quantifying tissue changes in global DNA methylation and mitochondrial DNA abundance. No significant changes in DNA molecular markers were observed in relation to fur THg concentration, suggesting mercury exposure to local bats did not impact molecular level changes at the DNA level. Higher mercury in bats was not associated with local aquatic contamination or genotoxicity in this study area.

Effects of low doses of methylmercury (MeHg) exposure on definitive endoderm cell differentiation in human embryonic stem cells.

Fetal development is one of the most sensitive windows to methylmercury (MeHg) toxicity. Laboratory and epidemiological studies have shown a dose-response relationship between fetal MeHg exposure and neuro performance in different life stages from infants to adults. In addition, MeHg exposure has been reported to be associated with disorders in endoderm-derived organs, such as morphological changes in liver cells and pancreatic cell dysfunctions. However, the mechanisms of the effects of MeHg on non-neuronal organs or systems, especially during the early development of endoderm-derived organs, remain unclear. Here we determined the effects of low concentrations of MeHg exposure during the differentiation of definitive endoderm (DE) cells from human embryonic stem cells (hESCs). hESCs were exposed to MeHg (0, 10, 100, and 200nM) that covers the range of Hg concentrations typically found in human maternal blood during DE cell induction. Transcriptomic analysis showed that sub-lethal doses of MeHg exposure could alter global gene expression patterns during hESC to DE cell differentiation, leading to increased expression of endodermal genes/proteins and the over-promotion of endodermal fate, mainly through disrupting calcium homeostasis and generating ROS. Bioinformatic analysis results suggested that MeHg exerts its developmental toxicity mainly by disrupting ribosome biogenesis during early cell lineage differentiation. This disruption could lead to aberrant growth or dysfunctions of the developing endoderm-derived organs, and it may be the underlying mechanism for the observed congenital diseases later in life. Based on the results, we proposed an adverse outcome pathway for the effects of MeHg exposure during human embryonic stem cells to definitive endoderm differentiation.

Assessing the role of the gut microbiome in methylmercury demethylation and elimination in humans and gnotobiotic mice.

The risk of methylmercury (MeHg) toxicity following ingestion of contaminated foodstuffs (e.g., fish) is directly related to the kinetics of MeHg elimination among individuals. Yet, the factors driving the wide range of inter-individual variability in MeHg elimination within a population are poorly understood. Here, we investigated the relationship between MeHg elimination, gut microbiome demethylation activity, and gut microbiome composition using a coordinated human clinical trial and gnotobiotic mouse modeling approach together with metagenomic sequence analysis. We first observed MeHg elimination half-lives (t1/2) ranging from 28 to 90days across 27 volunteers. Subsequently, we found that ingestion of a prebiotic induced changes in the gut microbiome and mixed effects (increased, decrease, and no effect) on elimination in these same individuals. Nonetheless, elimination rates were found to correlate with MeHg demethylation activity in cultured stool samples. In mice, attempts to remove the microbiome via generation of germ-free (GF) animals or through antibiotic (Abx) treatment both diminished MeHg demethylation to a similar extent. While both conditions substantially slowed elimination, Abx treatment resulted in significantly slower elimination than the GF condition, indicating an additional role for host-derived factors in supporting elimination. Human fecal microbiomes transplanted to GF mice restored elimination rates to that seen in control mice. Metagenomic sequence analysis of human fecal DNA did not identify genes encoding proteins typically involved in demethylation (e.g., merB, organomercury lyase). However, the abundance of several anaerobic taxa, notably Alistipes onderdonkii, were positively correlatedwith MeHg elimination. Surprisingly, mono-colonization of GF free mice with A. onderdonkii did not restore MeHg elimination to control levels. Collectively, our findings indicate the human gut microbiome uses a non-conventional pathway of demethylation to increase MeHg elimination that relies on yet to be resolved functions encoded by the gut microbes and the hostClinical Trial NCT04060212, prospectively registered 10/1/2019.

Evaluation of The Ameliorative Effect of Green Tea Versus Berberine on Methyl Mercury Toxicity of Cerebellum in Adult Male Albino Rats, Histological & Immunohistochemical Study.

Evaluation of The Ameliorative Effect of Green Tea Versus Berberine on Methyl Mercury Toxicity of Cerebellum in Adult Male Albino Rats, Histological & Immunohistochemical Study.

Maternal methylmercury exposure during early-life periods adversely affects mature enamel structure of offspring rats at human exposure levels: a concern for oral health.

Although there are many studies on the health effects of methylmercury (MeHg) toxicity during in utero and early development, little is known about its effects on mineralized tissues present in the oral cavity, such as enamel structure. Therefore, this study evaluated the effects of MeHg exposure on the physico-chemical, ultrastructural and functional properties of mature tooth enamel. Specifically, we studied offspring of mothers exposed to MeHg during the prenatal and postnatal periods which are the developmental stages associated with tooth enamel formation. Female rats were exposed to MeHg at a dose of 40 μg/kg/day for 42 days of pregnancy and lactation. The enamel of offspring was analyzed by (1) Fourier Transform Infrared Spectroscopy and Raman to assess physicochemical composition, (2) Scanning Electron Microscopy for ultrastructural evaluation, (3) Transmitted Polarizing Light Microscopy for analysis of the enamel extracellular matrix, and (4) resistance and hardness were evaluated by microhardness. The results showed that MeHg exposure during this sensitive enamel formation period induced changes in inorganic and organic content and enamel prisms ultrastructure alterations and disturbed the organic extracellular matrix due to a decreased enamel strength. These novel findings establish for the first time that maternal exposure to MeHg pre and postnatal promoted relevant changes in mature enamel of their offspring rats.

Methylmercury directly modifies the 105th cysteine residue in oncostatin M to promote binding to tumor necrosis factor receptor 3 and inhibit cell growth.

We previously found that methylmercury induces expression of oncostatin M (OSM), which is released extracellularly and binds to tumor necrosis factor receptor 3 (TNFR3), possibly enhancing its own toxicity. However, the mechanism by which methylmercury causes OSM to bind to TNFR3 rather than to its known receptors, OSM receptor and LIFR, is unknown. In this study, we aimed to elucidate the effect of methylmercury modification of cysteine residues in OSM on binding to TNFR3. Immunostaining of TNFR3-V5-expressing cells suggested that methylmercury promoted binding of OSM to TNFR3 on the cell membrane. In an in vitro binding assay, OSM directly bound to the extracellular domain of TNFR3, and this binding was promoted by methylmercury. Additionally, the formation of a disulfide bond in the OSM molecule was essential for the binding of both proteins, and LC/MS analysis revealed that methylmercury directly modified the 105th cysteine residue (Cys105) in OSM. Next, mutant OSM, in which Cys105 was replaced by serine or methionine, increased the binding to TNFR3, and a similar effect was observed in immunoprecipitation using cultured cells. Furthermore, cell proliferation was inhibited by treatment with Cys105 mutant OSMs compared with wildtype OSM, and this effect was cancelled by TNFR3 knockdown. In conclusion, we revealed a novel mechanism of methylmercury toxicity, in which methylmercury directly modifies Cys105 in OSM, thereby inhibiting cell proliferation via promoting binding to TNFR3. This indicates a chemical disruption in the interaction between the ligand and the receptor is a part of methylmercury toxicity.

Apitoxin alleviates methyl mercury-induced peripheral neurotoxicity in male rats by regulating dorsal root ganglia neuronal degeneration and oxidative stress

Methylmercury (MeHg) toxicity is associated with extensive neuronal degeneration of dorsal root ganglia (DRG). This study aimed to assess the ameliorative effect of bee venom (BV) on methyl mercury chloride (MeHgCl)-induced peripheral neurotoxicity using DRGs in rats. Forty-eight adult male Sprague Dawley rats were allocated into four equal groups: G I: control (gavaged MilliQ water 1 ml/rat), G II: subcutaneously injected with BV (0.5 mg/kg b.wt), G III: gavaged MeHgCl (6.7 mg/kg b.wt), and G IV: received MeHgCl+BV. Dosing was done five times/week for 2 weeks. Ataxic behavior and visual impairments were significantly increased, whereas the movement behavior and motility gait were suppressed in the MeHgCl group. MeHgCl significantly decreased total antioxidant capacity (TAC) in DRG and significantly decreased the serum levels of glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Tumor necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β) levels were significantly elevated, whereas interleukin 10 (IL-10) levels were significantly decreased in the MeHgCl group compared with the control group. DRGs of the MeHgCl-exposed rats showed pyknotic shrunken neurons with perineural vacuolations, demyelination of nerve axons, and proliferation of the satellite cells. MeHgCl significantly induced a higher positive index ratio of Iba-1, SOX10, neurofilament, pan-neuron, and vimentin immunostaining in the DRG. BV administration significantly mitigated the MeHgCl-induced alterations in oxidative stress-related indices. BV modified the immunostaining of Iba-1, SOX10, neurofilament, pan-neuron, and vimentin-positive index ratio in the DRG of the MeHgCl group. Our findings acknowledged that BV could enhance in vivo neuroprotective effects against MeHgCl-induced DRGs damage in male rats.

Evidence on Neurotoxicity after Intrauterine and Childhood Exposure to Organomercurials.

Although the molecular mechanisms underlying methylmercury toxicity are not entirely understood, the observed neurotoxicity in early-life is attributed to the covalent binding of methylmercury to sulfhydryl (thiol) groups of proteins and other molecules being able to affect protein post-translational modifications from numerous molecular pathways, such as glutamate signaling, heat-shock chaperones and the antioxidant glutaredoxin/glutathione system. However, for other organomercurials such as ethylmercury or thimerosal, there is not much information available. Therefore, this review critically discusses current knowledge about organomercurials neurotoxicity-both methylmercury and ethylmercury-following intrauterine and childhood exposure, as well as the prospects and future needs for research in this area. Contrasting with the amount of epidemiological evidence available for methylmercury, there are only a few in vivo studies reporting neurotoxic outcomes and mechanisms of toxicity for ethylmercury or thimerosal. There is also a lack of studies on mechanistic approaches to better investigate the pathways involved in the potential neurotoxicity caused by both organomercurials. More impactful follow-up studies, especially following intrauterine and childhood exposure to ethylmercury, are necessary. Childhood vaccination is critically important for controlling infectious diseases; however, the safety of mercury-containing thimerosal and, notably, its effectiveness as preservative in vaccines are still under debate regarding its potential dose-response effects to the central nervous system.

Proteasome and p62/SQSTM1 are involved in methylmercury toxicity mitigation in mouse embryonic fibroblast cells.

Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that targets ubiquitinated substrates to undergo autophagy and plays a key role in ameliorating MeHg toxicity. p62 also delivers ubiquitinated substrates to proteasomes. However, the role of these degradation systems in mitigating MeHg toxicity remains unknown. Herein, we explored the impact of the proteasome inhibitor MG132 on MeHg toxicity and examined the toxicity of co-treatment with MG132 and MeHg in p62KO mouse embryonic fibroblasts (MEFs) by analyzing cell viability, immunoblotting, mRNA levels, immunofluorescence, and the mercury content. The proteasome inhibitor MG132 enhanced MeHg-induced cytotoxicity while reducing intracellular mercury levels in MEFs. Co-treatment with MG132 and MeHg markedly increased levels of p62 and ubiquitinated proteins. Furthermore, co-treatment with MG132 and MeHg reduced p62KO MEF viability compared to that of wild-type MEFs. Our findings suggest that the proteasome participates in mitigating MeHg cytotoxicity, while p62 may play an important role in transporting MeHg-induced ubiquitinated proteins to the proteasome, as well as in autophagy. Collectively, these results imply that p62, and proteasome, and autophagy are vital for cytoprotection against MeHg toxicity.

Methylmercury Toxicity During Heart Development: A Combined Analysis of Morphological and Functional Parameters.

The heart of higher vertebrates develops early as a tubular structure, which requires cellular and molecular events for proliferation, differentiation and apoptosis for growth, and individualization of cardiac chambers. Exposure to different stressors can cause disturbances in the normal development and functionality of the cardiovascular system. This study aimed to characterize the impact of methylmercury (MeHg) on heart development, specifically related to tissue morphology and parameters of vascular integrity and contractility, also focusing on cell cycle and apoptosis, using Gallus domesticus embryos as a model. The results showed morphological alterations, reduction in the thickness of the ventricular walls, and trabeculae changes in the hearts of embryos exposed to 0.1µg MeHg/50 µL saline solution. These impacts were associated with increased contents of proteins related to cell cycle arrest and reduced cardiomyocyte proliferation. In addition, the contents of endothelial mediators for contractility and vascular integrity were imbalanced. The quantity and morphology of mitochondria of cardiomyocytes were injured. Together, these negative measurements impacted the reduction of heartbeats. In general, the parameters identified here demonstrate the relevance of combined molecular cellular tissue and physiological diagnosis for a better understanding of the cardiotoxicity of MeHg duringdevelopment.

Mercury in Dried Market Fish of Hong Kong and San Francisco: Human Health Implications

Asian, Asian Pacific Islanders, and Asian American residents of San Francisco have higher exposure to mercury and the associated health risks associated with methylmercury toxicity from fish consumption than other demographics across the United States. Due to their higher annual fish consumption, Hong Kong Chinese residents have elevated risks to methylmercury exposure. Objectives: We investigate samples of dried market fish from San Francisco and from Hong Kong as potential sources of mercury contamination in fish commonly consumed by Asian and Asian American residents. Methods: We analyze 81 samples of dried market fish from San Francisco and Hong Kong for mercury concentration using Inductively Coupled Plasma Emission Spectrograph and Processing Cold Vapor Atomic Fluorescence Spectrometry. We binned into market categories, trophic level, and habitat type for statistical analysis. Results: No significant difference was observed in the mercury levels of samples between San Francisco and Hong Kong (p-value = 0.47). Dried samples did show higher rates of mercury than wet samples reported by the FDA. Data from dried market fish samples also show evidence of bioaccumulation: the concentration of toxins in higher trophic levels of fish (p-value < 0.01). Eliminating apex predators, nearly all samples of fish from both locations and from lower trophic levels had levels below the lowest health advisory thresholds of 0.5 ppm methylmercury by weight. Discussion: Dried fish samples from markets in San Francisco and Hong Kong showed mercury levels with the potential to exceed guidelines set by the EPA and the EFSA, but consumption rates are lacking to know if this threshold is actually being exceeded by consumers. We make recommendations regarding the health risks of dried market fish and of consuming or avoiding fish from certain trophic groups.

Potentiation of methylmercury toxicity by combined metal exposure: In vitro and in vivo models of a restricted metal exposome

Methylmercury (MeHg) is a prevalent toxic metal that readily modifies protein thiols. Reactive persulfides that play a role in redox homeostasis are able to inactivate this metal through sulfur adduct formation. Although humans are exposed to other metals that could consume reactive persulfides on a daily basis, the health effects of combined exposure to MeHg and other metals remain unexplored. This study aimed to examine potential MeHg toxicity during exposure to MeHg with other metals capable of consuming reactive persulfides. We designed a simple system to assess the risk of combined exposure to metals based on reactivity to reactive persulfides and mercury accumulation. Among the metals examined in a cell-free system, copper, cadmium, nickel, and MeHg consumed Na2S2, used as a model of reactive persulfides, whereas zinc, iron, lithium, strontium, tin, and aluminum did not. In HepG2 cells, binary exposure to MeHg and copper, but not aluminum, increased the consumption of extracellular reactive persulfides. Binary exposure exacerbated MeHg-induced cytotoxicity by promoting the modification of intracellular proteins by MeHg. In a mouse model, binary exposure to MeHg and copper resulted in elevated mercury accumulation in the fetuses and placenta of pregnant mice, as well as the brain and liver of non-pregnant mice. Our study suggests that MeHg sensitivity can be increased by combined exposure with other electrophilic metals. In particular, binary exposure to MeHg and copper during pregnancy exacerbated mercury accumulation in offspring.

In vivo evaluation of the potential protective effects of prolactin against damage caused by methylmercury.

Non-biodegradable metals such as mercury accumulate in living organisms during life (bioaccumulation) and also within trophic webs (biomagnification) and may reach high concentrations in humans. The contamination of humans by mercury in drinking water and food may be common, in particular in riverside communities that have a diet rich in fish. In vitro studies of human cell lines exposed to the cytotoxic and mutagenic effects of methylmercury have shown that prolactin has potential cytoprotective properties and may act as a co-mitogenic factor and inhibitor of apoptosis. The present in vivo study investigated the protective potential of prolactin against the toxic effects of methylmercury in the mammal Mus musculus. Histological and biochemical analyses, together with biomarker of genotoxicity, were used to verify the protective potential of prolactin in mice exposed to methylmercury. The reduction in kidney and liver tissue damage was not significant. However, results of biochemical and genotoxic analyses were excellent. After prolactin treatment, a significant reduction was observed in biochemical parameters and mutagenic effects of methylmercury. The study results therefore indicated that prolactin has protective effects against the toxicity of methylmercury and allowed us to suggest the continuation of research to propose prolactin in the future, as an alternative to prevent the damage caused by mercury, especially in populations that are more exposed.

Preliminary evaluation of the mechanism underlying vulnerability/resistance to methylmercury toxicity by comparative gene expression profiling of rat primary cultured cerebrocortical and hippocampal neurons.

Methylmercury (MeHg), an environmentally toxic substance, causes site-specific neuronal cell death; while MeHg exposure causes death in cerebrocortical neurons, interestingly, it does not in hippocampal neurons, which are generally considered to be vulnerable to toxic substances. This phenomenon of site-specific neuronal cell death can be reproduced in animal experiments; however, the mechanism underlying the resistance of hippocampal neurons to MeHg toxicity has not been clarified. In this study, we comparatively analyzed the response to MeHg exposure in terms of viability and the expression characteristics of primary cultured cerebrocortical neurons and hippocampal neurons derived from fetal rat brain. Neuronal differentiated hippocampal neurons were more resistant to MeHg toxicity than cerebrocortical neurons, as indicated by a 2‒3 fold higher half-maximal inhibitory concentration (IC50; 3.3 μM vs. 1.2 μM), despite similar intracellular mercury concentrations in both neuronal cell types. Comprehensive RNA sequencing-based gene expression analysis of non-MeHg-exposed cells revealed that 80 out of 15,208 genes showed at least 10-fold higher expression in hippocampal neurons than in cerebrocortical neurons, whereas six genes showed at least 10-fold higher expression in cerebrocortical neurons than in hippocampal neurons. In particular, genes related to neuronal function, including those encoding transthyretin and brain-derived neurotrophic factor, showed approximately 50-fold higher expression in hippocampal neurons than in cerebrocortical neurons. In conclusion, the resistance of hippocampal neurons to MeHg toxicity may be related to the high expression of neuronal function-related proteins.