Toxics — Open Access Journal

Xanthone is an organic compound mostly found in mangosteen pericarp and widely known for its anti-proliferating effect on cancer cells. In this study, we evaluated the effects of xanthone crude extract (XCE) and α-mangostin (α-MG) on normoxic and hypoxic human hepatocellular carcinoma (HepG2) cells and their toxicity towards zebrafish embryos. XCE was isolated using a mixture of acetone and water (80:20) and verified via high performance liquid chromatography (HPLC). Both XCE and α-MG showed higher anti-proliferation effects on normoxic HepG2 cells compared to the control drug, 5-fluorouracil (IC₅₀ = 50.23 ± 1.38, 8.39 ± 0.14, and 143.75 ± 15.31 μg/mL, respectively). In hypoxic conditions, HepG2 cells were two times less sensitive towards XCE compared to normoxic HepG2 cells (IC₅₀ = 109.38 ± 1.80 μg/mL) and three times less sensitive when treated with >500 μg/mL 5-fluorouracil (5-FU). A similar trend was seen with the α-MG treatment on hypoxic HepG2 cells (IC₅₀ = 10.11 ± 0.05 μg/mL) compared to normoxic HepG2 cells. However, at a concentration of 12.5 μg/mL, the α-MG treatment caused tail-bend deformities in surviving zebrafish embryos, while no malformation was observed when embryos were exposed to XCE and 5-FU treatments. Our study suggests that both XCE and α-MG are capable of inhibiting HepG2 cell proliferation during normoxic and hypoxic conditions, more effectively than 5-FU. However, XCE is the preferred option as no malformation was observed in surviving zebrafish embryos and it is more cost efficient than α-MG. Full article

Structural isomeric pesticides are used in agriculture and may be challenging to differentiate for accurate identification in pesticide monitoring programs. Due to structural similarity, isomeric pesticides are difficult to separate chromatographically, and thus, their accurate identification may rely solely on mass spectrometric analysis (MS). In this study, we challenged the ability of high-resolution quadrupole-orbitrap (Q-Orbitrap) mass spectrometry to produce and evaluate the tandem mass spectrometry (MS/MS) product ions for the selected five pairs of isomeric pesticides from different classes: Pebulate and vernolate, methiocarb and ethiofencarb, uniconazole and cyproconazole, sebuthylazine and terbuthylazine, and orbencarb and thiobencarb. The use of Q-Orbitrap instrument with a mass error <3 ppm allowed proposed elucidation of the product ion structures with consideration of the ion formulae, data interpretation, and literature searches. Product ions unique to pebulate, vernolate, methiocarb, ethiofencarb, and uniconazole were observed. Elucidation of the observed MS/MS product ion structures was conducted, and the fragmentation pathways were proposed. This information is valuable to increase selectivity in MS/MS analysis and differentiate isomeric pesticides, and thereby reduce the rates of false positives in pesticide monitoring programs. Full article

Acute paracetamol poisoning due to a single overdose may be effectively treated by the early administration of N-acetylcysteine (NAC) as an antidote. The prognosis may be different in the case of intoxication due to multiple ingestions or when the antidote is started with delay. The aim of this work was to investigate the outcome of paracetamol poisoning according to the pattern of ingestion and determine the factors associated with the outcome. We performed a retrospective analysis over the period 2007–2017 of the patients who were referred to a tertiary hospital for paracetamol-related hepatotoxicity. Inclusion criteria were: accidental or voluntary ingestion of paracetamol, delay for NAC therapy of 12 h or more, liver enzymes (ALT) >1000 IU/L on admission. Ninety patients were considered. Poisoned patients following multiple ingestion were significantly older (45 ± 12 vs. 33 ± 14) (p = 0.001), with a higher incidence of liver steatosis (p = 0.016) or chronic ethanol abuse (p = 0.04). In comparison with the subgroup of favorable outcome, the patients with poor outcome were older, had higher values for ALT, bilirubin, lactate, and lower values for factor V and arterial pH. In multivariate analysis, the arterial lactate value was associated with a bad prognosis (p < 0.02) (adjusted odds ratio 1.74 and CI 95:1.09–2.77). The risk of poor outcome was greater in the subgroup with staggered overdose (p = 0.02), which had a higher mortality rate (p = 0.01). This retrospective analysis illustrates the different population patterns of patients who were admitted for a single ingestion of a paracetamol overdose versus multiple ingestions. This last subgroup was mainly represented by older patients with additional risk factors for hepatotoxicity; arterial lactate was a good predictor of severity. Full article

Biological water pollution, including organic pollutants and their possible transportation, via biofouling and ballast water, has the potential to cause severe economic and health impacts on society and environment. Current water pollution monitoring methods are limited by transportation of samples to the laboratory for analysis, which could take weeks. There is an urgent need for a water quality monitoring technique that generates real-time data. The study aims to assess the feasibility of three sensing techniques to detect and monitor the concentrations of the model species Tetraselmis suecica in real-time using eleven samples for each method. Results showed UV-Vis spectrophotometer detected increasing concentration of Tetraselmis suecica with R² = 0.9627 and R² = 0.9672, at 450 nm and 650 nm wavelengths, respectively. Secondly, low-frequency capacitance measurements showed a linear relationship with increasing concentration of Tetraselmis suecica at 150 Hz (R² = 0.8463) and 180 Hz (R² = 0.8391). Finally, a planar electromagnetic wave sensor measuring the reflected power S₁₁ amplitude detected increasing cell density at 4 GHz (R² = 0.8019). Full article

Large-scale manufacturing of poly- and perfluorinated compounds in the second half of the 20th century has led to their ubiquity in the environment, and their unique structure has made them persistent contaminants. A recent drinking water advisory level issued by the United States Environmental Protection Agency lowered the advisory level concentration of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) from 200 nanograms per liter and 400 nanograms per liter, respectively, to 70 nanograms per liter separately or combined. Small temporal variations in PFOS and PFOA concentrations could be the difference between meeting or exceeding the recommended limit. In this study, newly sampled data from a contaminated military site in Alaska and historical data from former Pease Air Force Base were collected. Data were evaluated to determine if monthly variations within PFOS and PFOA existed. No statistically significant temporal trend was observed in the Alaska data, while the results from Pease, although statistically significant, showed the spread of observed contaminant concentrations around the fitted line is broad (as indicated by the low R² values), indicating that collection date has little value in predicting contaminant concentrations. Though not currently the subject of a US EPA health advisory, data on perfluorobutanesulfonic acid (PFBS), perfluorohexane sulfonic acid (PFHxS), perfluoroheptanoic acid (PFHpA), and perfluorononanoic acid (PFNA) were collected for each site and their average concentrations evaluated. Full article

Previous studies have proposed that cadmium (Cd) is a metabolic disruptor, which is associated with insulin resistance, metabolic syndrome, and diabetes. This metal is not considered by international agencies for the study of metabolic diseases. In this study, we investigate the effect of metformin on Cd-exposed Wistar rats at a lowest-observed-adverse-effect level (LOAEL) dose (32.5 ppm) in drinking water. Metabolic complications in the rats exposed to Cd were dysglycemia, insulin resistance, dyslipidemia, dyslipoproteinemia, and imbalance in triglyceride and glycogen storage in the liver, muscle, heart, kidney, and adipose tissue. Meanwhile, rats treated orally with a No-observable-adverse-effect level (NOAEL) dose of metformin (200 mg/kg/day) showed mild improvement on serum lipids, but not on glucose tolerance; in tissues, glycogen storage was improved, but lipid storage was ineffective. In conclusion, metformin as a first-line pharmacological therapy must take into consideration the origin and duration of metabolic disruption, because in this work the NOAEL dose of metformin (200 mg/kg/day) showed a limited efficiency in the metabolic disruption caused by chronic Cd exposure. Full article

Although the increased incidence of type 2 diabetes since the 1950s is thought to be primarily due to coincident alterations in lifestyle factors, another potential contributing factor in industrialized countries is exposure of the population to environmental pollutants and industrial chemicals. Exposure levels of many environmental toxicants have risen in the same time-frame as the disease incidence. Of particular interest in this regard is the metal lead. Although overall lead exposure levels have diminished in recent decades, there is an under-recognized but persistent occurrence of lead exposure in poor underserved urban populations. Although the neural developmental pathologies induced by lead exposures have been well documented, very little is known about the effect of lead exposure on the incidence of chronic metabolic diseases such as type 2 diabetes. Although our understanding of the metabolic health effects of lead exposure is incomplete, there are studies in model systems and a small amount of epidemiological data that together suggest a deleterious effect of environmental lead exposure on metabolic health. This article reviews the human, animal and in vitro studies that have examined the effects of lead exposure on the development of diabetes and related metabolic conditions. Full article

During embryonic development, some hypoxia occurs due to incipient vascularization. Under hypoxic conditions, gene expression is mainly controlled by hypoxia-inducible factor 1 (HIF-1). The activity of this transcription factor can be altered by the exposure to a variety of compounds; among them is cadmium (Cd), a nephrotoxic heavy metal capable of crossing the placenta and reaching fetal kidneys. The goal of the study was to determine Cd effects on HIF-1 on embryonic kidneys. Pregnant Wistar rats were exposed to a mist of isotonic saline solution or CdCl₂ (D_Del = 1.48 mg Cd/kg/day), from gestational day (GD) 8 to 20. Embryonic kidneys were obtained on GD 21 for RNA and protein extraction. Results show that Cd exposure had no effect on HIF-1α and prolyl hydroxylase 2 protein levels, but it reduced HIF-1 DNA-binding ability, which was confirmed by a decrease in vascular endothelial growth factor (VEGF) mRNA levels. In contrast, the protein levels of VEGF were not changed, which suggests the activation of additional regulatory mechanisms of VEGF protein expression to ensure proper kidney development. In conclusion, Cd exposure decreases HIF-1-binding activity, posing a risk on renal fetal development. Full article

Butyrylcholinesterase (BChE) is the evolutionary counterpart to acetylcholinesterase (AChE). Both are expressed early in nervous system development prior to cholinergic synapse formation. The organophosphate pesticide chlorpyrifos (CPF) primarily exerts toxicity through the inhibition of AChE, which results in excess cholinergic stimulation at the synapse. We hypothesized that the inhibition of AChE and BChE by CPF may impair early neurogenesis in neural stem cells (NSCs). To model neurodevelopment in vitro, we used human NSCs derived from induced pluripotent stem cells (iPSCs) with a focus on the initial differentiation mechanisms. Over the six days of NSC differentiation, the BChE activity and mRNA expression significantly increased, while the AChE activity and expression remained unchanged. The CPF treatment (10 μM) caused 82% and 92% inhibition of AChE and BChE, respectively. The CPF exposure had no effect on the cell viability or the expression of the differentiation markers HES5, DCX, or MAP2. However, the shRNA-knockdown of the BChE expression resulted in the decreased or delayed expression of the transcription factors HES5 and HES3. BChE may have a role in the differentiation of NSCs independent of, or in addition to, its enzymatic activity. Full article

Tetramethylenedisulfotetramine (TETS, tetramine) is a toxic organic compound that is used as an effective rodenticide. However, this neurotoxin is not only toxic to rodents, it also causes poisoning in humans. Due to its high level of toxicity for humans, the use of TETS as a rodenticide has been banned and its production has been discontinued. Despite this, human poisoning by this substance is unfortunately still very common. The largest number of poisonings are reported in China, but in the United States, dozens of poisonings still happen annually. TETS is one of the most hazardous pesticides and also a possible chemical warfare agent with no known antidote. In this article, we aim to summarize the biochemical and toxicological data of TETS and hope to cast some light on the toxicological risk to human health. Full article

The present study shows the results of perfuorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), brominated dioxins (PBDDs) and furans (PBDFs) measured in several marine fish and seafood of commercial interest at different trophic levels of the food chain. The aims were to investigate the level of the contamination in Mediterranean aquatic wildlife, and in farmed fish, to assess human exposure associated to fishery products consumption. Samples of wild fish were collected during three different sampling campaigns in different Food and Agriculture Organization (FAO) 37 areas of the Mediterranean Sea. In addition, farmed fish (gilthead sea bream and European sea bass) from off-shore cages from different marine aquaculture plants. Results showed contamination values of PFOS and PFOA were lower than those detected in sea basins other than the Mediterranean Sea. Concentration values of PFOS were generally higher than those of PFOA; moreover, levels in farmed fish were lower than in wild samples from the Mediterranean Sea. Intake of PFOS and PFOA through fishery products consumption was estimated to be 2.12 and 0.24 ng/kg·BW·day, respectively, for high consumers (95th percentile). Results of 2,3,7,8-substituted congeners of PBDDs and PBDFs were almost all below the limit of detection (LOD), making it difficult to establish the contribution of these compounds to the total contamination of dioxin-like compounds in fish and fishery products. Full article

Seafood is an important component in a healthy diet and may contain methylmercury or other contaminants. It is important to recognize the risks and benefits of consuming seafood. A longitudinal prospective birth cohort study has been conducted to clarify the effects of neurotoxicants on child development—the Tohoku Study of Child Development (TSCD) in Japan. TSCD comprises two cohorts; a polychlorinated biphenyls (PCB) cohort (urban area) and a methylmercury cohort (coastal area). Our previous results from the coastal area showed prenatal methylmercury exposure affected psychomotor development in 18-month-olds, and boys appear to be more vulnerable to the exposure than girls. In this report, we have added the urban area cohort and we reanalyzed the impact of prenatal exposure to methylmercury, which gave the same results as before. These findings suggest prenatal exposure to low levels methylmercury may have adverse effects on child development, especially in boys. Full article

Mercury compounds are known to cause central nervous system disorders; however the detailed molecular mechanisms of their actions remain unclear. Methylmercury increases the expression of several chemokine genes, specifically in the brain, while metallothionein-III (MT-III) has a protective role against various brain diseases. In this study, we investigated the involvement of MT-III in chemokine gene expression changes in response to methylmercury and mercury vapor in the cerebrum and cerebellum of wild-type mice and MT-III null mice. No difference in mercury concentration was observed between the wild-type mice and MT-III null mice in any brain tissue examined. The expression of Ccl3 in the cerebrum and of Cxcl10 in the cerebellum was increased by methylmercury in the MT-III null but not the wild-type mice. The expression of Ccl7 in the cerebellum was increased by mercury vapor in the MT-III null mice but not the wild-type mice. However, the expression of Ccl12 and Cxcl12 was increased in the cerebrum by methylmercury only in the wild-type mice and the expression of Ccl3 in the cerebellum was increased by mercury vapor only in the wild-type mice. These results indicate that MT-III does not affect mercury accumulation in the brain, but that it affects the expression of some chemokine genes in response to mercury compounds. Full article

Methylmercury (MeHg) is a hazardous environmental pollutant, which elicits significant toxicity in humans. The accumulation of MeHg through the daily consumption of large predatory fish poses potential health risks, and the central nervous system (CNS) is the primary target of toxicity. Despite well-described neurobehavioral effects (i.e., motor impairment), the mechanisms of MeHg-induced toxicity are not completely understood. However, several lines of evidence point out the oxidative stress as an important molecular mechanism in MeHg-induced intoxication. Indeed, MeHg is a soft electrophile that preferentially interacts with nucleophilic groups (mainly thiols and selenols) from proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress, which can produce damage by several interacting mechanisms, impairing the function of various molecules (i.e., proteins, lipids, and nucleic acids), potentially resulting in modulation of different cellular signal transduction pathways. This review summarizes the general aspects regarding the interaction between MeHg with regulators of the antioxidant response system that are rich in thiol and selenol groups such as glutathione (GSH), and the selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx). A particular attention is directed towards the role of the PI3K/Akt signaling pathway and the nuclear transcription factor NF-E2-related factor 2 (Nrf2) in MeHg-induced redox imbalance. Full article

Several studies have shown the presence of aldehydes (i.e., formaldehyde, acrolein) in mainstream emissions of some e-cigarettes. For this reason, concerns have been raised regarding potential toxicity. The purpose of this research was to measure levels of carbonyls in exhaled breath of e-cigarette users during “vaping” sessions and estimate the respiratory tract (RT) uptake of specific aldehydes, including formaldehyde and acetaldehyde. We measured concentrations of 12 carbonyls in e-cigarette aerosols produced directly by e-cigarettes and in the exhaled breath of 12 participants (19 sessions). Carbonyls were sampled on 2,4-dinitrophenylhydrazine (DNPH) cartridges and analyzed with high performance liquid chromatography (HPLC) coupled with a UV/Vis photodiode detector. We found that in most cases, levels of aldehydes and methyl ethyl ketone (MEK) were significantly higher (2–125 times) in exhaled e-cigarette breaths than in pre-exposed breath. Exposure levels for the most abundant individual carbonyls in e-cigarette emissions—formaldehyde, acetaldehyde, acrolein—were between the limit of quantification (LOQ) and 24.4 μg·puff⁻¹. The mean retention of formaldehyde in the respiratory tract was 99.7 ± 0.9% for all participants, while acetaldehyde retention was 91.6 ± 9.9%. Within the limitation of a small number of participants, our results showed that there is an increase in breath carbonyls during e-cigarette use. Full article

The main chemical forms of mercury are elemental mercury, inorganic divalent mercury, and methylmercury, which are metabolized in different ways and have differing toxic effects in humans. Among the various chemical forms of mercury, methylmercury is known to be particularly neurotoxic, and was identified as the cause of Minamata disease. It bioaccumulates in fish and shellfish via aquatic food webs, and fish and sea mammals at high trophic levels exhibit high mercury concentrations. Most human methylmercury exposure occurs through seafood consumption. Methylmercury easily penetrates the blood-brain barrier and so can affect the nervous system. Fetuses are known to be at particularly high risk of methylmercury exposure. In this review, we summarize the health effects and exposure assessment of methylmercury as follows: (1) methylmercury toxicity, (2) history and background of Minamata disease, (3) methylmercury pollution in the Minamata area according to analyses of preserved umbilical cords, (4) changes in the sex ratio in Minamata area, (5) neuropathology in fetuses, (6) kinetics of methylmercury in fetuses, (7) exposure assessment in fetuses. Full article

The purpose of this updated meta-analysis was to investigate the effect of nitric oxide synthase-3 (NOS3) G894T polymorphisms, air pollution and their interaction on ischemic heart disease (IHD) risk across populations worldwide. Recursive partition trees, nonlinear association curve fit and geographic information system maps were incorporated to verify results of conventional pooled analyses for sources of heterogeneity. Results from 61 studies (16,219 cases, 12,222 controls) revealed a significant increased relative risk (RR) of IHD associated with NOS3 894 polymorphisms TT (RR = 1.44) and GT (RR = 1.37). Subgroup analysis revealed that the TT polymorphism genotype had significantly increased risk of IHD in Caucasian, East Asian, South Asian, and Middle Eastern populations (all p < 0.05). It is important to point out that many countries demonstrated an average risk of greater than two, which identifies the NOS3 894 TT polymorphism as a potential causal factor and biological marker of IHD, based on criteria for strong evidence used in international consensus panels. These 10 countries include Ukraine, the United Kingdom, Brazil, Chile, Japan, South Korea, India, Iran, Egypt and Morocco. For these countries with elevated risk (RR > 2) from the NOS3 894 TT polymorphism, meta-predictive analysis demonstrated an increasing trend in air pollution association with increased NOS3 894 polymorphisms. Further studies are needed to explore the complexity of the associations among NOS3 gene polymorphisms per population stratifications within countries, detailed air pollution data for added specificity for geographic location across time, and disease risk. Full article

Maternal smoking during pregnancy leads to gestational complications and organ disorders in the offspring. As nicotine replacement therapy is often ineffective for smoking cessation, pregnant women turn to alternatives such as heat-not-burn tobacco and e-cigarettes. Recently, the popularly of e-cigarettes has been increasing especially among the youth and pregnant women, mainly due to the advertisements claiming their safety. This has even led to some clinicians recommending their use during pregnancy. E-cigarettes heat e-liquid to produce an aerosol (e-vapor), delivering flavorings and nicotine to the user. However, e-vapor also contains toxins such as formaldehyde along with heavy metals and carcinogenic nitrosamines. In addition, specific flavoring compounds such as diacetyl can be toxic themselves or decompose into toxic compounds such as benzaldehydes. These compounds can induce toxicity, inflammation and oxidative stress in the mothers and can accumulate in the developing fetus, affecting intrauterine development. Recent animal studies suggest that maternal e-vapor exposure during pregnancy could cause respiratory and neurological disorders in the offspring. This review will examine the available literature to shed light on the current understanding of this problem-to-be from lessons learned in animal models. Full article

Lead exposure and a marker of oxidative stress (gamma-glutamyl transferase—GGT), and their effects on life course variables (age, country of birth, education levels, gender, ethnicity, income, and occupation) were explored in this cross-sectional study of United States (U.S.) adults’ ≥ 20 years of age via the National Health and Nutrition Examination Survey (NHANES) 2007–2010 datasets. Country of birth, education levels, gender, ethnicity, income, and occupation showed significant differences depending on the degree of lead exposure, with higher levels of exposure resulting in worse outcomes. Age and GGT were significantly associated with lead exposure. More must be done to mitigate sources of lead exposure, to prevent it from altering the life course of at-risk populations. Full article