Toxics — Open Access Journal

Piper aduncum, commonly known as matico, is a plant that grows in the mountainous and coastal regions of Peru, and is studied for its antimicrobial properties and various ethnopharmacological uses. The main objective of this study was to determine the cytoprotective and antioxidant effects of the methanolic extract of Piper aduncum leaves in Mus musculus previously administered with sodium fluoride (NaF) using the Micronucleus test and the Comet assay. The extract was administrated orally in four different concentrations: 150, 300, 600, and 1200 mg/Kg for ten days. At the 11th day, a single dose of NaF was administrated via intraperitoneal at 20 mg/Kg. The genotoxicity study was performed with mice from the strain BALB/c, using the Micronucleus test on bone marrow and the Comet assay on peripheral blood according to OECD guidelines 474 and 489, respectively. The statistical analysis was performed by median analysis with ANOVA. Significant differences were found in Micronucleus frequency between the highest concentrations of Piper aduncum and NaF. The Comet assay showed significant reduction of NaF-induced damage on erythrocytes depending on the different concentrations of the extract which were evaluated in this study. It is concluded that the methanolic extract of P. aduncum leaves has cytoprotective and antioxidant activity against sodium fluoride. Full article

This review summarizes recent developments in radiocarbon tracer technology and applications. Technologies covered include accelerator mass spectrometry (AMS), including conversion of samples to graphite, and rapid combustion to carbon dioxide to enable direct liquid sample analysis, coupling to HPLC for real-time AMS analysis, and combined molecular mass spectrometry and AMS for analyte identification and quantitation. Laser-based alternatives, such as cavity ring down spectrometry, are emerging to enable lower cost, higher throughput measurements of biological samples. Applications covered include radiocarbon dating, use of environmental atomic bomb pulse radiocarbon content for cell and protein age determination and turnover studies, and carbon source identification. Low dose toxicology applications reviewed include studies of naphthalene-DNA adduct formation, benzo[a]pyrene pharmacokinetics in humans, and triclocarban exposure and risk assessment. Cancer-related studies covered include the use of radiocarbon-labeled cells for better defining mechanisms of metastasis and the use of drug-DNA adducts as predictive biomarkers of response to chemotherapy. Full article

Patients with Parkinson’s disease (PD) have increased susceptibility to bisphenol A (BPA) exposure since they have an impaired biotransformation capacity to metabolize BPA. PD subjects have reduced levels of conjugated BPA compared to controls. Reduced ability to conjugate BPA provides increased opportunity for unconjugated BPA to bind to albumin in human serum and protein disulfide isomerase on neurons. Once unconjugated BPA binds to proteins, it changes the allosteric structure of the newly configured protein leading to protein misfolding and the ability of the newly configured protein to act as a neoantigen. Once this neoantigen is formed, the immune system produces antibodies against it. The goal of our research was to investigate associations between unconjugated BPA bound to human serum albumin (BPA–HSA) antibodies and alpha-synuclein antibodies and between Protein Disulfide Isomerase (PDI) antibodies and alpha-synuclein antibodies. Enzyme–linked immunosorbent assay was used to determine the occurrences of alpha-synuclein antibodies, antibodies to BPA–HSA adducts, and PDI antibodies in the sera of blood donors. Subjects that exhibited high levels of unconjugated BPA–HSA antibodies or PDI antibodies had correlations and substantial risk for also exhibiting high levels of alpha-synuclein antibodies (p < 0.0001). We conclude that there are significant associations and risks between antibodies to BPA–HSA adducts and PDI antibodies for developing alpha-synuclein antibodies. Full article

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 μg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain Pitx3 expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations. Full article

The chemical structure of organophosphate compounds (OPs) is a well-known factor which modifies the acute toxicity of these compounds. We compared ventilation at rest and cholinesterase activities in male Sprague-Dawley rats poisoned with dimethyl paraoxon (DMPO) and diethyl paraoxon (DEPO) at a subcutaneous dose corresponding to 50% of the median lethal dose (MLD). Ventilation at rest was recorded by whole body plethysmography. Total cholinesterase activities were determined by radiometric assay. Both organophosphates decreased significantly the respiratory rate, resulting from an increase in expiratory time. Dimethyl-induced respiratory toxicity spontaneously reversed within 120 min post-injection. Diethyl-induced respiratory toxicity was long-lasting, more than 180 min post-injection. Both organophosphates decreased cholinesterase activities from 10 to 180 min post-injection with the same degree of inhibition of total cholinesterase within an onset at the same times after injection. There were no significant differences in residual cholinesterase activities between dimethyl and diethyl paraoxon groups at any time. The structure of the alkoxy-group is a determinant factor of the late phase of poisoning, conditioning duration of toxicity without significant effects on the magnitude of alteration of respiratory parameters. For same duration and magnitude of cholinesterase inhibition, there was a strong discrepancy in the time-course of effects between the two compounds. Full article

Phthalates (diesters of phthalic acid) are widely used as plasticizers and additives in many consumer products. Laboratory animal studies have reported the endocrine-disrupting and reproductive effects of phthalates, and human exposure to this class of chemicals is a concern. Several phthalates have been recognized as substances of high concern. Human exposure to phthalates occurs mainly via dietary sources, dermal absorption, and air inhalation. Phthalates are excreted as conjugated monoesters in urine, and some phthalates, such as di-2-ethylhexyl phthalate (DEHP), undergo secondary metabolism, including oxidative transformation, prior to urinary excretion. The occurrence of phthalates and their metabolites in urine, serum, breast milk, and semen has been widely reported. Urine has been the preferred matrix in human biomonitoring studies, and concentrations on the order of several tens to hundreds of nanograms per milliliter have been reported for several phthalate metabolites. Metabolites of diethyl phthalate (DEP), dibutyl- (DBP) and diisobutyl- (DiBP) phthalates, and DEHP were the most abundant compounds measured in urine. Temporal trends in phthalate exposures varied among countries. In the United States (US), DEHP exposure has declined since 2005, whereas DiNP exposure has increased. In China, DEHP exposure has increased since 2000. For many phthalates, exposures in children are higher than those in adults. Human epidemiological studies have shown a significant association between phthalate exposures and adverse reproductive outcomes in women and men, type II diabetes and insulin resistance, overweight/obesity, allergy, and asthma. This review compiles biomonitoring studies of phthalates and exposure doses to assess health risks from phthalate exposures in populations across the globe. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cholinergic dysfunctions and impaired redox homeostasis. The plant Centella asiatica (CA) is renowned for its nutritional benefits and herbal formulas for promoting health, enhancing cognition, and its neuroprotective effects. The present study aims to investigate the protective role of CA on D-gal/AlCl₃-induced cognitive deficits in rats. The rats were divided into six groups and administered with donepezil 1 mg/kg/day, CA (200, 400, and 800 mg/kg/day) and D-gal 60 mg/kg/day + AlCl₃ 200 mg/kg/day for 10 weeks. The ethology of the rats was evaluated by the Morris water maze test. The levels of acetylcholinesterase (AChE), phosphorylated tau (P-tau), malondialdehyde (MDA) and activities of superoxide dismutase (SOD), in the hippocampus and cerebral cortex were estimated by enzyme-linked immunosorbent assay (ELISA). Additionally, the ultrastructure of the prefrontal cortex of the rats’ was observed using transmission electron microscopy (TEM). Rats administered with D-gal/AlCl₃ exhibited cognitive deficits, decreased activities of SOD, and marked increase in AChE and MDA levels. Further, prominent alterations in the ultrastructure of the prefrontal cortex were observed. Conversely, co-administration of CA with D-gal/AlCl₃ improved cognitive impairment, decreased AChE levels, attenuated the oxidative stress in hippocampus and cerebral cortex, and prevented ultrastructural alteration of neurons in the prefrontal cortex. Irrespective of the dose of CA administered, the protective effects were comparable to donepezil. In conclusion, this study suggests that CA attenuated the cognitive deficits in rats by restoring cholinergic function, attenuating oxidative stress, and preventing the morphological aberrations. Full article

It has been extensively demonstrated that plants accumulate organic substances emanating from various sources, including soil and water. This fact suggests the potentiality of contamination of certain vital bioresources, such as medicinal plants, by persistent contaminants, such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorobutane sulfonate (PFBS). Hence, in this study, the propensity of Tagetes erecta L. (a commonly used medicinal plant) to accumulate PFOA, PFOS, and PFBS was determined using liquid chromatography/tandem mass spectrometry (LC–MS/MS-8030). From the results, PFOA, PFOS, and PFBS were detected in all the plant samples and concentration levels were found to be 94.83 ng/g, 5.03 ng/g, and 1.44 ng/g, respectively, with bioconcentration factor (BCF) ranges of 1.30 to 2.57, 13.67 to 72.33, and 0.16 to 0.31, respectively. Little evidence exists on the bioaccumulative susceptibility of medicinal plants to these persistent organic pollutants (POPs). These results suggest that these medicinal plants (in particular, Tagetes erecta L., used for the management of diabetes) are also potential conduits of PFOA, PFOS, and PFBS into humans. Full article

Living organisms respond to environmental changes and xenobiotic exposures by regulating gene expression. While heat shock, unfolded protein, and DNA damage stress responses are well-studied at the levels of the transcriptome and proteome, tRNA-mediated mechanisms are only recently emerging as important modulators of cellular stress responses. Regulation of the stress response by tRNA shows a high functional diversity, ranging from the control of tRNA maturation and translation initiation, to translational enhancement through modification-mediated codon-biased translation of mRNAs encoding stress response proteins, and translational repression by stress-induced tRNA fragments. tRNAs need to be heavily modified post-transcriptionally for full activity, and it is becoming increasingly clear that many aspects of tRNA metabolism and function are regulated through the dynamic introduction and removal of modifications. This review will discuss the many ways that nucleoside modifications confer high functional diversity to tRNAs, with a focus on tRNA modification-mediated regulation of the eukaryotic response to environmental stress and toxicant exposures. Additionally, the potential applications of tRNA modification biology in the development of early biomarkers of pathology will be highlighted. Full article

DNA adducts are believed to play a central role in the induction of cancer in cigarette smokers and are proposed as being potential biomarkers of cancer risk. We have summarized research conducted since 2012 on DNA adduct formation in smokers. A variety of DNA adducts derived from various classes of carcinogens, including aromatic amines, polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, alkylating agents, aldehydes, volatile carcinogens, as well as oxidative damage have been reported. The results are discussed with particular attention to the analytical methods used in those studies. Mass spectrometry-based methods that have higher selectivity and specificity compared to ³²P-postlabeling or immunochemical approaches are preferred. Multiple DNA adducts specific to tobacco constituents have also been characterized for the first time in vitro or detected in vivo since 2012, and descriptions of those adducts are included. We also discuss common issues related to measuring DNA adducts in humans, including the development and validation of analytical methods and prevention of artifact formation. Full article

Industrial advances have led to generation of multi-component chemicals, materials and pharmaceuticals which are directly or indirectly affecting the environment. Although toxicity data are available for individual chemicals, generally there is no toxicity data of chemical mixtures. Most importantly, the nature of toxicity of these studied mixtures is completely different to the single components, which makes the toxicity evaluation of mixtures more critical and challenging. Interactions of individual chemicals in a mixture can result in multifaceted and considerable deviations in the apparent properties of its ingredients. It results in synergistic or antagonistic effects as opposed to the ideal case of additive behavior i.e., concentration addition (CA) and independent action (IA). The CA and IA are leading models for the assessment of joint activity supported by pharmacology literature. Animal models for toxicity testing are time- and money-consuming as well as unethical. Thus, computational approaches are already proven efficient alternatives for assessing the toxicity of chemicals by regulatory authorities followed by industries. In silico methods are capable of predicting toxicity, prioritizing chemicals, identifying risk and assessing, followed by managing, the risk. In many cases, the mechanism behind the toxicity from species to species can be understood by in silico methods. Until today most of the computational approaches have been employed for single chemical’s toxicity. Thus, only a handful of works in the literature and methods are available for a mixture’s toxicity prediction employing computational or in silico approaches. Therefore, the present review explains the importance of evaluation of a mixture’s toxicity, the role of computational approaches to assess the toxicity, followed by types of in silico methods. Additionally, successful application of in silico tools in a mixture’s toxicity predictions is explained in detail. Finally, future avenues towards the role and application of computational approaches in a mixture’s toxicity are discussed. Full article

Aristolochic acids (AAs) are nitrophenanthrene carboxylic acids naturally produced by Aristolochia plants. These plants were widely used to prepare herbal remedies until AAs were observed to be highly nephrotoxic and carcinogenic to humans. Although the use of AA-containing Aristolochia plants in herbal medicine is prohibited in countries worldwide, emerging evidence nevertheless has indicated that AAs are the causative agents of Balkan endemic nephropathy (BEN), an environmentally derived disease threatening numerous residents of rural farming villages along the Danube River in countries of the Balkan Peninsula. This perspective updates recent findings on the identification of AAs in food as a result of the root uptake of free AAs released from the decayed seeds of Aristolochia clematitis L., in combination with their presence and fate in the environment. The potential link between AAs and the high prevalence of chronic kidney diseases in China is also discussed. Full article

Environmental research has widely utilized the ambient concentrations of hazardous air pollutants (HAPs) modeled by the National-Scale Air Toxics Assessment (NATA) program; however, limited studies have evaluated the model’s performance. This study aims to evaluate the model-to-monitor agreement of the 2011 NATA data with the monitoring data reported to the U.S. Environmental Protection Agency’s (EPA) Air Quality System (AQS). Concentrations of 27 representative HAPs measured at 274 sites in the U.S. in 2011 were merged with NATA data by census tract. The comparison consisted of two steps for each HAP: first, the model-monitor difference at each site was compared with the limit of quantitation (LOQ); second, the modeled annual average was compared to the 95% confidence interval of the monitored annual average. Nationally, NATA could predict national medians of most HAPs well; however, it was unable to capture high concentrations. At individual sites, a large portion of model-monitor differences was below the LOQs, indicating they were unquantifiable. Model-to-monitor agreement displayed inconsistent patterns in terms of chemical groups or EPA regions and was strongly impacted by the comparison methods. The substantial non-agreements of NATA predictions with monitoring data require caution in environmental epidemiology and justice studies that are based on NATA data. Full article

Silver nanoparticles (AgNPs) are used intensively in medical and industrial applications. Environmental concerns have arisen from the potential release of this material into aquatic ecosystems. The aims of this research were to evaluate the potential accumulation of silver in the whole body of organisms and analyze the effects of AgNPs on the survival and reproduction of the snail Biomphalaria glabrata. Results show slow acute toxicity with a 10-day LC₅₀ of 18.57 mg/L and an effective decrease in the eggs and egg clutches per organism exposed to tested concentrations. Based on these data, the No Observed Effect Concentration (NOEC) observed was <1 mg/L for snail reproduction. For silver accumulation, we observed that uptake was faster than elimination, which was very slow and still incomplete 35 days after the end of the experiment. However, the observed accumulation was not connected with a concentration/response relationship, since the amount of silver was not equivalent to a higher reproductive effect. The data observed show that AgNPs are toxic to B. glabrata, and suggest that the snail has internal mechanisms to combat the presence of Ag in its body, ensuring survival and reduced reproduction and showing that the species seems to be a potential indicator for Ag presence in contaminated aquatic ecosystems. Full article

Preterm birth is an obstetric condition associated with a high risk of infant mortality and morbidities in both the neonatal period and later in life, which has also a significant public health impact because it carries an important societal economic burden. As in many cases the etiology is unknown, it is important to identify environmental factors that may be involved in the occurrence of this condition. In this review, we report all the studies published in PubMed and Scopus databases from January 1992 to January 2019, accessible as full-text articles, written in English, including clinical studies, original studies, and reviews. We excluded articles not written in English, duplicates, considering inappropriate populations and/or exposures or irrelevant outcomes and patients with known risk factors for preterm birth (PTB). The aim of this article is to identify and summarize the studies that examine environmental toxicants exposure associated with preterm birth. This knowledge will strengthen the possibility to develop strategies to reduce the exposure to these toxicants and apply clinical measures for preterm birth prevention. Full article

Background: The efficacy of chemotherapy is undermined by adverse side effects and chemoresistance of target tissues. Developing a drug delivery system can reduce off-target side effects and increase the efficacy of drugs by increasing their accumulation in target tissues. Inorganic salts have several advantages over other drug delivery vectors in that they are non-carcinogenic and less immunogenic than viral vectors and have a higher loading capacity and better controlled release than lipid and polymer vectors. Methods: MgF₂ crystals were fabricated by mixing 20 mM MgCl₂ and 10 mM NaF and incubating for 30 min at 37 °C. The crystals were characterized by absorbance, dynamic light scattering, microscopic observance, pH sensitivity test, SEM, EDX and FTIR. The binding efficacy to doxorubicin was assessed by measuring fluorescence intensity. pH-dependent doxorubicin release profile was used to assess the controlled release capability of the particle-drug complex. Cellular uptake was assessed by fluorescence microscopy. Cytotoxicity of the particles and the drug-particle complex were assessed using MTT assay to measure cell viability of MCF-7 cells. Results and Discussion: Particle size on average was estimated to be <200 nm. The crystals were cubic in shape. The particles were pH-sensitive and capable of releasing doxorubicin in increasing acidic conditions. MgF₂ nanocrystals were safe in lower concentrations, and when bound to doxorubicin, enhanced its uptake. The protein corona formed around MgF₂ nanoparticles lacks typical opsonins but contains some dysopsonins. Conclusion: A drug delivery vector in the form of MgF₂ nanocrystals has been developed to transport doxorubicin into breast cancer cells. It is pH-sensitive (allowing for controlled release), size-modifiable, simple and cheap to produce. Full article