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Changes in gene expression underlie many pathogenic endpoints including carcinogenesis. Metals, like arsenic, alter gene expression; however, the consequences of co-exposures of metals with other stressors are less understood. Although arsenic acts as a co-carcinogen by enhancing the development of UVR skin cancers, changes in gene expression in arsenic UVR co-carcinogenesis have not been investigated. We performed RNA-sequencing analysis to profile changes in gene expression distinct from arsenic or UVR exposures alone. A large number of differentially expressed genes (DEGs) were identified after arsenic exposure alone, while after UVR exposure alone fewer genes were changed. A distinct increase in the number of DEGs was identified after exposure to combined arsenic and UVR exposure that was synergistic rather than additive. In addition, a majority of these DEGs were unique from arsenic or UVR alone suggesting a distinct response to combined arsenic-UVR exposure. Globally, arsenic alone and arsenic plus UVR exposure caused a global downregulation of genes while fewer genes were upregulated. Gene Ontology analysis using the DEGs revealed cellular processes related to chromosome instability, cell cycle, cellular transformation, and signaling were targeted by combined arsenic and UVR exposure, distinct from UVR alone and arsenic alone, while others were related to epigenetic mechanisms such as the modification of histones. This result suggests the cellular functions we identified in this study may be key in understanding how arsenic enhances UVR carcinogenesis and that arsenic-enhanced gene expression changes may drive co-carcinogenesis of UVR exposure., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Biological organisms are exposed to low-dose arsenic or N-nitro compounds (NOCs) alone or in combination worldwide, especially in areas with high cancer prevalence through drinking water or food exposure; however, information on their combined exposure effects is limited. Here, we conducted an in-depth study of the effects on the gut microbiota, metabolomics, and signaling pathways using rat models exposed to arsenic or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), one of the most active carcinogenic NOCs, separately or in combination with metabolomics and high-throughput sequencing. Compared to exposure alone, combined exposure to arsenic and MNNG exacerbated damage to gastric tissue morphology, interfered with intestinal microflora and substance metabolism, and exerted a stronger carcinogenic effect. This may be related to intestinal microbiota disorders, including Dyella, Oscillibacter, Myroides, and metabolic pathways such as glycine, serine, and threonine metabolism, arginine biosynthesis, central carbon metabolism in cancer, and purine and pyrimidine metabolism, thereby enhancing the cancer-causing effects of gonadotrophin-releasing hormone (GnRH), P53, and Wnt signaling pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We performed a mixture risk assessment (MRA) case study of dietary exposure to the food contaminants lead, methylmercury, inorganic arsenic (iAs), fluoride, non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs), all substances associated with declines in cognitive abilities measured as IQ loss. Most of these chemicals are frequently measured in human biomonitoring studies. A component-based, personalised modified reference point index (mRPI) approach, in which we expressed the exposures and potencies of our chosen substances as lead equivalent values, was applied to perform a MRA for dietary exposures. We conducted the assessment for four different age groups (toddlers, children, adolescents, and women aged 18-45 years) in nine European countries. Populations in all countries considered exceeded combined tolerable levels at median exposure levels. NDL-PCBs in fish, other seafood and dairy, lead in grains and fruits, methylmercury in fish and other seafoods, and fluoride in water contributed most to the combined exposure. We identified uncertainties for the likelihood of co-exposure, assessment group membership, endpoint-specific reference values (ESRVs) based on epidemiological (lead, methylmercury, iAs, fluoride and NDL-PCBs) and animal data (PBDE), and exposure data. Those uncertainties lead to a complex pattern of under- and overestimations, which would require probabilistic modelling based on expert knowledge elicitation for integration of the identified uncertainties into an overall uncertainty estimate. In addition, the identified uncertainties could be used to refine future MRA for cognitive decline., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Metals play an important role in the development of diabetes mellitus (DM). The association of metals with diabetes among the Dong ethnicity in China remains poorly understood. The current study aimed to evaluate the association of single metal exposure and multi-metal co-exposure with DM risk. Urinary concentrations of arsenic, cadmium, chromium, copper, iron, lead, manganese, mercury, molybdenum, nickel, strontium, vanadium, and zinc were measured using inductively coupled plasma-mass spectrometry (ICP-MS) among 4479 Dong ethnic participants aged 30-79 years from the China Multi-Ethnic Cohort (CMEC) study. Based on tertiles, the metal exposure can be divided into three groups: low, middle, and high exposure. Multivariate logistic regression models and principal component analysis were performed to determine exposure to single-metal and multi-metal co-exposure in relation to DM. A decrease in risk of DM was associated with iron (OR = 0.78, 95% CI: 0.61-1.00 and 0.68, 0.53-0.88 for the middle and high vs. low) and strontium (OR = 0.87, 95% CI: 0.69-1.12 and 0.67, 0.51-0.86 for the middle and high vs. low), respectively. A principal component 3 (PC3) characterized by iron and strontium showed an inverse association with DM. A principal component 4 (PC4) characterized by manganese and lead positively associated with DM. Exposure to high concentrations of urinary iron and strontium may reduce the risk of diabetes mellitus. This study revealed an increase in the risk of diabetes mellitus by co-exposure to high concentrations of urinary manganese and lead., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The current study aimed to assess the connection between the mixture of lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg) and decabrominated diphenyl ether (decaBDE) and thyroid function, by using in silico toxicogenomic data-mining approach. To obtain the linkage between investigated toxic mixture and thyroid diseases (TDs), the Comparative Toxicogenomics Database (CTD) was used, while gene ontology (GO) enrichment analysis was performed by ToppGeneSuite portal. The analysis has shown 10 genes connected to all chemicals present in the mixture and TDs (CAT, GSR, IFNG, IL1B, IL4, IL6, MAPK1, SOD2, TGFB1, TNF), most of which were in co-expression (45.68%), or belonged to the same pathway (30.47%). Top 5 biological processes and molecular functions affected by the investigated mixture emphasized the role of two common mechanisms - oxidative stress and inflammation. Cytokines and inflammatory response was listed as the main molecular pathway that may be triggered by simultaneous exposure to toxic metal(oid)s and decaBDE and connected to TDs. The direct relations between Pb/decaBDE and redox status impairment in thyroid tissue was confirmed by our chemical-phenotype interaction analysis, while the strongest linkage between Pb, As and decaBDE and thyroid disorders was found. The obtained results provide better understanding of molecular mechanisms involved in the thyrotoxicity of the investigated mixture, and can be used to direct further research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Arsenic (As), and fluoride (F - ) are potent contaminants with established carcinogenic and non-carcinogenic impacts on the exposed populations globally. Despite elevated groundwater As and F - levels being reported from various regions of Pakistan no biomonitoring study has been reported yet to address the co-exposure impact of As and F - among school children. We aimed to investigate the effects of these two contaminants on dental fluorosis and intelligence quotient (IQ) along with the induction of oxidative stress in rural children under co-exposed conditions. A total of 148 children (5 to 16 years old) from the exposed and control group were recruited in the current study from endemic rural areas of Lahore and Kasur districts, Pakistan having elevated As and F - levels in drinking water than permissible limits. We monitored malondialdehyde and its probable association with antioxidants activity (SOD, CAT, and GR) as a biomarker of oxidative stress. GSTM1/T1 polymorphisms were measured to find the impact of As on health parameters. Mean urinary concentrations of As (2.70 vs. 0.016 µg/L, P < 0.000) and F - (3.27 vs. 0.24 mg/L, P < 0.000) as well as the frequency of dental fluorosis were found elevated among the exposed group. The cases of children with lower IQ were observed high in the exposed group. Additionally, lower concentrations of antioxidants (SOD, CAT, and GR) were found suggesting high susceptibility to F - toxicity. The findings suggest that F - accounted for high variations in health parameters of children under the co-exposure conditions with As., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Considering the increasing emergence of new contaminants, such as nanomaterials, mixing with legacy contaminants, including metal(loid)s, it becomes imperative to understand the toxic profile resulting from these interactions. This work aimed at assessing and comparing the individual and combined hepatotoxic and neurotoxic potential of titanium dioxide nanoparticles (TiO 2 NPs 0.75-75 mg/L), cerium oxide nanoparticles (CeO 2 NPs 0.075-10 μg/L), arsenic (As 0.01-2.5 mg/L), and mercury (Hg 0.5-100 mg/L) on human hepatoma (HepG2) and neuroblastoma (SH-SY5Y) cells. Viability was assessed through WST-1 (24 h) and clonogenic (7 days) assays and it was affected in a dose-, time- and cell-dependent manner. Higher concentrations caused greater toxicity, while prolonged exposure caused inhibition of cell proliferation, even at low concentrations, for both cell lines. Cell cycle progression, explored by flow cytometry 24 h post-exposure, revealed that TiO 2 NPs, As and Hg but not CeO 2 NPs, changed the profiles of SH-SY5Y and HepG2 cells in a dose-dependent manner, and that the cell cycle was, overall, more affected by exposure to mixtures. Exposure to binary mixtures revealed either potentiation or antagonistic effects depending on the composition, cell type and time of exposure. These findings prove that joint toxicity of contaminants cannot be disregarded and must be further explored.

Humans are often exposed to mixtures of environmental pollutants especially environmental chemical carcinogens, representing a significant environmental health issue. However, our understanding on the carcinogenic effects and mechanisms of environmental carcinogen mixture exposures is limited and mostly relies on the findings from studying individual chemical carcinogens. Both arsenic and benzo(a)pyrene (BaP) are among the most common environmental carcinogens causing lung cancer and other types of cancer in humans. Millions of people are exposed to arsenic via consuming arsenic-contaminated drinking water and even more people are exposed to BaP via cigarette smoking and consuming BaP-contaminated food. Thus arsenic and BaP combined-exposure in humans is common. Previous epidemiology studies indicated that arsenic-exposed people who were cigarette smokers had significantly higher lung cancer risk than those who were non-smokers. Since BaP is one of the major carcinogens in cigarette smoke, it has been speculated that arsenic and BaP combined-exposure may play important roles in the increased lung cancer risk observed in arsenic-exposed cigarette smokers. In this review, we summarize important findings and inconsistencies about the co-carcinogenic effects and underlying mechanisms of arsenic and BaP combined-exposure and propose new areas for future studies. A clear understanding on the mechanism of co-carcinogenic effects of arsenic and BaP combined exposure may identify novel targets to more efficiently treat and prevent lung cancer resulting from arsenic and BaP combined-exposure., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Co-exposure to inorganic arsenic (iAs) and fluoride (F - ) and their collective actions on cardiovascular systems have been recognized as a global public health concern. Emerging studies suggest an association between the perturbation of gut bacterial microbiota and adverse cardiovascular effects (CVEs), both of which are the consequence of iAs and F - exposure in human and experimental animals. The aim of this study was to fill the gap of understanding the relationship among co-exposure to iAs and F - , gut microbiota perturbation, and adverse CVEs. We systematically assessed cardiac morphology and functions (blood pressure, echocardiogram, and electrocardiogram), and generated gut microbiota profiles using 16S rRNA gene sequencing on rats exposed to iAs (50 mg/L NaAsO 2 ), F - (100 mg/L NaF) or combined iAs and F - (50 mg/L NaAsO 2  + 100 mg/L NaF), in utero and during early postnatal periods (postnatal day 90). Correlation analysis was then performed to examine relationship between significantly altered microbiota and cardiac performance indices. Our results showed that co-exposure to iAs and F - resulted in more prominent effects in CVEs and perturbation of gut microbiota profiles, compared to iAs or F - treatment alone. Furthermore, nine bacterial genera (Adlercreutzia, Clostridium sensu stricto 1, Coprococcus 3, Romboutsia, [Bacteroides] Pectinophilus group, Lachnospiraceae NC2004 group, Desulfovibrio, and two unidentified genera in Muribaculaceae and Ruminococcaceae family), which differed significantly in relative abundance between control and iAs and F - co-exposure group, were strongly correlated with the higher risk of CVEs (correlation coefficient = 0.70-0.88, p < 0.05). Collectively, these results suggest that co-exposure to iAs and F - poses a higher risk of CVEs, and the part of the mode of action is potentially through inducing gut microbiota disruption, and the strong correlations between them indicate a high potential for the development of novel microbiome-based biomarkers of iAs and/or F - associated CVEs., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Environmental exposure to arsenic (As) and fluoride (F) in the recent year has been increased because of excessive use of naturally contaminated ground water. Surface water is also regularly contaminated with these elements in various industrial areas. Arsenicosis and fluorosis upon individual exposure of As and F are reported in many studies. A syndrome of endemic As poisoning and fluorosis occurs during concurrent exposure of As and F. Previous reports showed synergistic, antagonistic and independent effects of these two compounds, although few recent reports also revealed antagonistic effects after co-exposure. Interaction during intestinal absorption and influence of F on As metabolism might be the cause of antagonism. The synergism/antagonism is thought to depend on the dose and duration of the co-exposure. However, the detailed mechanism is still not fully understood and needs further studies. Removal technologies of As and F from contaminated water is available but removal of such contaminants from food is yet to be developed. Antioxidants are useful to mitigate the toxic effects of As and F. This review focused on the effect of co-exposure, amelioration as well as removal techniques of As and F., (© 2019 John Wiley & Sons, Ltd.)

Background: Human are often simultaneously exposed to polycyclic aromatic hydrocarbons (PAHs) and metals, yet relatively little is known regarding their co-exposure effects on oxidative damage. Genetic factors and the gene-environment interactions can also determine the severity of oxidative damage. Four polymorphisms in microRNA (miRNA) genes (rs11614913, rs2292832, rs2910164, and rs3746444) have been well-studied to be associated with oxidative damage-related diseases., Objective: To investigate the influences of PAH-metal co-exposure, four polymorphisms, and their interactions on oxidative damage levels., Methods: We conducted a cross-sectional study in 1385 coke oven workers. We quantified exposure levels of PAHs and metals by urinary monohydroxy-PAHs, plasma benzo[a]pyrene-7,8-diol-9,10-epoxide-albumin adducts, and urinary metals, respectively, and measured oxidative damage levels by 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine. We also genotyped four polymorphisms., Results: In multiple-pollutant models, 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were associated with multiple PAH exposure biomarkers, as well as with multiple metals (p trend  < 0.05). Metabolites of phenanthrene and pyrene interacted synergistically with lead and zinc to influence 8-iso-prostaglandin-F2α (β interaction  > 7.75%, false discovery rate-adjusted p interaction  ≤ 2.25 × 10 - 5 ). Significantly higher 8-hydroxydeoxyguanosine was observed in carriers of rs11614913 CC variant homozygote than TC carriers (p = 0.037). Associations of the number of rs11614913 C allele with increased 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were significant (β std  > 0, p trend  < 0.05) and more pronounced in workers with lower metals [p for modifying effect (p ME ) < 0.040]. Positive associations of some PAHs and metals with 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were weaker in carriers of rs11614913 CC genotype or C allele (p ME  < 0.05)., Conclusion: PAH-metal co-exposure, rs11614913, and their interactions may affect oxidative damage levels in Chinese population in a complex manner that are worthy of further investigation., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An unsafe level of manganese (Mn) was detected in the drinking water in some arsenic (As)-contaminated areas in Bangladesh. Mn is an essential trace element; however, the intake of a higher level of Mn through the drinking water is associated with the development of toxicity in humans. This study was designed to evaluate the effects of As and Mn co-exposure on neurobehavioral and biochemical alterations in a mouse model. Sodium arsenite (10 mg/kg body weight) and manganese chloride tetrahydrate (10 mg/kg body weight) were given to mice individually and in combination with drinking water for 90 days. Results showed that individual As and Mn exposure as well as co-exposure of As and Mn significantly (p < 0.05) reduced the percent of time spent in the open arms when compared with that of control mice. In addition, percent of time spent in open arms significantly (p < 0.05) increased in co-exposed mice compared with As exposure in elevated plus maze (42.05 ± 1.10 versus 38.94 ± 0.66). In the Morris water maze test, the mean time latency to find the platform was longer in metal-treated mice in comparison to that of control mice (p < 0.05). Importantly, the co-exposed group had shorter time when compared with the As-exposed group during the training periods (p < 0.05). Moreover, co-exposed mice stayed significantly (p < 0.05) more time in the target quadrant in the probe trial in comparison with that of As-exposed mice (27.25 ± 1.21 versus 23.83 ± 0.87 s) but less time than control mice (27.25 ± 1.21 versus 43.17 ± 1.49 s). In addition, a significant (p < 0.05) alteration of biochemical parameters such as ALT, AST, ALP, BChE, and SOD as well as urea and creatinine levels were noted in the As-exposed group compared with the control group and Mn significantly (p < 0.05) attenuated the effects of As in co-exposed mice. Therefore, the results of this study suggest that As and Mn may have some antagonistic effect and Mn could attenuate the As-induced neurobehavioral and biochemical alterations in co-exposed mice.

Nrf2 is a crucial transcription factor that regulates the expression of cytoprotective enzymes and controls cellular redox homeostasis. Both arsenic and fluoride are potent toxicants that are known to induce Nrf2. They are reported to coexist in many areas of the world leading to complex mixture effects in exposed organisms. The present study investigated the expression of Nrf2 and related xenobiotic metabolizing enzymes along with other stress markers such as histopathological alterations, catalase activity, reduced glutathione content and lipid peroxidation in zebrafish liver as a function of combined exposure to environmentally relevant concentrations of arsenic (37.87 μgL -1 or 5.05 × 10 -7 M) and fluoride (6.8 mg L -1 or 3.57 × 10 -4 M) for 60 days. The decrease in the total reduced glutathione level was evident in all treatment conditions. Hyperactivity of catalase along with conspicuous elevation in reactive oxygen species, malondialdehyde content and histo-architectural anomalies signified the presence of oxidative stress in the treatment groups. Nrf2 was seen to be induced at both transcriptional and translational levels in case of both individual and co-exposure. The same pattern was observed in case of its nuclear translocation also. From the results of qRT-PCR it was evident that at each time point co-exposure to arsenic and fluoride seemed to alter the gene expression of Cu/Zn Sod, Mn Sod, Gpx and Nqo1 just like their individual exposure but at a very low magnitude. In conclusion, this study demonstrates for the first time the differential expression and activity of Nrf2 and other stress response genes in the zebrafish liver following individual and combined exposure to arsenic and fluoride., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study, the influence of sample matrix on the relative bioavailability of arsenic (As), cadmium (Cd) and lead (Pb) was assessed following exposure of C57BL/6 mice to spiked aged (12years) soils. AIN93G mouse chow was amended with individual and tertiary As, Cd and Pb soil combinations which were administered to mice over a 9day exposure period. Contaminant relative bioavailability was calculated by comparing As urinary excretion and Cd-kidney/Pb-liver accumulation to corresponding values for compounds used to derive the respective toxicity reference value. Strong linear dose-responses were observed for mice exposed to AIN93G mouse chow augmented with individually spiked soil with As, Cd and Pb. When mice were exposed to co-contaminants, As relative bioavailability (RBA) decreased similar to results from previous co-contaminant salt experiments presumably due to the influence of Cd on phosphate transport proteins, which are utilized for As absorption. However, a decrease in Cd-kidney and Pb-liver accumulation was also observed following co-co-exposure. It was postulated that this resulted from interactions with other (essential) metals (e.g. iron, aluminium, manganese, magnesium) within the soil matrix and their influence on absorption via divalent metal transporters., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Despite the fact that most environmental exposures to metals do not occur in isolation, the combined effects of metal mixtures on brain-pituitary-gonadal axis are poorly known. The present study investigated the impacts of co-exposure to arsenic (As) and manganese (Mn) on sperm characteristics, reproductive hormones and selected oxidative stress indices in the brain, testes and epididymis of rats following exposure for 15 consecutive days to 60mg/L of AsO 2 Na and 30mg/L of MnCl 2 in drinking water. The results showed that while the brain weight remained unaffected, the fluid intake and the weights of testes and epididymis significantly (p<0.05) decreased in all the treatment groups. A significant decrease in the body weight gain when compared with control was noted only in the co-exposed rats. Moreover, the significant decreases in the antioxidant status in brain, testes and epididymis as well as in the circulatory concentrations of follicle-stimulating hormone, luteinizing hormone and testosterone were similar following separate or combined exposure of rats to As and Mn. The marked oxidative damage in the investigated tissues was accompanied by a significant decrease in the sperm quantity and quality in all the treated rats when compared with the control. Interestingly, most of the parameters determined immediately after the exposure period persisted in rats from the withdrawal experiment. Collectively, co-exposure to As and Mn suppressed the brain-pituitary-testicular axis function and the post-testicular events such as sperm function possibly via a mechanism involving persistent oxidative stress and endocrine disruption in the exposed rats., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Arsenic (As) and Cadmium (Cd) are toxic to rice plants. However, selenium (Se) has the potential to regulate As and Cd toxicity. The present study aimed to evaluate the co-exposure to As5+ and Se6+ species in two rice cultivars, BRS Pampa and EPAGRI 108. The plants were divided into six groups and cultivated until complete maturation of the grains, under greenhouse conditions. Regarding total As and inorganic As (i-As) accumulation in grains, the highest concentrations were found for BRS Pampa. For Se, EPAGRI 108 presented the highest concentration of inorganic and organic Se (i-Se and o-Se). The exposure assessments showed that Se biofortification can mitigate the As accumulation in rice and, consequently, the risk of As and Cd toxicity in grains for human consumption. The combined effect of As and Se in rice plants could represent an alternative to biofortify this food in a safe way and with a higher percentage of bioavailable Se. Although Se is able to mitigate As toxicity in rice plants, in the present study we showed that co-exposure in different cultivars under the same growing conditions may present different responses to As and Se exposure. [ABSTRACT FROM AUTHOR]

Biological organisms are exposed to low-dose arsenic or N-nitro compounds (NOCs) alone or in combination worldwide, especially in areas with high cancer prevalence through drinking water or food exposure; however, information on their combined exposure effects is limited. Here, we conducted an in-depth study of the effects on the gut microbiota, metabolomics, and signaling pathways using rat models exposed to arsenic or N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), one of the most active carcinogenic NOCs, separately or in combination with metabolomics and high-throughput sequencing. Compared to exposure alone, combined exposure to arsenic and MNNG exacerbated damage to gastric tissue morphology, interfered with intestinal microflora and substance metabolism, and exerted a stronger carcinogenic effect. This may be related to intestinal microbiota disorders, including Dyella, Oscillibacter, Myroides, and metabolic pathways such as glycine, serine, and threonine metabolism, arginine biosynthesis, central carbon metabolism in cancer, and purine and pyrimidine metabolism, thereby enhancing the cancer-causing effects of gonadotrophin-releasing hormone (GnRH), P53, and Wnt signaling pathways.

Arsenic (As) and Cadmium (Cd) are toxic to rice plants. However, selenium (Se) has the potential to regulate As and Cd toxicity. The present study aimed to evaluate the co-exposure to As5+ and Se6+ species in two rice cultivars, BRS Pampa and EPAGRI 108. The plants were divided into six groups and cultivated until complete maturation of the grains, under greenhouse conditions. Regarding total As and inorganic As (i-As) accumulation in grains, the highest concentrations were found for BRS Pampa. For Se, EPAGRI 108 presented the highest concentration of inorganic and organic Se (i-Se and o-Se). The exposure assessments showed that Se biofortification can mitigate the As accumulation in rice and, consequently, the risk of As and Cd toxicity in grains for human consumption. The combined effect of As and Se in rice plants could represent an alternative to biofortify this food in a safe way and with a higher percentage of bioavailable Se. Although Se is able to mitigate As toxicity in rice plants, in the present study we showed that co-exposure in different cultivars under the same growing conditions may present different responses to As and Se exposure.

Background: Artisanal and small-scale gold mining (ASGM) is associated with release of neurotoxic metallic or metalloid chemical elements including lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As). Objective: To examine associations between prenatal exposure and co-exposure to total lead (T-Pb), total mercury (T-Hg), total cadmium (T-Cd) and total arsenic (T-As) and infant neurodevelopment at 6 to 12 months of age in areas with ASGM activities in Tanzania. Methods: Women in their second trimester of pregnancy who resided in ASGM areas were enrolled from 2015 to 2017 (n = 883). At 6 to 12 months of age, children were assessed with the Malawi Developmental Assessment Tool (MDAT) (n = 439). We measured T-Pb, T-Hg, and T-Cd in maternal dried blood spots and T-As in maternal urines. Poisson regression was used to examine associations between prenatal concentrations of these elements and neurodevelopmental outcomes. Results: Prenatal T-Hg concentration was associated with global neurodevelopment status (aPR 1.03, CI:1.01–1.04; p

Humans are typically exposed to environmental contaminants’ mixtures that result in different toxicity than exposure to the individual counterparts. Yet, the toxicology of chemical mixtures has been overlooked. This work aims at assessing and comparing viability and cell cycle of A549 cells after exposure to single and binary mixtures of: titanium dioxide nanoparticles (TiO2NP) 0.75−75 mg/L; cerium oxide nanoparticles (CeO2NP) 0.75−10 μg/L; arsenic (As) 0.75−2.5 mg/L; and mercury (Hg) 5−100 mg/L. Viability was assessed through water-soluble tetrazolium (WST-1) and thiazolyl blue tetrazolium bromide (MTT) (24 h exposure) and clonogenic (seven-day exposure) assays. Cell cycle alterations were explored by flow cytometry. Viability was affected in a dose- and time-dependent manner. Prolonged exposure caused inhibition of cell proliferation even at low concentrations. Cell-cycle progression was affected by TiO2NP 75 mg/L, and As 0.75 and 2.5 μg/L, increasing the cell proportion at G0/G1 phase. Combined exposure of TiO2NP or CeO2NP mitigated As adverse effects, increasing the cell surviving factor, but cell cycle alterations were still observed. Only CeO2NP co-exposure reduced Hg toxicity, translated in a decrease of cells in Sub-G1. Toxicity was diminished for both NPs co-exposure compared to its toxicity alone, but a marked toxicity for the highest concentrations was observed for longer exposures. These findings prove that joint toxicity of contaminants must not be disregarded.

Arsenic (As) toxicity has caused an environmental tragedy affecting millions of people in the world. Little is known about the toxic effects of As on neurobehavioral and biochemical changes in vivo. Along this line of metal toxicity, co-exposure of lead (Pb) could aggravate the situation in the host. The present study was designed to explore the combined effects of As and Pb on behavioral changes like anxiety, spatial memory and learning impairment, and blood indices related to organ dysfunction. Exposure of mice to As (10 mg/kg body weight), Pb (10 mg/kg body weight), and As + Pb via drinking water significantly decreased the time spent exploring the open arms while it increased the time spent in the closed arms compared to control mice in the elevated plus maze. The mean latency time of the control group to find the platform decreased significantly during the learning for 7 days compared to all three treated groups in the Morris water maze test, and the As-exposed group spent significantly less time in the desired quadrant as compared to the control group in the probe trial. Both metals posed an anxiety-like behavior and deficits in spatial memory and learning, and also altered blood indices related to liver and kidney dysfunction, and a combined exposure of these metals inhibited the individual accumulation of As and Pb. Taken together, these data suggest that As has more toxic effects on neurobehavioral and biochemical changes than Pb, and there may be antagonism in the effects and accumulation between these two toxicants. [ABSTRACT FROM AUTHOR]

Abstract: Arsenic is a ubiquitous environmental factor that has been identified as a risk factor for a wide range of human diseases. Alcohol is clearly a toxic substance when consumed in excess. Alcohol abuse results in a variety of pathological effects, including damages to liver, heart, and brain, as well as other organs, and is associated with an increased risk of certain types of cancers. In history, arsenic-contaminated beers caused severe diseases. There are populations who are exposed to relatively high levels of arsenic in their drinking water and consume alcohol at the same time. In this focused review, we aim to discuss important molecular mechanisms responsible for arsenic toxicity and potential combined toxic effects of alcohol and arsenic. [ABSTRACT FROM AUTHOR]

Arsenic is an environmental contaminant, while acetaminophen is an extensively used nonsteroidal analgesic–antipyretic drug. We evaluated whether subacute co-exposure to arsenic and acetaminophen would produce more toxicity than that caused by exposure to either of the xenobiotics in rats. Toxicity was evaluated through changes in body weight, feed consumption, liver weight and microsomal drug-metabolizing enzymes, lipid peroxidation and antioxidants in liver. Arsenic had no effect on body weight and feed consumption. Acetaminophen-mediated decrease in body weight was attenuated in the co-exposed rats. Acetaminophen alone or its co-administration with arsenic decreased feed consumption. Arsenic reduced acetaminophen-mediated increase in the activities of drug-metabolizing enzymes. The co-exposure caused lesser lipid peroxidation than the individual exposure. Arsenic or acetaminophen given alone depleted GSH and decreased the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and these effects remained mostly unaffected after co-exposure. The results suggest that co-exposure to arsenic and acetaminophen may be less hazardous than their independent exposure in rats. [Copyright &y& Elsevier]

Arsenic is a known global groundwater contaminant, while malathion is one of the most widely used pesticides in agriculture and public health practices in the world. Here, we investigated whether repeated exposure to arsenic at the groundwater contamination levels and to malathion at sublethal levels exerts adverse effects on the hepatic drug-metabolizing system in rats, and whether concurrent exposure is more hazardous than the single agent. Male Wistar rats were exposed daily to 4 or 40 ppm of arsenic via drinking water, 50 or 500 ppm of malathion-mixed feed and in a similar fashion co-exposed to 4 ppm of arsenic and 50 ppm of malathion or 40 ppm of arsenic and 500 ppm of malathion for 28 days. At term, toxicity was assessed by evaluating changes in body weight, liver weight, levels of cytochrome P450 (CYP), cytochrome b 5 and microsomal and cytosolic proteins, and activities of aminopyrine- N-demethylase (ANDM), aniline- P-hydroxylase (APH), glutathione- S-transferase (GST) and uridine diphosphate glucuronosyltransferase (UGT) in liver. Arsenic and malathion alone did not alter body weight and liver weight, but these were significantly decreased in both the co-exposed groups. These treatments decreased the activities of ANDM and APH and the levels of liver microsomal and cytosolic proteins, increased GST activity and had no effect on UGT activity. The effects of exposure to low-dose and high-dose combinations on the activities of either phase I or phase II drug-metabolizing enzymes and protein content were mostly similar to that produced by the respective low and high dose of either arsenic or malathion, except APH activity. The effect of arsenic (40 ppm) on APH activity was partially, but significantly, inhibited by malathion (500 ppm). Results indicate that the body or liver weights and the biochemical parameters were differentially affected in male rats following concurrent subacute exposure to arsenic and malathion, with the co-exposure appearing more hazardous to physical variables based on body or liver weights whilst producing biochemical changes comparable to those caused by the individual agents. From these findings, no specific toxicological interaction between arsenic and malathion can be conclusively generalized. [ABSTRACT FROM AUTHOR]

• Infants in mining communities in Tanzania are exposed prenatally to Pb, Hg, Cd and As. • 31% of infants in these mining communities displayed neurodevelopmental impairment. • Higher levels of prenatal exposure to Hg increased the risk of neurodevelopmental impairment. • Co-exposure to As and Pb potentiated the adverse effects of prenatal Hg exposure. Artisanal and small-scale gold mining (ASGM) is associated with release of neurotoxic metallic or metalloid chemical elements including lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As). To examine associations between prenatal exposure and co-exposure to total lead (T-Pb), total mercury (T-Hg), total cadmium (T-Cd) and total arsenic (T-As) and infant neurodevelopment at 6 to 12 months of age in areas with ASGM activities in Tanzania. Women in their second trimester of pregnancy who resided in ASGM areas were enrolled from 2015 to 2017 (n = 883). At 6 to 12 months of age, children were assessed with the Malawi Developmental Assessment Tool (MDAT) (n = 439). We measured T-Pb, T-Hg, and T-Cd in maternal dried blood spots and T-As in maternal urines. Poisson regression was used to examine associations between prenatal concentrations of these elements and neurodevelopmental outcomes. Prenatal T-Hg concentration was associated with global neurodevelopment status (aPR 1.03, CI:1.01–1.04; p < 0.001) and language impairment (aPR 1.05, CI:1.03–1.07; p < 0.001) on the MDAT. When prenatal T-Hg and T-As values were at or above the human biomonitoring reference values (≥95%) of the German Environmental Survey for Human Biomonitoring, that is 0.80 µg/L and 15 µg/L, respectively, the prevalence ratio of global neurodevelopmental impairment was two times higher (aPR 2.1, CI:1.0–4.3; p = 0.034). There was a 40% increase in the prevalence ratio of global neurodevelopmental impairment (aPR 1.4, CI:0.90–2.10, p = 0.027), when prenatal T-Hg was at or above the reference value of 0.80 µg/L and T-Pb was at or above the reference value of 35 µg/L. When prenatal T-Hg was at or above the reference value of 0.80 µg/L and T-As was at or above the reference value of 15 µg/L, the prevalence ratio of global neurodevelopmental impairment was two times higher (aPR 2.1, CI:1.0–4.3; p < 0.034). Infants born to women in areas with ASGM activities are at significant risk for neurodevelopmental impairment and this is associated with exposure to higher concentrations of Hg prenatally. Co-exposure to high concentrations of Hg and Pb, or Hg and As appeared to have negative potentiated effects on infants' neurodevelopment. [ABSTRACT FROM AUTHOR]

Humans are typically exposed to environmental contaminants' mixtures that result in different toxicity than exposure to the individual counterparts. Yet, the toxicology of chemical mixtures has been overlooked. This work aims at assessing and comparing viability and cell cycle of A549 cells after exposure to single and binary mixtures of: titanium dioxide nanoparticles (TiO2NP) 0.75–75 mg/L; cerium oxide nanoparticles (CeO2NP) 0.75–10 μg/L; arsenic (As) 0.75–2.5 mg/L; and mercury (Hg) 5–100 mg/L. Viability was assessed through water-soluble tetrazolium (WST-1) and thiazolyl blue tetrazolium bromide (MTT) (24 h exposure) and clonogenic (seven-day exposure) assays. Cell cycle alterations were explored by flow cytometry. Viability was affected in a dose- and time-dependent manner. Prolonged exposure caused inhibition of cell proliferation even at low concentrations. Cell-cycle progression was affected by TiO2NP 75 mg/L, and As 0.75 and 2.5 μg/L, increasing the cell proportion at G0/G1 phase. Combined exposure of TiO2NP or CeO2NP mitigated As adverse effects, increasing the cell surviving factor, but cell cycle alterations were still observed. Only CeO2NP co-exposure reduced Hg toxicity, translated in a decrease of cells in Sub-G1. Toxicity was diminished for both NPs co-exposure compared to its toxicity alone, but a marked toxicity for the highest concentrations was observed for longer exposures. These findings prove that joint toxicity of contaminants must not be disregarded. [ABSTRACT FROM AUTHOR]

Despite arsenic being one of the most widely distributed toxicants over the world, its reported occurrence in Latin America is relatively low when compared to North America, Europe, and Asia. Regardless, it still requires proper assessment; especially considering its potential interaction with other new contaminants, such as nanomaterials. In the present study, a brief introduction to arsenic contamination in Latin America is made, its main methods of intake by humans are described, and concerns regarding its interaction with other contaminants, especially nanomaterials, are presented. A multigenerational approach through five generations of Caenorhabditis elegans was performed to assess, at ecotoxicological relevant concentrations, the toxic effects of arsenic/nanomaterial interaction through the measurement of biochemical and physiological parameters. The reactive oxygen species (ROS) and lipid peroxidation levels were assessed, levels of reduced glutathione (GSH) determined, and the enzyme activities of glutamate cysteine ligase (GCL), glutathione-S-transferase (GST), and catalase (CAT) were measured. Fertility, reproduction, and growth parameters were also assessed and compared. A nanomaterial modulatory effect was found to accentuate the toxicity of arsenic on some of the most important enzymes in the antioxidant defense system; deleterious effects were also found in the development and reproduction of the animals throughout the generations. This work shows that multigenerational approaches can unveil toxic effects that would remain cryptic when evaluated in only one generation. Unlabelled Image • Multiple generation approach assesses arsenic toxic effects. • Arsenic long-term exposure decreases development and reproduction. • Assessment of arsenic and nanomaterial at environmental concentrations • Contaminants interaction is more harmful than arsenic sole exposure. • Biochemical biomarkers are progressively inhibited through generations. [ABSTRACT FROM AUTHOR]