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Carcinogenicity of hexavalent chromium [Cr (VI)] has been supported by a number of epidemiological and animal studies; however, its carcinogenic mode of action is still incompletely understood. To identify mechanisms involved in cancer development, we analyzed gene expression data from duodena of mice exposed to Cr(VI) in drinking water. This analysis included (i) identification of upstream regulatory molecules that are likely responsible for the observed gene expression changes, (ii) identification of annotated gene expression data from public repositories that correlate with gene expression changes in duodena of Cr(VI)-exposed mice, and (iii) identification of hallmark and oncogenic signature gene sets relevant to these data. We identified the inactivated CFTR gene among the top scoring upstream regulators, and found positive correlations between the expression data from duodena of Cr(VI)-exposed mice and other datasets in public repositories associated with the inactivation of the CFTR gene. In addition, we found enrichment of signatures for oncogenic signaling, sustained cell proliferation, impaired apoptosis and tissue remodeling. Results of our computational study support the tumor-suppressor role of the CFTR gene. Furthermore, our results support human relevance of the Cr(VI)-mediated carcinogenesis observed in the small intestines of exposed mice and suggest possible groups that may be more vulnerable to the adverse outcomes associated with the inactivation of CFTR by hexavalent chromium or other agents. Lastly, our findings predict, for the first time, the role of CFTR inactivation in chemical carcinogenesis and expand the range of plausible mechanisms that may be operative in Cr(VI)-mediated carcinogenesis of intestinal and possibly other tissues., (Published by Elsevier Inc.)

Tramadol is among the most famous analgesic drugs used for the management, treatment and relief of moderate to severe pain conditions. The present study investigated the effects of tramadol on the behavior, mortality, morphometric, hematology and oxidative stress parameters of C. gariepinus juveniles. The 96 h LC 50 value of tramadol determined by probit analysis was 88.76 mg/L. Based on this value, fish were exposed to sublethal concentrations of 4.44, 8.88, 17.75 mg/L tramadol and 0.0 mg/L (control) for the period of 15 days and allowed to recover for 5 days. Fish exposed to tramadol showed some abnormal behavioral responses and mortality increased with increase in the exposure duration and concentrations except for the control. There were variations in hepatosomatic index (HSI) and condition factor (CF) in fish exposed to tramadol. Exposure of C. gariepinus to tramadol elicited reduction in the values of white blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), packed cell volume (PCV) and mean corpuscular volume (MCV) while the values of mean corpuscular hemoglobin (MCH) and the mean corpuscular hemoglobin concentration (MCHC) increased. The values of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), reduced glutathione (GSH) and lipid peroxidation (LPO) increased significantly in the exposed fish compared with the control. The values of glutathione peroxidase (GPx) however decreased. The results of the present study demonstrate that tramadol is toxic to fish and its use should be monitored in the aquatic environment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Zebrafish possess hair cells on the body surface similar to that of mammals inner hear, in particular in the neuromasts, and due to its ability in regenerating damaged hair cells, is regularly used as a powerful animal model to study in vivo cytotoxicity. Among the factors leading to hair cell disruption, metal ions are of particular concern since they are important environmental pollutants. To date, several studies on zebrafish hair cell regeneration after metal exposure exist, while no data on regeneration during continuous metal exposure are available. In the present study, neuromast hair cell disruption and regeneration were assessed in zebrafish larvae for the first time during zinc (Zn) and cadmium (Cd) continuous exposure and a visual and molecular approach was adopted. Fluorescent vital dye DASPEI was used to assess hair cell regeneration and the gene expression of claudin b (cldnb) and phoenix (pho), was analyzed. Metallotionein-2 (mt2) gene expression was used as standard molecular marker of metal toxicity and confirmed the higher toxicity of Cd compared to Zn. In addition, Cd caused a delay in hair cell regeneration compared to Zn. Molecular analysis showed cldnb gene expression increased in relation to the metal concentrations used, confirming the involvement of this gene in hair cell regeneration. On the contrary, a dramatic decrease of pho gene expression was observed in Cd exposed groups, suggesting a negative impact of Cd on pho expression, thus negatively interfering with hair cell regeneration in zebrafish larvae exposed to this metal., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is largely used as a monomer in some types of plastics. It accumulates in tissues and fluids and is able to bypass the placental barrier, affecting various organs and systems. Due to huge developmental processes, children, foetuses, and neonates could be more sensitive to BPA-induced toxicity. To investigate the multi-systemic effects of chronic exposure to a low BPA dose (100 μg/L), pregnant Wistar rats were exposed to BPA in drinking water during gestation and lactation. At weaning, newborn rats received the same treatments as dams until sex maturation. Free and conjugated BPA levels were measured in plasma and adipose tissue; the size of cerebral ventricles was analysed in the brain; morpho-functional and molecular analyses were carried out in the liver with a focus on the expression of inflammatory cytokines and Sirtuin 1 (Sirt1). Higher BPA levels were found in plasma and adipose tissue from BPA treated pups (17 PND) but not in weaned animals. Lateral cerebral ventricles were significantly enlarged in lactating and weaned BPA-exposed animals. In addition, apart from microvesicular steatosis, liver morphology did not exhibit any statistically significant difference for morphological signs of inflammation, hypertrophy, or macrovesicular steatosis, but the expression of inflammatory cytokines, Sirt1, its natural antisense long non-coding RNA ( Sirt1-AS LncRNA ) and histone deacetylase 1 (Hdac1) were affected in exposed animals. In conclusion, chronic exposure to a low BPA dose could increase the risk for disease in adult life as a consequence of higher BPA circulating levels and accumulation in adipose tissue during the neonatal period.

Inflammation is a form of innate immune response of living organisms to harmful stimuli. In marine bivalves, inflammation is a common defense mechanism. Several studies have investigated the morphological features of inflammation in bivalves, such as hemocyte infiltration. However, the molecular and biochemical responses associated with inflammation in marine bivalves remain unexplored. Here, we investigated changes in nitric oxide (NO) levels, cyclooxygenase 2 (COX-2) activity, and allograft inflammatory factor-1 (AIF-1) gene expression levels in hemolymph samples collected from Manila clam (Ruditapes philippinarum) exposed to pro- and anti-inflammatory substances. These included the pro-inflammatory agent lipopolysaccharide (LPS), and the nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and diclofenac, all widely used in vertebrates. Our study showed that NO levels, COX-2 activity, and AIF-1 expression increased in response to the treatments with LPS and decreased in response to the treatments with NSAIDs in a concentration-dependent manner. These results suggest that the mechanism of inflammatory responses in bivalves is very similar to that of vertebrates, and we propose that inflammatory responses can be quantified using these techniques and used to determine the physiological status of marine bivalves exposed to biotic or abiotic stresses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite the rapid increase of nanotechnology in a wide array of industrial sectors, the biosafety profile of nanomaterials remains undefined. The accelerated use of nanomaterials has increased the potential discharge of nanomaterials into the environment in different ways. The aquatic environment is mainly susceptible as it is likely to act as an ultimate sink for all contaminants. Therefore, this study assessed the toxicological impacts of waterborne engineered copper nanoparticles (Cu-NPs) on histology, lipid peroxidation (LPO), catalase (CAT), and glutathione (GSH) levels in the gills of common carp ( Cyprinus carpio ). Nanoparticles were characterized by XRD and SEM techniques. Before starting the sub-acute toxicity testing, 96 h LC50 of Cu-NPs for C. carpio was calculated as 4.44 mg/l. Then based on LC50, C. carpio of 40-45 g in weight were exposed to three sub-lethal doses of waterborne engineered Cu-NPs (0 or 0.5 or 1 or 1.5 mg/l) for a period of 14 days. The waterborne Cu-NPs have appeared to induce alterations in gill histology and oxidative stress parameters in a dose-dependent manner. The gill tissues showed degenerative secondary lamellae, necrotic lamella, fused lamella, necrosis of the primary and secondary lamella, edema, complete degeneration, epithelial lifting, degenerative epithelium, and hyperplasia in a dose-dependent manner. In the gill tissues, waterborne Cu-NPs caused a decreased level of CAT and elevated levels of LPO, and GSH in the fish exposed to the highest dose of 1.5 mg Cu-NPs/l of water. Our results indicate that the exposure to waterborne Cu-NPs was toxic to the aquatic organisms as shown by the oxidative stresses and histological alterations in C. carpio , a freshwater fish of good economic value.

Scientifically robust selections of epidemiological studies and assessments of the dose-response of inorganic arsenic in the low-dose range must consider key issues specific to arsenic in order to reduce risk of bias. The abundance of toxicological, mechanistic, and epidemiological evidence on arsenic enables a nuanced assessment of risk of bias in epidemiological studies of low-level arsenic, as opposed to a generic evaluation based only on standard principles. Important concepts in this context include 1) arsenic metabolism and mode of action for toxicity and carcinogenicity; 2) effects of confounding factors such as diet, health status including nutritional deficiencies, use of tobacco and other substances, and body composition; 3) strengths and limitations of various metrics for assessing relevant exposures consistent with the mode of action; and 4) the potential for bias in the positive direction for the observed dose-response relationship as exposure increases in the low-dose range. As an example, evaluation of a recent dose-response modeling using eight epidemiological studies of inorganic arsenic and bladder cancer demonstrated that the pooled risk estimate was markedly affected by the single study that was ranked as having a high risk of bias, based on the above factors. The other seven studies were also affected by these factors to varying, albeit lesser, degrees that can influence the apparent dose-response in the low-dose range (i.e., drinking water concentration of 65 µg/L or dose of approximately ≤1 µg/kg-day). These issues are relevant considerations for assessing health risks of oral exposures to inorganic arsenic in the U.S. population, and setting evidence-based regulatory limits to protect human health., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The linear no-threshold (LNT) model has historically been the default assumption in assessing carcinogenic risk from arsenic ingestion based on epidemiological studies. This contrasts with the threshold model used in assessing carcinogenic risk from arsenic ingestion derived from toxicological investigations of experimental animals. We present here a review of our epidemiological work that has examined models that may better explain the human cancer risk from the ingestion of arsenic, particularly from low level exposures, than does the LNT model. While previous epidemiology studies have demonstrated increased risks of bladder, lung, and skin cancers at arsenic exposures of 200 ug/L or greater, we seek here to examine the dose-response patterns at lower exposure levels. These include ecological, case/control, and cohort designs. Methodologic issues include choice of continuous or stratified analysis of exposure data, search for sources of non-conformity or variability, and distinctions in water sources and geography. Multiple studies have yielded useful data-based models, including threshold models, hockey-stick models, and "J-shaped" linear-quadratic models. These models have found that increased cancer risk may only begin at specific arsenic exposure levels greater than zero. These results provide guidance in seeking toxicological explanations and public health reference levels., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Abundant epidemiological evidence has shown that there is a strong causal relationship between long-term exposure to inorganic arsenic (iAs) through drinking water and a few types of cancer (e.g., lung and bladder cancer). Traditionally, a linear low-dose extrapolation assumption was applied in risk assessment for iAs which resulted in a relatively conservative cancer risk estimate. Growing biological evidence suggests that the mode of action of iAs-induced cancer follows a threshold process (e.g., sufficient concentration of trivalent arsenic is required to disrupt normal cellular function). In this study, we applied the benchmark dose (BMD) methodology to model the relationship between the relative risk of bladder and lung cancer and the iAs concentration in drinking water using the high-quality epidemiological data reported in recently published papers, with a special focus on the low exposure range (i.e., <150 μg/L). Because of its biological plausibility and statistical flexibility, the Hill model has been chosen to model the data under a Bayesian framework. A Bayesian hierarchal model together with a bootstrap method for exposure estimation were applied to quantify uncertainty from various sources, including the within-study, between-study, and exposure uncertainties. Dose-response assessment results obtained from a number of alternative model structures and methods consistently demonstrate a threshold type dose-response curve with a threshold in the range between 40-60 μg/L of iAs concentration in drinking water. The BMD for iAs in drinking water associated with 0.1 % increase in relative risk of bladder cancer is 42.2 μg/L (BMDL 39.2 μg/L); for 0.05 % increase, the BMD is 41.6 μg/L (BMDL 38.6 μg/L). For lung cancer, the two counterpart BMD estimates are 57.0 μg/L (BMDL 43.6 μg/L) and 55.7 μg/L (BMDL 42.5 μg/L) for 0.1 % and 0.05 % increase, respectively. These analyses provide additional statistical support for a non-linear dose response for cancer risk from inorganic arsenic which may have important policy implications., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Depression is one of the most common neuropsychiatric disorders. Although the pathogenesis of depression is still unknown, environmental risk factors and genetics are implicated. Copper (Cu), a cofactor of multiple enzymes, is involved in regulating depression-related processes. Depressed patients carrying the apolipoprotein ε 4 allele display more severe depressive symptoms, indicating that ApoE4 is closely associated with an increased risk of depression. The study explored the effect of low-dose Cu exposure and ApoE4 on depression-like behavior of mice and further investigates the possible mechanisms. The ApoE4 mice and wild-type (WT) mice were treated with 0.13 ppm CuCl 2 for 4 months. After the treatment, ApoE4 mice displayed obvious depression-like behavior compared with the WT mice, and Cu exposure further exacerbated the depression-like behavior of ApoE4 mice. There was no significant difference in anxiety behavior and memory behavior. Proteomic analysis revealed that the differentially expressed proteins between Cu-exposed and nonexposed ApoE4 mice were mainly involved in the Ras signaling pathway, protein export, axon guidance, serotonergic synapse, GABAergic synapse, and dopaminergic synapse. Among these differentially expressed proteins, immune response and synaptic function are highly correlated. Representative protein expression changes are quantified by western blot, showing consistent results as determined by proteomic analysis. Hippocampal astrocytes and microglia were increased in Cu-exposed ApoE4 mice, suggesting that neuroglial cells played an important role in the pathogenesis of depression. Taken together, our study demonstrated that Cu exposure exacerbates depression-like behavior of ApoE4 mice and the mechanisms may involve the dysregulation of synaptic function and immune response and overactivation of neuroinflammation., Competing Interests: All authors declare that they have no conflict of interest., (Copyright © 2021 Jia Xu et al.)

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 μg/L, 10 μg/L, 100 μg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 μg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 μg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 μg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 β hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 μg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Organophosphorus flame retardants (OPFRs) have been extensively used as chemical additives in polymer based consumer products. Among them, Isopropylphenyl phosphate (IPPP) and tripropyl phosphate (TPP) are predominant, which have potential to cause neuro-toxic effects on non-target organisms. As behavior (swimming activity) response is the first adjustment due to neurotoxic stress on the fitness of fish. In this study, the quantified swimming activity of zebrafish (Danio rerio) under IPPP and TPP exposure in an online monitoring system was investigated to assess the neurotoxin effects under long-term exposure periods, no swimming anomalies were observed in the control group. Whereas, in the OPFR exposures ((treatment I: 5 μg/L and treatment II: 25 μg/L), a series of anomalies were identified. Hyperactivity was shown in IPPP treatment I group (5 μg/L), whereas zebrafish swimming activity was declined throughout the study period in IPPP treatment II (25 μg/L), and TPP groups (5 μg/L and 25 μg/L) when compared to the control group. Circadian rhythm was not affected in the present study. The results of the present study indicated that the fitness of test individuals was a valid biomarker for eco-toxicity assessment under unescapable conditions. Hypoactivity of zebrafish signified the neurotoxic effects of IPPP and TPP. A concentration based improvement in swimming activity was observed under recovery conditions, which suggested that recovery capacity along with toxicity responses could be a comprehensive non-invasive technique to assess the eco-toxicity of waterborne chemicals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The research objective was to study the presence of DNA damages in haddock exposed to petrogenic or pyrogenic polyaromatic hydrocarbons (PAHs) from different sources: 1) extracts of oil produced water (PW), dominated by 2-ring PAHs; 2) distillation fractions of crude oil (representing oil-based drilling mud), dominated by 3-ring PAHs; 3) heavy pyrogenic PAHs, mixture of 4/5/6-ring PAHs. The biological effect of the different PAH sources was studied by feeding juvenile haddock with low doses of PAHs (0.3-0.7 mg PAH/kg fish/day) for two months, followed by a two-months recovery. In addition to the oral exposure, a group of fish was exposed to 12 single compounds of PAHs (4/5/6-ring) via intraperitoneal injection. The main endpoint was the analysis of hepatic and intestinal DNA adducts. In addition, PAH burden in liver, bile metabolites, gene and protein expression of CYP1A, GST activity, lipid peroxidation, skeletal deformities and histopathology of livers were evaluated. Juvenile haddock responded quickly to both intraperitoneal injection and oral exposure of 4/5/6-ring PAHs. High levels of DNA adducts were detected in livers three days after the dose of the single compound exposure. Fish had also high levels of DNA adducts in liver after being fed with extracts dominated by 2-ring PAHs (a PW exposure scenario) and 3-ring PAHs (simulating an oil exposure scenario). Elevated levels of DNA adducts were observed in the liver of all exposed groups after the 2 months of recovery. High levels of DNA adduct were found also in the intestines of individuals exposed to oil or heavy PAHs, but not in the PW or control groups. This suggests that the intestinal barrier is very important for detoxification of orally exposures of PAHs., Competing Interests: The authors have declared that no competing interests exist.

Accumulation, contents of protein, non-enzymatic antioxidant glutathione (GSH and GSSG), lipid peroxidation product (melondialdehyde-MDA) and organic acids (fumarate, succinate, malate and citrate), and activities of neurological (acetylcholinesterase-AChE), detoxification (glutathione S-transferase-GST) and metabolic (lactate dehydrogenase-LDH, aspartate transaminase-AST and alanine transaminase-ALT) enzymes were recorded in the hatchlings of Cyprinus carpio, Ctenopharyngodon idella, Labeo rohita and Cirrhinus mrigala after 7 and 14 days exposure and 10 days post exposure (recovery period) to sublethal concentrations (0.005, 0.01, 0.02 and 0.05 mg/L) of triclosan, a highly toxic and persistent biocide used in personal care products. Accumulation was maximum between 7-14 days at 0.01 mg/L for C. carpio and L. rohita but at 0.005 mg/L for C. idella and C. mrigala. No triclosan was observed at 0.005 mg/L in C. carpio and C. mrigala after recovery. Significant decline in protein, glutathione and acetylcholinesterase but increase in glutathione S-transferase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, melondialdehyde and organic acids over control during exposure continued till the end of recovery period. Integrated biomarker response (IBR) analysis depicted higher star plot area for glutathione and glutathione S-transferase during initial 7 days of exposure, thereafter, during 7-14 days of exposure and the recovery period, higher star plot area was observed for acetylcholinesterase, aspartate transaminase, alanine transaminase and organic acids. Higher star plot area was observed for protein in all the species throughout the study. The study shows that L. rohita is most sensitive and glutathione, acetylcholinesterase, aspartate transaminase and alanine transaminase are the biomarkers for the toxicity of sublethal concentrations of TCS.

Response to simultaneous stressors is an important facet of plant ecology and land management. In a greenhouse trial, we studied how eight plant species responded to single and combined effects of three soil concentrations of the phytotoxic munitions constituent RDX and two levels of water-resourcing. In an outdoor trial, we studied the effects of high RDX soil concentration and two levels of water-resourcing in three plant species. Multiple endpoints related to RDX fate, plant health, and plant survival were evaluated in both trials. Starting RDX concentration was the most frequent factor influencing all endpoints. Water-resourcing also had significant impacts, but in fewer cases. For most endpoints, significant interaction effects between RDX concentration and water-resourcing were observed for some species and treatments. Main and interaction effects were typically variable (significant in one treatment, but not in another; associated with increasing endpoint values for one treatment and/or with decreasing endpoint values in another). This complexity has implications for understanding how RDX and water-availability combine to impact plants, as well as for applications like phytoremediation. As an additional product of these greenhouse and outdoor trials, three plants native or naturalized within the southeastern United States were identified as promising species for further study as in situ phytoremediation resources. Plumbago auriculata exhibited relatively strong and markedly consistent among-treatment mean proportional reductions in soil RDX concentrations (112% and 2.5% of the means of corresponding values observed within other species). Likewise, across all treatments, Salvia coccinea exhibited distinctively low variance in mean leaf chlorophyll content index levels (6.5% of the means of corresponding values observed within other species). Both species also exhibited mean wilting and chlorosis levels that were 66% and 35%, and 67% and 84%, of corresponding values observed in all other plants, respectively. Ruellia caroliniensis exhibited at least 43% higher mean survival across all treatments than any other test species in outdoor trials, despite exhibiting similar RDX uptake and bioconcentration levels., Competing Interests: The authors have declared that no competing interests exist.

The present study exposed adult zebrafish to 0, 10, and 100 μg/L perfluorobutanesulfonate (PFBS) with or without dietary supplement of probiotic Lactobacillus rhamnosus . Interaction between probiotic and PFBS on sex endocrine and reproduction was investigated. It was striking to find that PFBS and probiotic coexposures almost ceased the fecundity, which was accompanied by disturbances in sex hormones and oocyte maturation in females. In contrast, probiotic additive efficiently antagonized the estrogenic activity of PFBS in males. For the first time, this study reported that probiotic heavily depended on sex to modulate the endocrine disruption and reproductive toxicity of aquatic pollutants.

Present study was undertaken to investigate the toxic effect of sodium fluoride (NaF)- and fluoride (F)-contaminated ground water on reproductive performances of male rats. Healthy adult male rats were categorised into three groups, first group of rats were served as control, whereas second group of rats were orally intubated with NaF (10 mg/kgbw/1 ml/rat) and third group of rats were allowed to drink F-contaminated ground water (5 mg/L) through drinking water bottles for 52 days. Exposure of NaF- and F-contaminated ground water caused significant decline in sperm motility, serum concentration of testosterone, and increase in sperm abnormality compared with controls. Further, significant histological alterations characterized with shrunken seminiferous tubules and degeneration of different stages of spermatogonial cells were observed in rats treated with NaF- and F-contaminated ground water. After the confirmation of toxic effect of F, these NaF- and F-contaminated ground water-treated male rats were allowed to mate with proven fertile untreated female rats to study the reproductive performances of male rats. There was a decline in parturition index, fertility index of male and female, gestation index and number of pups delivered in NaF-treated male rats compared with controls. However, gestation index and number of pups delivered were declined in F-contaminated ground water-treated male rats compared with controls. These results clearly indicate that F exposure affected the reproductive performances of male rats. The present study further revealed the fact that F-induced decline in testosterone levels, reduced sperm motility, and loss of spermatogonial cells affected the reproductive performances of male rats.

Mercury (Hg) is among the most deleterious contaminant in the aquatic environment and presents a serious risk to humans and ecosystems. This study evaluated the effects of Hg on oxidative stress biomarkers, DNA integrity and histological structure of the respiratory tree of Holothuria forskali exposed to different concentrations of mercury chloride HgCl 2 (0.04, 0.08 and 0.16 mg L -1 ) for 96 h. Exposure of H. forskali to Hg led to oxidative stress with an increase in Malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), advanced oxidation protein product (AOPP) and protein carbonyls (PCO) levels in the treated groups. Alteration of the antioxidant system was also confirmed by the significant increase in glutathione (GSH), nonprotein thiol (NPSH) and vitamin C contents. Moreover, the enzymatic activity of superoxide dismutase (SOD), Glutathione peroxidase (GPX) and Catalase (CAT) increased significantly. Our research revealed that total Metallothionein (MTs) content enhanced in a dose-dependent manner. Interestingly, the exposure to this metal provoked a decrease in Acetylcholinesterase (AChE) activity. Hg genotoxicity was further evidenced by a random DNA degradation that was observed in the treated groups. The histopathological findings confirmed the biochemical results. Overall, our results indicated that mercury-induced genotoxicity, oxidative damage and histopathological injuries in the respiratory tree of H. forskali.

Titanium dioxide nanoparticles (nTiO 2 ) have raised environmental concerns and display potential hazards to aquatic organisms and even humans. However, only a few reports tested the toxicity of nTiO 2 to rotifers. In the present study, acute and chronic toxicity of nTiO 2 to the freshwater rotifer Brachionus calyciflorus was investigated at different temperatures. At 25°C, the 24 and 48-hr LC 50 was 117.14 and 60.11 mg/L, respectively. At 15°C, 20°C, 25°C, and 30°C, exposure to nTiO 2 significantly decreased life expectancy at birth, net reproductive rate, generation time, average lifespan, and/or intrinsic rate of population increase of B. calyciflorus (p < .05). High temperature enhanced the toxicity of nTiO 2 to rotifers. The swimming linear speed of rotifers significantly increased (p < .05) in treatments with 200 µg/L nTiO 2 , compared with the control. In addition, treatments with 8 µg/L to 5 mg/L nTiO 2 significantly increased superoxide dismutase activity (p < .05). Glutathione content and catalase activity increased significantly after exposure to 8 µg/L nTiO 2  but decreased significantly in treatments with nTiO 2 concentrations ranging from 40 µg/L to 5 mg/L (p < .05). There were no significant changes in malondialdehyde contents among nTiO 2 treatments and control. Overall, the present study indicated that nTiO 2 revealed high toxicity to rotifers, displaying high environmental risks to aquatic ecosystems., (© 2020 Wiley Periodicals, Inc.)

The photodegradation of benzisothiazolinone was studied in water under UV-Vis irradiation and led to fourteen photoproducts. Chemical structures of these compounds were elucidated using GC-MS, LCMS/MS, and FT-ICR-MS experiments. Based on the chemical structures determined and their appearance order, a photo induced-degradation mechanism of benzisothiazolinone has been proposed, which combines isomerization, oxidation, hydroxylation, hydrolysis, and elimination processes. In silico tests on mutagenicity, Fathead minnow LC50 and oral rat LD50 were carried out to estimate the toxicity of the photoproducts. Compared with experimental data, the calculated oral rat LD50 values were found to be the most relevant and thus used for toxicity estimation. The photoproducts including a phenolic or a sulfino group or both functions were found potentially more toxic than benzisothiazolinone., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Simvastatin (SIM), a hypocholesterolaemic drug belonging to the statins group, is a widely prescribed pharmaceutical for prevention of cardiovascular diseases. Several studies showed that lipophilic statins, as SIM, cross the blood-brain barrier and interfere with the energy metabolism of the central nervous system in humans and mammalian models. In fish and other aquatic organisms, the effects of SIM on the brain energy metabolism are unknown, particularly following exposure to low environmentally relevant concentrations. Therefore, the present study aimed at investigating the influence of SIM on gene signaling pathways involved in brain energy metabolism of adult zebrafish ( Danio rerio ) following chronic exposure (90 days) to environmentally relevant SIM concentrations ranging from 8 ng/L to 1000 ng/L. Real-time PCR was used to determine the transcript levels of several genes involved in different pathways of the brain energy metabolism ( glut1b, gapdh, acadm, accα, fasn, idh3a, cox4i1 , and cox5aa ). The findings here reported integrated well with ecological and biochemical responses obtained in a parallel study. Data demonstrated that SIM modulates transcription of key genes involved in the mitochondrial electron transport chain, in glucose transport and metabolism, in fatty acid synthesis and β-oxidation. Further, SIM exposure led to a sex-dependent transcription profile for some of the studied genes. Overall, the present study demonstrated, for the first time, that SIM modulates gene regulation of key pathways involved in the energy metabolism in fish brain at environmentally relevant concentrations.

Copper (Cu) in an essential trace metal but it can also contaminate coastal waters at high concentrations mainly from agricultural run-off and mining activities which are detrimental to marine organisms including seagrasses. The molecular mechanisms driving Cu toxicity in seagrasses are not clearly understood yet. Here, we investigated the molecular responses of the Australian seagrass, Z. muelleri at the whole transcriptomic level after 7 days of exposure to 250 μg Cu L -1 and 500 μg Cu L -1 . The leaf-specific whole transcriptome results showed a concentration-dependent disturbance in chloroplast function, regulatory stress responses and defense mechanisms. This study provided new insights into the responses of seagrasses to trace metal stress and reports possible candidate genes which can be considered as biomarkers to improve conservation and management of seagrass meadows., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Arsenic is a common toxic contaminant in food and drinking water. Metabolic activation of arsenic species produces reactive trivalent intermediates that can disrupt cellular regulatory systems by covalent binding to thiol groups. Arsenic exposures have been associated with human diseases including cancer, diabetes, lung and cardiovascular disorders and there is accumulating evidence that early life exposures are important in the etiology. Previous toxicokinetic studies of arsenite ingestion in neonatal CD-1 mice showed consistent evidence for metabolic and physiologic immaturity that led to elevated internal exposures to trivalent arsenic species in the youngest mice, relative to adults. The current study in rhesus monkeys showed that metabolism and binding of trivalent intermediates after arsenite ingestion were similar between adult monkeys and CD-1 mice. Unlike neonatal mice, monkeys from the age of 5-70 days showed similar metabolism and binding profiles, which were also similar to those in adults. The absence of evidence for metabolic immaturity in monkeys suggests that toxicological effects observed in mice from early postnatal exposures to arsenic could over-predict those possible in primates, based on significantly higher internal exposures., (Published by Elsevier Ltd.)

Recently, the residues of some common and widely used herbicides (acetochlor, bispyribac-sodium, bentazon, bensulfuron-methyl, halosulfuron-methyl, and quinclorac) were detected in the surface water, soil, sediments, and fish tissues as the agricultural drainage problems. In this study, juveniles of Nile tilapia Oreochromis niloticus were exposed to sub-lethal concentrations of these herbicides as 2.625, 0.800, 36.00, 2.50, 1.275, and 11.250 mg/l for acetochlor, bispyribac-sodium, bentazon, bensulfuron-methyl, halosulfuron-methyl, and quinclorac respectively for 96 h. Some hemato-biochemical parameters were evaluated. In comparison with the control group, sub-lethal concentrations of all tested herbicides induced alterations in the shape of erythrocytes. Also, in all tested herbicides, hematological parameters of exposed fish exhibited a significant decrease in red blood cell count except bentazon. However, all tested herbicides showed an insignificant reduction in mean corpuscular hemoglobin concentration and total white blood cells except bensulfuron-methyl. For biochemical parameters, most tested herbicides induced a significant increase in levels of cholesterol, albumin, globulin, albumin/globulin ratio, activity of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total plasma protein (only with acetochlor), urea, and creatinine (except bentazon and halosulfuron-methyl that exhibited non-significant decrease in creatinine level) compared with the control. In conclusion, the fish blood profiles can be used as good biomarkers for laboratory study to assess the toxicity of the tested rice herbicides at a sub-acute level especially acetochlor on O. niloticus. Graphical Abstract.

Mice have been frequently used to study the adverse effects of inorganic arsenic (iAs) exposure in laboratory settings. Like humans, mice metabolize iAs to monomethyl-As (MAs) and dimethyl-As (DMAs) metabolites. However, mice metabolize iAs more efficiently than humans, which may explain why some of the effects of iAs reported in humans have been difficult to reproduce in mice. In the present study, we searched for mouse strains in which iAs metabolism resembles that in humans. We examined iAs metabolism in male mice from 12 genetically diverse Collaborative Cross (CC) strains that were exposed to arsenite in drinking water (0.1 or 50 ppm) for 2 weeks. Concentrations of iAs and its metabolites were measured in urine and livers. Significant differences in total As concentration and in proportions of total As represented by iAs, MAs, and DMAs were observed between the strains. These differences were more pronounced in livers, particularly in mice exposed to 50 ppm iAs. In livers, large variations among the strains were found in percentage of iAs (15-48%), MAs (11-29%), and DMAs (29-66%). In contrast, DMAs represented 96-99% of total As in urine in all strains regardless of exposure. Notably, the percentages of As species in urine did not correlate with total As concentration in liver, suggesting that the urinary profiles were not representative of the internal exposure. In livers of mice exposed to 50 ppm, but not to 0.1 ppm iAs, As3mt expression correlated with percent of iAs and DMAs. No correlations were found between As3mt expression and the proportions of As species in urine regardless of exposure level. Although we did not find yet a CC strain in which proportions of As species in urine would match those reported in humans (typically 10-30% iAs, 10-20% MAs, 60-70% DMAs), CC strains characterized by low %DMAs in livers after exposure to 50 ppm iAs (suggesting inefficient iAs methylation) could be better models for studies aiming to reproduce effects of iAs described in humans.

Arsenic is prevalent in contaminated drinking water and affects more than 140 million people in 50 countries. While the wide-ranging effects of arsenic on neurological development and cancer draw the majority of concern, arsenic's effects on the gut mucosa-associated immune system are often overlooked. In this study, we show that 24 h after a single dose [low dose (50 μg/kg bw), medium dose (100 μg/kg bw) or high dose (200 μg/kg bw)] of arsenic by oral gavage, mice show significantly reduced gut mucosa-associated mRNA expression for the key genes involved in the signaling pathways central to immune responses, such as Nuclear factor κB (NFκB), Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), p38 and Myeloid differentiation protein 88-dependent (Myd88) pathways. Additionally, mRNA expression of apoptosis, inflammasomes and inflammatory response genes are significantly downregulated in the animals exposed to arsenic. Comparisons of time-dependent effects (24 h vs 48 h) from low dose arsenic exposed animals showed a significant shift in expression of Myd88 alone, suggesting that the down regulation was sustained for the key genes/signaling pathway. An extended eight-day exposure to arsenic showed a decreased state of immune preparedness, though not as diminished as seen in the single dose exposure., (Published by Elsevier Ltd.)

The importance of trace elements in ecotoxicological investigations is a well-known issue when monitoring polluted areas such as commercial harbors. Copper represents one of the most common metal contaminants, often detected in these areas as it is widely employed in various fields and has many sources of inflow in the marine environment. Pachygrapsus marmoratus is a widespread intertidal crab species that has been extensively studied in ecology, ethology and population genetics. Ecotoxicological studies have also been performed, exclusively on the adult stage. In the present study we investigated the mortality and biochemical (oxidative stress and neurotoxicity) responses of P. marmoratus larvae exposure to environmental relevant concentration of copper. Results showed dose-dependent responses in terms of larval mortality, with a calculated LC 50 value of 0.5 mg/L of Cu 2+ . The LC 50 concentration was used as the starting point for subsequent biochemical response evaluation. Results also demonstrated dose-dependent activation of antioxidant systems assuming a compensatory antioxidant activity to prevent higher cellular damage when larvae were exposed to the highest concentrations of copper. Moreover, a significant enhancement of neurotransmitter activities was observed, assuming a possible direct interaction of copper with the enzymes or an increase of free copper ion aliquot into the cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sea-Nine™ 211 is an emerging biocide that has an adverse impact on aquatic environments. In this study, the marine polychaete Perinereis aibuhitensis was exposed to Sea-Nine (0.1, 1, and 10 μg L -1 ), and acute toxicity and biochemical responses such as changes in the intracellular contents of malondialdehyde (MDA) and glutathione (GSH) and enzymatic activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and acetylcholinesterase (AChE) were evaluated over a period of 14 d. Determined median lethal doses, LC50 were 268 μg L -1 , 142 μg L -1 , and 55 μg L -1 at 24 h, 96 h, and 14 d, respectively. The MDA content increased significantly in a dose- and time-dependent manner, indicative of lipid peroxidation-related oxidative damage. Significantly higher intracellular GSH levels and antioxidant defense-related enzyme (CAT, SOD, GPx, GR, and GST) activities were observed after exposure to 10 μg L -1 Sea-Nine. In contrast, Sea-Nine treatment significantly reduced AChE activity at the highest concentration of Sea-Nine used (10 μg L -1 ). Taken together, these results indicate that sublethal concentrations of Sea-Nine are toxic to marine polychaetes through potential lipid peroxidation, induction of oxidative stress, and modulation of the cholinergic system. Our results can contribute to biomonitoring of aquatic environments and ecotoxicological research through the measurements of polychaete cellular defenses against waterborne biocides., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fluoride (F - ), a harmful compound if present in high concentration, is typically found in groundwater. It is important to investigate the F - concentrations in groundwaters of areas where individuals use groundwater for drinking purposes. The objectives of this study were: (a) to estimate the F - exposure, and (b) to assess the non-carcinogenic risk through consumption of groundwater among urban population (different age groups) of Agra city. A total of 28 groundwater samples were collected from Agra city in May 2016, which comprised 22 samples from hand pump and 6 samples from tube wells from shallow aquifers at different sites. The F - concentrations varied from 0.90 to 4.12 mg/L with an average value of 1.88 mg/L. The results obtained reveal that about 64% of the samples exceeded the F - permissible limit of 1.5 mg/L. Nevertheless, 32% of the samples were well within the WHO drinking water guidelines and 3.5% of the samples from the groundwater were below the 1.0 mg/L threshold. The maximum estimated exposure doses were 0.69, 0.31 and 0.12 mg/kg/day for infants, children and adults, respectively. A dental fluorosis becomes evident when the results obtained are compared with an oral reference dose of 0.06 mg/kg/day. The hazard quotient (HQ) was found to be more than 1 for infants and children in all the studied areas which indicates that young consumers are more vulnerable to non-carcinogenic risk due to exposure of F - . On the other hand, the adults at about 71% of the sampled sites may be victims of non-carcinogenic risk. From the results obtained in this study, it is recommended that there be implementation of the appropriate remediation for defluoridation of water to circumvent the population from the probable health risks of F - ., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Copper (Cu) and cadmium (Cd) are two kinds of abundant toxic metals in aquatic ecosystem. The present study evaluated the effects of waterborne Cu and Cd on oxidative stress responses and histological alterations in female rare minnow (Gobiocypris rarus). Fish were exposed for 7 days to: (i) control (no added Cu or Cd), (ii) waterborne Cu (39.2 μg L -1 ), (iii) waterborne Cd (299.6 μg L -1 ), and (iv) Cu and Cd in mixture (19.6 and 149.8 μg L -1 , respectively). Antioxidant enzyme activities and gene mRNA abundance in fish tissues (gills, liver, and ovaries) were induced by Cu and Cd exposures, both individually and in mixture, at day 1, but an asynchronous response was observed between most enzyme activities and gene mRNA abundance following 7 days exposure. Biochemical analysis and histological observation indicated that exposure to Cu and Cd, alone and in combination, caused evident damage to lipids and tissue structure in gills, liver and ovaries. Comparing with single Cu or Cd exposure, Cu and Cd co-exposure induced greater increase in the mRNA expression of most antioxidant genes and caused more severe lesions in fish tissues, which suggested that exposure to waterborne Cu and Cd in mixture might increase their individual toxicity. Furthermore, positive relationships between nuclear factor erythroid 2-related factor (Nrf2) expression and expression of manganese superoxide dismutase (Mn-SOD) and catalase (CAT) were also observed in the present study, which suggested that Cu or/and Cd induced expression of these antioxidant genes were might through activation of Nrf2., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Volatilization volumes and health risks associated with indirect inhalation exposure to formaldehyde evaporated from water have not been investigated quantitatively. We experimentally investigated formaldehyde volatility, compared with chloroform volatility, predicted formaldehyde inhalation exposure concentrations in Japanese bathrooms, and then re-evaluated drinking water quality standards. Although the Henry's law constant of formaldehyde is 1/10 4 that of chloroform, with a 30-min exposure period, the formaldehyde non-equilibrium partition coefficient (K' d ) was 1/500th the chloroform value because of formaldehyde's faster volatilization rate. We used this ratio to estimate the cumulative probability distribution of formaldehyde concentrations in bathroom air. For a formaldehyde concentration in water of ≤2.6 mg/L-water (WHO tolerable concentration), the probability that the incremental formaldehyde concentration due to volatilization would exceed 100 μg/m 3 -air (WHO indoor air quality guideline) was low. However, major sources of formaldehyde in indoor air are building materials and furniture. We therefore calculated the allowable concentration in water by allocating a small percentage of the indoor air guideline value to indirect inhalation exposure via volatilization from tap water. With an allocation factor of 20% (10%), the allowable concentration was 0.52 (0.26) mg/L-water. These concentrations are similar to the Health Canada guideline concentration but they are 3-6 times the Japanese water quality standard., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ammonium pulse attributed to runoff of urban surface and agriculture following heavy rain is common in inland aquatic systems and can cause profoundly effects on the growth of macrophytes, especially when combined with low light. In this study, three patterns of NH4-N pulse (differing in magnitude and frequency) were applied to examine their effects on the growth of three submersed macrophytes, namely, Myriophyllum spicatum, Potamogeton maackianus, and Vallisneria natans, in terms of biomass, height, branch/ramet number, root length, leaf number, and total branch length under high and low light. Results showed that NH4-N pulse caused negative effects on the biomass of the submerged macrphytes even on the 13th day after releasing NH4-N pulse. The negative effects on M. spicatum were significantly greater than that on V. natans and P. maackianus. The effects of NH4-N pulse on specific species depended on the ammonium loading patterns. The negative effects of NH4-N pulse on P. maackianus were the strongest at high loading with low frequency, and on V. natans at moderate loading with moderate frequency. For M. spicatum, no significant differences were found among the three NH4-N pulse patterns. Low light availability did not significantly aggregate the negative effects of NH4-N pulse on the growth of the submersed macrophytes. Our study contributes to revealing the roles of NH4-N pulse on the growth of aquatic plants and its species specific effects on the dynamics of submerged macrophytes in lakes., Competing Interests: The authors have declared that no competing interests exist.

During the past decade, the total population and overall reproductive performance of the oriental river prawn (Macrobrachium nipponense) in the Anzali international wetland and its basin rivers has been severely reduced. This seems to be caused by an increase in heavy metal pollution from industrial wastewaters. We investigated the effects of chronic levels of lead (Pb) and cadmium (Cd) on reproductive success, hemato-immunology, crustacean hyperglycemic hormone (cHH), Pb/Cd bioaccumulation and histopathology of hepatopancreas of oriental river prawn. The present study was separately carried out using four chronic treatments for Pb (0 (control), 0.024, 0.072 and 0.12 μM/l) and Cd (0 (control), 0.026, 0.053 and 0.08 μM/l) in experimental tanks during 60 days. The broodstock were fed by commercial shrimp diet, ad libitum, twice a day. The results revealed that reproductive activities ceased when Pb levels were 0.072 and 0.12 μM/l and also when Cd levels reached 0.08 μM/l. At 0.024 μM/l Pb, 0.026 and 0.053 μM/l Cd, the prawns showed initial reproductive activity but after spawning, the egg-clutches were found detached from the pleopods of the brood females. Hemato-immunology results showed that by increasing the Pb and Cd concentrations, large granular hemocyte (LGH) and cHH values also increased. However, small granular hemocyte (SGH) count was inversely affected. A significant increase in mortality (P < 0.05) was observed as both Pb and Cd concentrations increased. Histological observations are indicative of increased necrosis, lumen size, melanization, vacuolation and abnormal lumen shape, as the heavy metals concentrations increased. In conclusion, obtained results can help to elucidate effects of Pb and Cd on freshwater decapod crustaceans reproductive performance and related physiological parameters., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Flutolanil is a broad-spectrum amide fungicide that is widely used to prevent fungal pathogens in agriculture. However, its usage may have a potential environmental impact on organisms. So far, few literatures have investigated the chronic toxicity of flutolanil at concentrations relevant to environmental conditions in the nontarget aquatic organisms. This study was aimed at evaluating whether the long-term exposure of flutolanil affects oxidative stress, immune response, and apoptosis in the liver of zebrafish ( Danio rerio). The results showed that the activity of catalase (CAT) was significantly decreased in the liver in all flutolanil-treated groups. Interestingly, the malondialdehyde (MDA) contents were remarkably increased following the flutolanil exposure. Deoxyribonucleic acid (DNA) damage was increased with a concentration-dependent manner. The transcription level of genes involved in apoptosis and the immune system were significantly altered following flutolanil chronic exposure in zebrafish liver. Furthermore, the caspase-3 enzyme activity was significantly increased. Taken together, this study demonstrated that the resulting effects on oxidative stress, immune toxicity, and apoptosis may be responsible for the pathological alterations in zebrafish liver after flutolanil exposure at concentrations relevant to environmental conditions, advancing the knowledge of pesticide environmental risk assessment.

Historical uranium (U) mining in the Southwestern United States resulted in significant environmental contamination throughout this region and presents a significant risk of chronic metal exposure and toxicity for communities living in close proximity to mine waste sites. Uranium exposure is associated with numerous deleterious health effects including immune dysfunction; however, its effects on the immune system have yet to be fully characterized. We recently published that drinking water exposure to U, in the form of uranyl acetate (UA), results in low overall tissue retention of U (<0.01%), with very little accumulation in immune organs (blood, bone marrow, spleen, and thymus) of male and female mice. In the present study we characterized the immunotoxicity of U, in the form of UA, following a 60-day drinking water exposure to 5 and 50 ppm in male and female C57BL/6J mice. The following immunotoxicity endpoints were evaluated: hematology, immune tissue weights and total cell recoveries, immunophenotying of the spleen and thymus, and immune cell function (lymphocyte mitogenesis and T-dependent antibody response). Uranium exposure had subtle impacts on the immune endpoints evaluated, likely due to low U accumulation at these sites. The only significant alterations were a slight decrease in the percentages of splenic natural killer T-cells and macrophages in exposed male mice. Despite minimal immunological effects, this study highlights the importance of investigating toxicological endpoints in both sexes and developing accurate animal models that model epidemiological exposures in the future., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Acrylamide has been classified as a "Group 2A carcinogen" (probably carcinogenic to humans) by the International Agency for Research on Cancer. The carcinogenicity of acrylamide is attributed to its well-recognized genotoxicity. In the present study, we investigated the effect of acrylamide on epigenetic alterations in mice. Female B6C3F1 mice received acrylamide in drinking water for 28 days, at doses previously used in a 2 year cancer bioassay (0, 0.0875, 0.175, 0.35, and 0.70 mM), and the genotoxic and epigenetic effects were investigated in lungs, a target organ for acrylamide carcinogenicity, and livers, a nontarget organ. Acrylamide exposure resulted in a dose-dependent formation of N7-(2-carbamoyl-2-hydroxyethyl)guanine and N3-(2-carbamoyl-2-hydroxyethyl)adenine in liver and lung DNA. In contrast, the profiles of global epigenetic alterations differed between the two tissues. In the lungs, acrylamide exposure resulted in a decrease of histone H4 lysine 20 trimethylation (H4K20me3), a common epigenetic feature of human cancer, while in the livers, there was increased acetylation of histone H3 lysine 27 (H3K27ac), a gene transcription activating mark. Treatment with 0.70 mM acrylamide also resulted in substantial alterations in the DNA methylation and whole transcriptome in the lungs and livers; however, there were substantial differences in the trends of DNA methylation and gene expression changes between the two tissues. Analysis of differentially expressed genes showed a marked up-regulation of genes and activation of the gene transcription regulation pathway in livers, but not lungs. This corresponded to increased histone H3K27ac and DNA hypomethylation in livers, in contrast to hypermethylation and transcription silencing in lungs. Our results demonstrate that acrylamide induced global epigenetic alterations independent of its genotoxic effects, suggesting that epigenetic events may determine the organ-specific carcinogenicity of acrylamide. Additionally this study provides strong support for the importance of epigenetic alterations, in addition to genotoxic events, in the mechanism of carcinogenesis induced by genotoxic chemical carcinogens.

Environmentally mediated sensitivity of Lemna minor to copper (Cu) was evaluated for the first time in three experiments: the effects of two levels of nutrient concentration, light irradiance or Cu pre-exposure were tested. Various Cu concentrations (ranging from 0.05 to 0.25 mg/L) were used to assess the sensitivity of L. minor to this metal, using one common strain previously acclimatized to two different levels of light intensity, nutrient enrichment and Cu pre-exposure. Our results showed a phenotypic plastic response of the relative growth rates based on frond number and fresh mass production, and maximum quantum yield of photosystem II (F v /F m ). Growth was affected by the three environmental conditions both prior and during Cu exposure, whereas F v /F m was mostly affected during Cu exposure. Copper significantly influenced all the parameters measured in the three experiments. Environmental conditions significantly modified L. minor sensitivity to Cu in all experiments, with up to twofold difference depending on the treatment. Growth rate was the parameter that was most impacted. Our study revealed for the first time the existence of phenotypic plasticity in L. minor sensitivity to chemical contamination, and implies that environmental context needs to be taken into account for a relevant risk assessment.

Domoic Acid (DA) is a naturally-occurring excitotoxin, produced by marine algae, which can bioaccumulate in shellfish and finfish. The consumption of seafood contaminated with DA is associated with gastrointestinal illness that, in the case of high DA exposure, can evolve into a spectrum of responses ranging from agitation to hallucinations, memory loss, seizures and coma. Because algal blooms that produce DA are becoming more widespread and very little is known about the dangers of chronic, low-dose exposure, we initiated a preclinical study focused on the reproductive and developmental effects of DA in a nonhuman primate model. To this end, 32 adult female Macaca fascicularis monkeys were orally exposed to 0, 0.075 or 0.15 mg/kg/day DA on a daily basis, prior to and during pregnancy. Females were bred to non-exposed males and infants were evaluated at birth. Results from this study provided no evidence of changes in DA plasma concentrations with chronic exposure. DA exposure was not associated with reproductive toxicity or adverse changes in the physical characteristics of newborns. However, in an unanticipated finding, our clinical observations revealed the presence of subtle neurological effects in the form of intentional tremors in the exposed adult females. While females in both dose groups displayed increased tremoring, the effect was dose-dependent and observed at a higher rate in females exposed to 0.15 mg/kg/day. These results demonstrate that chronic, low-level exposure to DA is associated with injury to the adult CNS and suggest that current regulatory guidelines designed to protect human health may not be adequate for high-frequency shellfish consumers., (Published by Elsevier Inc.)

Fish (embryo) toxicity test guidelines are mostly based on aquatic exposures. However, in some cases, other exposure routes can be more practical and relevant. Micro-injection into the yolk of fish embryos could offer a particular advantage for administering hydrophobic compounds, such as many endocrine disruptors. Single-dose micro-injection was compared with continuous aquatic exposure in terms of compound accumulation and biological responses. 17α-Ethinyl estradiol (EE2) was used as a model compound. First, the optimal solvent and droplet size were optimized, and needle variation was assessed. Next, biological endpoints were evaluated. The accumulated internal dose of EE2 decreased over time in both exposure scenarios. Estrogen receptor activation was concentration/injected dose dependent, increased daily, and was related to esr2b transcription. Transcription of vitellogenin 1 (vtg1) and brain aromatase (cyp19a1b) was induced in both scenarios, but the cyp19a1b transcription pattern differed between routes. Injection caused an increase in cyp19a1b transcripts from 48 hours post fertilization (hpf) onward, whereas after aquatic exposure the main increase occurred between 96 and 120 hpf. Some malformations only occurred after injection, whereas others were present for both scenarios. We conclude that responses can differ between exposure routes and therefore micro-injection is not a direct substitute for, but can be complementary to aquatic exposure. Nevertheless, vtg1and cyp19a1b transcription and estrogen receptor activation are suitable biomarkers for endocrine disruptor screening in both scenarios. Environ Toxicol Chem 2019;38:533-547. © 2018 SETAC., (© 2018 SETAC.)

Tetrabromoethylcyclohexane (TBECH), as one emerging brominated flame retardants, is ubiquitous in the environment, including water and aquatic organisms. TBECH was found to exhibit endocrine-disrupting effects in different models, whereas a survey of comprehensive toxic effects of TBECH on zebrafish is limited. In the present study, zebrafish (Danio rerio) were waterborne exposed continuously to TBECH from embryonic stage (3 h post-fertilization (hpf)) to the time when the respective parameters were evaluated. Exposure to TBECH reduced hatchability of zebrafish embryos at 72 and 96 hpf, diminished heart rate of zebrafish larvae at 48 hpf, and increased malformation in zebrafish larvae at 96 hpf. In addition, exposure to TBECH diminished free swimming distance both in the light and under a photoperiod of 10 min light/10 min dark cycles in zebrafish larvae at 6 days post-fertilization (dpf). Moreover, exposure to TBECH elevated activities of superoxide dismutase (SOD) and catalase (CAT), malondialdehyde (MDA) content, whereas it reduced glutathione (GSH) content, in zebrafish larvae at 6 dpf. Accordingly, RT-qPCR analysis demonstrated that TBECH exposure increased the mRNA levels of sod1, sod2, cat, and gpx1 in zebrafish larvae at 6 dpf. With respect to the immune aspect, the mRNA levels of pro-inflammatory genes, including il-1b, il-6, il-8, and tnfa, in larval zebrafish at 6 dpf were increased by exposure to TBECH, while pretreatment with TBECH inhibited 24 h of exposure to LPS-stimulated elevation in the mRNA levels of the abovementioned four pro-inflammatory genes in zebrafish larvae at 6 dpf. Furthermore, TBECH treatment increased caspase-3 enzyme activities and regulated apoptosis-related genes in larval zebrafish at 6 dpf. Taken together, the data obtained in this study demonstrated that TBECH caused developmental and locomotor behavioral toxicity, immunotoxicity, oxidative stress and proapoptotic effects in early life zebrafish. The present study will help to understand the comprehensive toxicity of TBECH in zebrafish., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Antineoplastic drugs (AD) have been increasingly used, but the disposal of their wastes in the environment via hospital effluent and domestic sewage has emerged as an environmental issue. The current risks posed to these animals and effects of pollutants on the reptiles' population level remain unknown due to lack of studies on the topic. The aim of the present study was to evaluate the mutagenicity of neonate Podocnemis expansa exposed to environmental concentrations (EC) of cyclophosphamide (Cyc). The adopted doses were EC-I 0.2 μg/L and EC-II 0.5 μg/L Cyc. These doses correspond to 1/10 and ¼ of concentrations previously identified in hospital effluents. Turtles exposed to the CyC recorded larger total number of erythrocyte nuclear abnormalities than the ones in the control group after 48-h exposure. The total number of abnormalities for both groups (EC-I and EC-II) 96 h after the experiment had started was statistically similar to that of animals exposed to high Cyc concentration (positive control 5 × 10 4  μg/L). This outcome confirms the mutagenic potential of Cyc, even at low concentrations. On the other hand, when the animals were taken to a pollutant-free environment, their mutagenic damages disappeared after 240 h. After such period, their total of abnormalities matched the basal levels recorded for the control group. Therefore, our study is the first evidence of AD mutagenicity in reptiles, even at EC and short-term exposure, as well as of turtles' recovery capability after the exposure to Cyc.

Bisphenol A (BPA) is an organic pollutant derived from plastic degradation that has numerous and variable adverse effects on human health and wildlife. In particular, it has been reported that BPA can alter reproductive processes and nervous system development in vertebrates. Considering BPA presence in marine environment and the scant data available on its interaction with nervous system development, we analyzed the effect of BPA exposure on sperm viability, fertilization, embryogenesis, and neural differentiation of the ascidian Ciona robusta. Ascidians are members of the Phylum Tunicata, the sister group of Vertebrata, sharing with them fundamental developmental processes. Our results showed that first cell division was altered starting from 5 µM concentration. Lethal concentration (LC 50 ) was estimated to be 5.2 µM. Larvae developed from treated embryos showed specific malformations to the pigment cells even at 0.1 µM, corresponding to the highest environmental concentration reported so far. Moreover, GABAergic and dopaminergic neurons proved to be target organs of BPA teratogenic action, in accordance with similar results reported in vertebrate animal models. Overall, our results suggest that BPA can exert its effects on nervous system acting on different pathways and underline that C. robusta is a valuable invertebrate animal model for preliminary screenings of effects of pollutants on vertebrates., (© 2018 Wiley Periodicals, Inc.)

Marine copepods have been shown to readily ingest microplastics - a crucial first step in the transfer of plastics into the marine food chain. Copepods have also been shown to elicit a foraging behavioural response to the presence of olfactory stimuli, such as dimethyl sulfide (DMS) - a volatile compound produced by their algal prey. Here, we show that the temperate Calanoid copepod Calanus helgolandicus displays enhanced grazing rates of between 0.7 and 3-fold (72%-292%) on microplastics that have been infused in a DMS solution, compared to DMS-free controls. Environmental exposure of microplastics may result in the development of an olfactory signature that includes algal-derived compounds such as DMS. Our study provides evidence that copepods, which are known to use chemosensory mechanisms to identify and locate dense sources of palatable prey, may be at an increased risk of plastic ingestion if it mimics the scent of their prey., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Exposures to lead (Pb) during developmental phases can alter the normal course of development, with lifelong health consequences. Permanent Pb exposure leads to behavioral changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, the effects of an intermittent lead exposure are not yet studied. This pattern of exposure has been recently increasing due to migrations, implementation of school exchange programs and/or residential changes., Objective: To determine and compare lead effects on mammal's behavior and physiology, using a rat model of intermittent and permanent Pb exposures., Methods: Fetuses were intermittently (PbI) or permanently (PbP) exposed to water containing lead acetate (0.2% w/v) throughout life until adulthood (28 weeks of age). A control group (CTL) without any exposure to lead was also used. Anxiety was assessed by elevated plus maze (EPM) and locomotor activity and exploration by open field test (OFT). Blood pressure (BP), electrocardiogram (ECG), heart rate (HR), respiratory frequency (RF), sympathetic and parasympathetic activity and baro- and chemoreceptor reflex profiles were evaluated. Immunohistochemistry protocol for the assessment of neuroinflammation, neuronal loss (NeuN), gliosis and synaptic alterations (Iba-1, GFAP, Syn), were performed at the hippocampus. One-way ANOVA with Tukey's multiple comparison between means were used (significance p < 0.05) for statistical analysis., Results: The intermittent lead exposure produced a significant increase in diastolic and mean BP values, concomitant with a tendency to sympathetic overactivity (estimated by increased low-frequency power) and without significant changes in systolic BP, HR and RF. A chemoreceptor hypersensitivity and a baroreflex impairment were also observed, however, less pronounced when compared to the permanent exposure. Regarding behavioral changes, both lead exposure profiles showed an anxiety-like behavior without changes in locomotor and exploratory activity. Increase in GFAP and Iba-1 positive cells, without changes in NeuN positive cells were found in both exposed groups. Syn staining suffered a significant decrease in PbI group and a significant increase in PbP group., Conclusion: This study is the first to show that developmental Pb exposure since fetal period can cause lasting impairments in physiological parameters. The intermittent lead exposure causes adverse health effects, i.e, hypertension, increased respiratory frequency and chemoreflex sensitivity, baroreflex impairment, anxiety, decreased synaptic activity, neuroinflammation and reactive gliosis, in some ways similar to a permanent exposure, however some are lower-grade, due to the shorter duration of exposure. This study brings new insights on the environmental factors that influence autonomic and cardiovascular systems during development, which can help in creating public policy strategies to prevent and control the adverse effects of Pb toxicity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The neurological effects of manganese (Mn) exposure on adults consuming contaminated water remain unclear. Accordingly, the current experiment was planned to explore the neurotoxic consequences of subchronic Mn exposure via contaminated water and to examine whether ebselen (Ebs) improved these outcomes. Rats exposed to oral MnCl 2 (50 mg/kg body weight) for 30 successive days exhibited reduced rearing and ambulation. Furthermore, Mn administration increased brain Mn concentrations and induced superoxide dismutase, catalase, and glutathione depletion. Mn administration also increased lipid peroxidation biomarker levels. Additionally, Mn increased interleukin1-β and prostaglandin E2 levels and altered caspase-3 and Bcl-2 expression. Mn intoxication also induced marked gliosis, numerous vacuolations, and disoriented and pyknotic Purkinje cells as well as marked vascular congestion in brain tissue. Meanwhile, intraperitoneal administration of Ebs (15 mg/kg body weight) to Mn-intoxicated rats improved the behavioral performance and oxidative damage as well as inflammatory, apoptotic, and histopathological changes. The above results indicate that Ebs alleviated Mn neurotoxicity via its antioxidant, anti-inflammatory, and anti-apoptotic activities. Therefore, Ebs could represent a promising agent in the prevention of Mn-induced neurotoxicity.

This study evaluated the effects of short-term exposure to sublethal levels of nitrite on oxidative stress parameters and histology of juvenile Brazilian flounder Paralichthys orbignyanus. An assessment of fish recovery was also performed. Fish were exposed to 0.08 (control), 5.72, 10.43, and 15.27 NO 2 -N mg L -1 for 10 days followed by the same recovery time. Gill, liver, and muscle samples were collected after 1, 5, and 10 days of exposure and after recovery for the measurement of antioxidant capacity against peroxyl radicals (ACAP), glutathione-S-transferase (GST) activity, content of non-protein (NPSH) and protein thiols (PSH), and lipid peroxidation levels by thiobarbituric acid-reactive substances (TBARS) content. Nitrite exposure induced alterations which compromised the overall antioxidant system (reduced ACAP and GST activity) and enhanced oxidative damage in lipids and proteins. Increases in GST activity and NPSH and PSH contents were also demonstrated. The recovery period allowed for resumption of basal levels for all (treatment 5.72 NO 2 -N mg L -1 ) or some of the evaluated parameters (other treatments). In conclusion, exposure to nitrite concentrations from 5.72 to 15.27 NO 2 -N mg L -1 induced oxidative stress and antioxidant responses in juvenile Brazilian flounder. The 10-day recovery period was sufficient for a complete resumption of basal physiological condition of fish exposed to concentrations of up to 5.72 NO 2 -N mg L -1 .

Pharmaceutical drugs in the aquatic environment can induce adverse effects on nontarget organisms. This study aimed to assess the short-term effects of sublethal concentrations of both paracetamol and propranolol on the fish Phalloceros harpagos, specifically light/dark preference, swimming patterns, skin pigmentation, histopathology, and liver glycogen levels. Fish were acutely exposed to sublethal concentrations of both paracetamol (0.008, 0.08, 0.8, 8, 80 mg L -1 ) and propranolol (0.0001, 0.001, 0.01, 0.1, 1 mg L -1 ) under controlled conditions. For scototaxis, a significant preference for the dark compartment was observed for the group exposed to the highest concentration of paracetamol (80 mg L -1 ). Propranolol exposure significantly altered the swimming pattern, especially in fish exposed to the 0.001 mg L -1 concentration. Pigmentation was reduced in propranolol-exposed fish (0.1, 1 mg L -1 ). The lowest concentration of propranolol (0.0001 mg L -1 ) induced a decrease of histochemical reaction for hepatic glycogen. These data demonstrate that pharmaceuticals can induce sublethal effects in nontarget organisms, even at low concentrations, compromising specific functions of the individual with ecological relevance, such as energy balance and behavior.

Epidemiological data from Lake Taihu showed significantly higher incidences of type 2 diabetes mellitus (T2DM) than in other areas of China. This may be related to the occurrence of a Microcystis bloom in Lake Taihu in the summer and autumn every year. The objective of this study is to investigate whether the contaminated water from the Microcystis bloom and the derivative pollutant microcystin-LR (MC-LR) can explain the higher incidences of T2DM. Healthy male mice were fed with water from different regions of Lake Taihu, and were either acutely or chronically exposed to MC-LR through oral administration or intraperitoneal injection. Serum lipid profiles were determined, and the effects on T2DM-related gene expression and insulin receptor signaling pathway were investigated. Intraperitoneal glucose tolerance (IPGTT) and insulin resistance (IRT) tests were implemented, and the functions of pancreatic islet and β-cell were also evaluated. The results showed that both water sampled from the region with a Microcysis bloom and those containing MC-LR altered the serum glucide and lipid profiles in mice after exposure. The exposure to a Microcysis bloom water affected the expression T2DM-related genes: up-regulated the mRNA levels of FASn, ACACA, G6pc, LPL, and Insig2, and down-regulated the mRNA level of PEPCK and Gsk-3β. Both acute and chronic exposure of MC-LR, even at very low concentrations (1 μg/L), impaired the insulin receptor signalling pathway and induced hyperinsulinemia and insulin resistance in mice. In this study, the most important intracellular target of MC-LR was found to be hetapocellular mitochondria. Thus, exposure to Microcystis bloom water containing microcystin-LR can induce the incidence of T2DM, by impairing the function of mitochondria by microcystin-LR. The study suggests a review of the risk assessment concerning 1 μg/L MC-LR as the reference dose in surface water., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Microcystins (MCs) pollution has quickly risen in infamy and has become a major problem to public health worldwide. MCs are a group of monocyclic hepatotoxic peptides, which are produced by some bloom-forming cyanobacteria in water. More than 100 different MCs variants posing a great threat to animals and humans due to their potential carcinogenicity have been reported. To reduce MCs risks, the World Health Organization has set a provisional guideline of 1 μg/L MCs in human's drinking water. This paper provides an overview of exposure routes of MCs into the human system and health effects on different organs after MCs exposure including the liver, intestine, brain, kidney, lung, heart and reproductive system. In addition, some evidences on human poisoning and deaths associated with MCs exposure are presented. Finally, in order to protect human life against the health threats posed by MCs, this paper also suggests some directions for future research that can advance MCs control and minimize human exposure to MCs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Annual rates of plastic production have been increasing rapidly since the 1950s. Inadequate or improper disposal of plastic products has contributed to a significant increase in plastic debris in the world's oceans and a corresponding increase in the number of species negatively affected by this debris. Here we investigate trends in the type, amount, and colour of ingested plastic over time, and determine whether ingested plastic contributes to reduced health of Wedge-tailed Shearwaters (Ardenna pacifica) on Lord Howe Island, Australia. The results show no clear influence of ingested plastic on body condition, while trends in the prevalence, number, and mass of plastic items ingested per bird during 2005 and 2013-2018 were more variable. There was some evidence adult birds are selecting plastic by colour. Future monitoring of this pan-tropical seabird would provide a unique opportunity to gather data from multiple sites, concurrently., (Copyright © 2018 Elsevier Ltd. All rights reserved.)