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B., Teixeira, F. B., Fagundes, N. C. F., Fernandes, R. M., Fernandes, L. M. P., Da Silva, M. C. F., et al. (2014) showed overexpression of Ras in human prostate epithelial cells following As exposure. doi:10.1016/j.ijheh.2013.04.010, Wilhelm, T., Said, M., and Naim, V. (2020). (2016) proposed that activation of the Nrf2 signaling pathway could be effective to prevent liver lesions induced by Hg. 116 (6), 777783. Z., and Mahmood, T. (2010). J. Hyg. Respiratory symptoms and pulmonary function testes in lead exposed workers. J. Occup. It seems that increased expression of protooncogenes and silencing of tumor suppresser genes via intracellular ROS production are the underlying causes (Cheng et al., 2012). (2009). Osteoporosis and bone fracture could be observed following Cd toxicity. Maternal inorganic mercury exposure and renal effects in the Wanshan mercury mining area, southwest China. Sujatha, K., Srilatha, C., Anjaneyulu, Y., Rao, T., Sreenivasulu, D., and Amaravathi, P. (2011). SSBs and DSBs were found in rapidly dividing cells such as cancer cells as the collapse of replication fork during DNA replication, leading to cell cycle arrest and apoptosis via activation of p53 (Lee et al., 2016; Wilhelm et al., 2020). For example: There are no site observations that specifically provide evidence of the absence of metals. Besides, exposure to Pb induced necrotic changes in brain, liver, and kidneys (Jadhav et al., 2007). Toxicol. For example, arsenic has been shown to produce superoxide (O2. 375, 14. Environ. Puerarin protects rat kidney from lead-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. doi:10.1111/j.1365-2044.1991.tb11500.x, Joseph, C. L. M., Havstad, S., Ownby, D. R., Peterson, E. L., Maliarik, M., McCabe, M. J., et al. Nigerias lead poisoning crisis could leave a long legacy. Similar reactions can occur with the other heavy metals. Even though Pb can be absorbed from the skin, it is mostly absorbed from respiratory and digestive systems. Some metals are toxic in minute amounts. 24 (6), 287295. (2013). PloS One 9 (8), e103194. Res. Concentrations of mercury, lead, chromium, cadmium, arsenic and aluminum in irrigation water wells and wastewaters used for agriculture in Mashhad, northeastern Iran. Inhaled lead affects lung pathology and inflammation in sensitized and control Guinea pigs. J. Hyg. Toxicol. MBM advised on preparing the comparison of the toxic mechanisms of the heavy metals and revised the first and final drafts of the manuscript critically; KN, ZT, and MBK contributed to preparing three different parts of the manuscript; MS made the first and final drafts of the manuscript. Arsenic exposure from drinking water and birth weight. Blood mercury concentrations are associated with decline in liver function in an elderly population: a panel study. Biochem. Smoking-induced risk of future cardiovascular disease is partly mediated by cadmium in tobacco: Malm Diet and Cancer Cohort Study. doi:10.1007/s11356-016-6333-x, Xiao, C., Liu, Y., Xie, C., Tu, W., Xia, Y., Costa, M., et al. BMJ. Pharmacol. (2012). In general, oxidative DNA damage occurs either by the oxidation states of Cr(V) peroxo intermediates or via ROS action (Bokare and Choi, 2011). Nephrocarcinogenicity of cadmium might happen after substantial exposure in chemical industries (Pesch et al., 2000). Environ. Antioxidative effects of hesperetin against lead acetate-induced oxidative stress in rats. Me-Hg and Et-Hg have been used as fungicides to protect plants against infections. Int. doi:10.1289/ehp.7453, Kasperczyk, S., Birkner, E., Kasperczyk, A., and Kasperczyk, J. Advanced oxidation process based on the Cr(III)/Cr(VI) redox cycle. (2004). Ecological Applications 16(2):645-655. Cadmium toxicity induces ER stress and apoptosis via impairing energy homoeostasis in cardiomyocytes. Secure .gov websites use HTTPS Naturally metals-enriched regions become non-point sources when land cover alterations expose rock and soil to erosion. 179 (2), 172177. Binding to enzymes and proteins commonly occurs through thiol (SH) groups and modifies cysteine residues in proteins. J. Mol. doi:10.1016/j.etap.2014.03.002, Pan, C., Liu, H.-D., Gong, Z., Yu, X., Hou, X.-B., Xie, D.-D., et al. Pharmacol. Cancer Prev. Altered expression of genes involved in apoptosis and DNA repair is proposed for resistance to apoptosis induced by Cr6+ (Pritchard et al., 2005). This ranges from dermal, renal, neurological, and GI diseases to the development of several cancers including lungs, larynx, bladder, kidneys, testicles, bone, and thyroid (Fang et al., 2014). doi:10.1136/oemed-2017-104944, Lu, T., Liu, J., LeCluyse, E. L., Zhou, Y.-S., Cheng, M.-L., and Waalkes, M. P. (2001). doi:10.1021/tx9003402, Mazumdar, M., Bellinger, D. C., Gregas, M., Abanilla, K., Bacic, J., and Needleman, H. L. (2011). (2018). (2017). Some studies have reported the relationship between prevalence of renal dysfunction or deficit in lung function and measured urinary Cd levels. Me-Hg induces PLD activation. Curr. Salama et al. 43 (3), 244274. Inhibition of -glutamyltranspeptidase decreases renal deposition of mercury after mercury vapor exposure. Int. When listing metals, also consider how site water chemistry conditions influence metal bioavailability and toxicity. Increased PLD activity can lead to many diseases and cancers. Biol. Cadmium and cadmium/zinc ratios and tobacco-related morbidities. Mutat. Low pH of the water favors metal solubility, increasing free metal ion content, particularly when abiotic ligands are not abundant. Autophagy 11 (7), 10371051. Toxicol. (2004). doi:10.3390/ijerph2005010080, Patlolla, A. K., Barnes, C., Yedjou, C., Velma, V. R., and Tchounwou, P. B. Mutat. Chem. doi:10.1002/jat.3151, Bridges, C. C., and Zalups, R. K. (2017). 115 (7), 10941100. (2018) found increased levels of histone H3 methylation marks (H3K9me2 and H3K27me3) and histone methyltransferases (HMTases) (Wang Z. et al., 2018). (2008). Pharmacol. doi:10.1021/cr300015c, Son, Y.-O., Wang, L., Poyil, P., Budhraja, A., Hitron, J. Endoplasmic reticulum stress and the subsequent cell apoptosis is another proposed path of Cd toxicity (Chen et al., 2015). (2016). 1. This will be important in later stages of the assessment. Environmental Monitoring and Assessment 80:207-276. doi:10.2337/diacare.27.11.2741, Chen, L., Jin, T., Huang, B., Chang, X., Lei, L., Nordberg, G. F., et al. Health 18 (1), 56. doi:10.1186/s12940-019-0495-1, Liaw, J., Marshall, G., Yuan, Y., Ferreccio, C., Steinmaus, C., and Smith, A. H. (2008). Med. Comparison of the mechanisms of action reveals similar pathways for these metals to induce toxicity including ROS generation, weakening of the antioxidant defense, enzyme inactivation, and oxidative stress. Environ. Similarly, epigenetic changes may attribute to the Cd and As toxic and carcinogenic effects. Details on how to obtain uncompromised water samples can be found in: Information on appropriate sample handling and methods for analysis can be found in: Water samples often are filtered to measure dissolved metal concentrations and acidified to keep metals in solution. The flocculate that results coats the stream bed and can smother organisms and their benthic habitat. Cancer Res. (2003). Arsenic (arsine) toxicity. Oxid. Effect of Semecarpus anacardium against lead induced toxicity in rats. (2018). Environmental pollution has even reached the pristine places. Acid mine drainage can present a physical cause of impairment when drainage water mixes with the higher pH water of a receiving stream and metal hydroxides precipitate. doi:10.1007/s12291-011-0159-6. Stack releases in an area do not necessarily result in actual exposures due to differing release-specific fate and transport pathways. Case Rep. Emerg Med. (2010). After exposure for 24 hours to a copper concentration of 0.55 mg/l, rainbow trout showed a 55 per cent inhibition of sodium uptake and a 4 per cent reduction in affinity for sodium, which resulted in an overall decrease in total sodium concentration of sulphydryl-rich protein (Lauren and McDonald 1987a,b). Toxicol. doi:10.1016/j.tox.2003.09.009, Hazelhoff, M. H., and Torres, A. M. (2018). 2014, 435857. doi:10.1155/2014/435857, PubMed Abstract | CrossRef Full Text | Google Scholar. Sci. Unlike certain water quality parameters (e.g., pH, temperature, conductivity), metals are not commonly measured on site. For more details on metals speciation, see Langmuir et al. Cd-induced nephrotoxicity is mediated via oxidative stress, apoptosis, and necrosis. Heavy metal toxicity and the environment. Toxicol. (2016). The relationship between GGT and blood Hg concentration was significant, suggesting that GGT may be considered an early oxidative stress marker for mercury exposure (Choi et al., 2017). Bengtsson BE, Larsson A (1986) Vertebral deformities and physiological effects in fourhorn sculpin (, Borgmann U, Couillard Y, Doyle, Dixon DG (2005) Toxicity of sixty-three metals and metalloids to. Diabetes Care 27 (11), 27412751. (2016). The immunological effects of lead exposure on lymphocyte proliferation, IFN- production, and NK cell cytotoxicity in occupational Pb exposed subjects including wheeler drivers (30), battery workers (34), silver jewelry makers (20), and unexposed healthy subjects (30) were studied. Localization of mercury in CNS of the rat. Med. Monit. Pb-induced renal toxicity might lead to necrosis. Front. Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. Int. Rediscovering beta-2 microglobulin as a biomarker across the spectrum of kidney diseases. 24 (4), 378399. doi:10.5487/tr.2016.32.1.065, Clancy, H. A., Sun, H., Passantino, L., Kluz, T., Muoz, A., Zavadil, J., et al. Both Cr (VI) and Cr (III) are capable of producing ROS (Pavesi and Moreira, 2020). 56 (23), 1126211269. It was aimed at reviewing the toxic effects and mechanisms of five main heavy metals including mercury, lead, cadmium, chromium, and arsenic. However, some metals selectively bind to a specific protein as a unique mechanism of that metal. (2007). (2019). In addition, Pb significantly increased oxidative parameters including malondialdehyde (MDA) and H2O2 concentrations as well as expression of cyclooxygenase-2 (COX-2) (Omobowale et al., 2014). Comparison of therapeutic effects of garlic and d-penicillamine in patients with chronic occupational lead poisoning. Environ. Cadmium induced Drp1-dependent mitochondrial fragmentation by disturbing calcium homeostasis in its hepatotoxicity. (2005). doi:10.2174/138920012799320464, Vahter, M., kesson, A., Lidn, C., Ceccatelli, S., and Berglund, M. (2007). Consider listing metals as a candidate cause when the following sources and activities, site evidence and biological effects are present: Consider other causes with similar evidence when considering metals as a candidate cause: One reason to list metals as a candidate cause is the presence of metal sources or other evidence of metals in a stream or watershed. (2012) used a mouse model of colorectal cancer to investigate the carcinogenicity of Cr (VI) and As in drinking water. Moreover, it poses renal and respiratory harmful effects. Sci. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 35 (8), 598602. (2018). Epidemiol. 1992), Bartholomew JL, Lorz HV, Sollid SA, Stevens DG (2003) Susceptibility of juvenile and yearling bull trout to. Health Res. Dutta, K., Prasad, P., and Sinha, D. (2015). Toxicol. Int. ), oxygen (O2. doi:10.1007/s40489-014-0028-3, Gupta, D. K., Tiwari, S., Razafindrabe, B., and Chatterjee, S. (2017). More gradual releases occur over periods of snowmelt which can contribute metals to both soil moisture and direct runoff. Epigenetic dysregulations in human bronchial epithelial cells were reported following Cr6+ exposure. (2008). Environ. Life Sci. 27 (9), 25852597. Furthermore, Pb could disturb the balance of the oxidantantioxidant system and induce inflammatory responses in various organs. Toxicol. Microorganisms in marine environments perform natural biomethylation reactions to produce Me-Hg. (2014). Disturbance and redistribution of metals-contaminated sediments by dredging can result in repartitioning of metals into the water column. Chromium (Cr) is found in the earths crust and seawater and is a naturally occurring heavy metal in industrial processes (Tchounwou et al., 2012). (2011). Administration of Pb (1mg/kg, bw, ip.) Clin. 11, 283312. (2004) showed that the expression of Oat3 protein is strongly elevated by testosterone. Health 26 (6), 349359. Hexavalent chromium Cr(VI) up-regulates COX-2 expression through an NFB/c-jun/AP-1-dependent pathway. Metallomics 4 (8), 784793. Res. Mol. Transcription factors such as Activator Protein 1 (AP-1), Nuclear Factor-kappa B (NF-B), and p53 are targets for Cd and As. Copyright 2021 Balali-Mood, Naseri, Tahergorabi, Khazdair and Sadeghi. Toxicol. Environ. Health Perspect. J. Appl. On the other hand, low-dose exposure is a subtle and hidden threat, unless repeated regularly, which may then be diagnosed by its complications, e.g., neuropsychiatric disorders including fatigue, anxiety, and detrimental impacts on intelligence quotient (IQ) and intellectual function in children (Mazumdar et al., 2011). Environ. Res. Metals could also be listed as a candidate cause when the impairment involves gross pathologies or community changes indicative of adverse metals effects. The severity of episodic exposures is related to the amount of dry deposition built up in the period between events, saturation levels of non-impervious areas, and the volume of water discharged. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and total white blood cell count (11.44%) were increased in the automobile workers as compared to the controls. Moreover, higher Cr concentrations caused lung injury. 99 (10), 19921997. Soon afterward, the illness came to be known as Minamata disease. Toxicol. Vincent, J. doi:10.1002/jbt.21462, Batriov, A., Spvkov, V., Bene, B., ejchanov, M., md, J., and ern, M. (2006). J. Mol. Tragically, the outbreak of Itai-itai disease in Japan was due to the mass Cd contamination of food and water supplies. The relationship between blood and urine lead concentrations and clinical manifestations in car battery manufacturing workers showed a weak correlation between serum ALP and BLL in these workers (Dadpour et al., 2016). Environ. In Vitro 56, 184193. Concentration of heavy metals in water resources, air, and food is assessed with this regard (Mousavi et al., 2013; Ghorani-Azam et al., 2016; Luo et al., 2020). Toxic mechanisms of Hg, Pb, Cr, Cd, and As. doi:10.1016/s0300-483x(01)00345-6, Pavesi, T., and Moreira, J. C. (2020). Lead exposure affects inflammatory mediators, total and differential white blood cells in sensitized guinea pigs during and after sensitization. (2005). The results showed that lymphocyte proliferation to PHA is inhibited while IFN- significantly increased in stimulated peripheral blood mononuclear cells (PBMCs) compared with control subjects (Mishra et al., 2003). doi:10.1016/j.taap.2016.03.015, Macfie, A., Hagan, E., and Zhitkovich, A. Sci. J. Res. Cell Death Dis. 152 pp. Daily dosage limits for heavy metals in dietary supplements should be established by regulatory authorities. Gender differences in mercury-induced hepatotoxicity: potential mechanisms. [Change in peripheral nervous conduction velocity in patients with occupational chronic mercury poisoning and related influencing factors]. Cooking fish does not diminish its Hg content (Perello et al., 2008). The pretreatment of an organism with low doses of a metal may stimulate metallothionein synthesis and provide tolerance during a subsequent exposure (Pascoe and Beattie, 1979). Res. doi:10.1002/jat.2717, Choi, J., Bae, S., Lim, H., Lim, J.-A., Lee, Y.-H., Ha, M., et al. Sci. All authors reviewed and approved the final draft. Res. Although both men and women showed similar trends, the changes were significant in female population (Chen X. et al., 2019). 58, 1120. study (2019), comparing residents of two cadmium-polluted areas with a control region showed the association between osteoporosis and high level of Cd intake. (2018) investigated the molecular mechanisms of Cd nephrotoxicity in rats renal cortex. Other routes of exposure are from the skin contact and by inhalation. Toxicol. 38 (1), 30. Orally administered PbA (30 and 60mg/kg, bw) 3days in a week for 3months in rats reduced testicular weight, sperm count, and testicular ALP activity. In addition, the frequencies of respiratory symptoms including chest tightness (26%), cough (17%), and sputum (16%) were significantly higher in battery manufacturing workers compared to the control group (Khazdair et al., 2012). Identifying occupational carcinogens: an update from the IARC monographs. The metal species of primary toxicological concern are free ions. Inhalation of mercury vapor can cause the toxic effects on rat kidney. Adapted from Brown et al. Oncol. Note that blooms of sulfate-reducing bacteria may also alter the color of water. Toxicol. 147 (12), 22122219. Environ. Curr. (2019). Gender differences in the disposition and toxicity of metals. (2014). Autopsies were done on brain, stomach, small intestine, liver, kidneys, heart, and the lungs. 4 (2 April), 8086. Different species have different metal requirements and different sites have different naturally occurring levels of metals. 10 (2), 16. doi:10.1016/j.toxlet.2016.03.003, Jacobs, D. E., Wilson, J., Dixon, S. L., Smith, J., and Evens, A. doi:10.2136/sh2010.3.0072, Yu, H.-S., Liao, W.-T., and Chai, C.-Y. Several antioxidant molecules such as GSH and GSSG as well as antioxidant enzymes including SOD, CAT, GPx, and glutathione reductase (GR) may have fluctuations due to Pb exposure and consequent oxidative stress. Review of arsenic toxicity, speciation and polyadenylation of canonical histones. Exposure assessment and safe intake guidelines for heavy metals in consumed fishery products in the Republic of Korea. Environ. J. Appl. Lipid peroxidation induced by oxidative stress leads to DNA damage and ultimately brain cell death (Mochizuki, 2019). Chronic Cd-induced renal damage mainly involves the damage of glomerulus, especially the proximal tubules. Conceptual diagrams are used to describe hypothesized relationships among sources, stressors and biotic responses within aquatic systems. 138 (2), 268277. Furthermore, in a similar vein, chronic low level and moderate exposure to Cd influenced Cu concentrations in serum and internal organs. (2015). Metals entering the atmosphere from tailpipe and stack emissions are precipitated onto land or directly onto water. On the other hand, some researches have shown that the metals selectively bind to specific macromolecules. Mercury accumulation and its distribution to metallothionein in mouse brain after sub-chronic pulse exposure to mercury vapor. Public Health 50 (6), 377. doi:10.3961/jpmph.17.099, Choong, G., Liu, Y., and Templeton, D. M. (2014). Carcinogenic metals such as arsenic, cadmium, and chromium can disrupt DNA synthesis and repair (Clancy et al., 2012; Koedrith et al., 2013). Shekhawat, K., Chatterjee, S., and Joshi, B. doi:10.1016/j.jhazmat.2015.03.057, Coogan, T. P., Motz, J., Snyder, C. A., Squibb, K. S., and Costa, M. (1991). Prospective role of ascorbic acid (vitamin C) in attenuating hexavalent chromium-induced functional and cellular damage in rat thyroid. Here, we reviewed the mechanistic action of these heavy metals according to the available animal and human studies. A., Zhang, Z., et al. Front. While different types of mercury compounds are found in the environment, the organic forms of Hg are more toxic than the inorganic species. Only 4days of oral exposure to Hg compounds (HgCl2 and Me-HgCl) in rats caused intestinal fluid accumulation, mucosal injuries, and diarrhea. Toxicity of organic and inorganic mercury to Saccharomyces cerevisiae. Namgung, U., and Xia, Z. (2006). Trace element deposition on Mount Everest. The toxic mechanism of heavy metals functions in similar pathways usually via reactive oxygen species (ROS) generation, enzyme inactivation, and suppression of the antioxidant defense. Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet. This impairs gill respiratory function and the ability to regulate blood pH and ion concentrations. 20 (19), 4901. doi:10.3390/ijms20194901, Gazwi, H. S. S., Yassien, E. E., and Hassan, H. M. (2020). SSBs, DSBs, and protein-Cr-DNA crosslinks were indicated in the liver cells of F344 rats orally exposed to potassium chromate via drinking water for 3weeks (Coogan et al., 1991). Yeo and Langley-Turnbaugh (2010) found that all snow samples from Everest had As and Cd levels higher than the USEPA drinking water guidelines. Cheng, J. P., Wang, W. H., Jia, J. P., Zheng, M., Shi, W., and Lin, X. Y. Toxicol. Pharmacol. Blood mercury concentration among residents of a historic mercury mine and possible effects on renal function: a cross-sectional study in southwestern China. Consequently, an imbalanced antioxidant defense contributes to the development of liver injury. In Vitro 20 (8), 13311342. Liver cancers hepatocellular carcinoma and angiosarcoma have been associated with As poisoning (Lu et al., 2001; Liaw et al., 2008). In general the concentrations of metals in invertebrates is inversely related to their body mass. 13, 18. Rev. Land disturbance in metals-enriched areas can increase erosion and mobilize metals into streams. This influences their vulnerability to effects on respiration and the regulation of blood pH and ion concentrations (Di Toro et al. Taken together, the concentration of metal ions relative to nutrient ions, the abundance of abiotic ligands and pH determine the biologically available fraction and toxicity of metals in water (Di Toro et al. Sci. The hepatotoxicity of mercury was determined by histopathological analysis and investigating elevated liver enzymes level including alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Hence, human exposure to metals is inevitable, and some studies have reported gender differences in the toxicity of metals (Vahter et al., 2007; Tchounwou et al., 2012). doi:10.1016/j.tox.2005.05.003, Fang, Z., Zhao, M., Zhen, H., Chen, L., Shi, P., and Huang, Z. It was found that exposure to Cr and As increased the tumor incidence and size. Med. Reduced water transpiration due to devegetation and reduced infiltration due to the increased impervious surface cover (compacted soil, roofs, parking lots, and roads) increases the volume and velocity of stormwater runoff entering surface waters. Certain metal forms may diffuse into the gill epithelium, but these routes of absorption are considered minor relative to free ion binding. It has been reported that PbA (500mgPb/L) in drinking water promoted apoptosis by activation of mitochondria cytochrome C release and inhibited Bcl-2 proteins and activation of caspase-3 in kidneys of the exposed rats (Liu et al., 2012). For more details on the ecological effects of metals, see Kapustka et al. (2005). 24 (1), 6673. Annu. Tolerance to metals has also been recorded in invertebrates and in fish. doi:10.1080/15548627.2015.1052208, Pritchard, D. E., Ceryak, S., Ramsey, K. E., O'brien, T. J., Ha, L., Fornsaglio, J. L., et al. These include specific organ dysfunctions, metabolic abnormalities, altered hormones, congenital disorder, immune system dysfunction, and cancer (Khazdair et al., 2012; Fang et al., 2014; Li L. et al., 2017; Deng et al., 2019). Toxicol. doi:10.3760/cma.j.issn.1001-9391.2017.08.011, Li, R., Wu, H., Ding, J., Fu, W., Gan, L., and Li, Y. It is believed that a main cause of As neurological disorders is the ability to cause oxidative stress and mitochondrial dysfunction.

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