Assessing the impact of antineoplastic drugs in the aquatic environment: State of the art and future perspective for freshwater organisms.

Since the late 70s, the continuous pharmaceuticals` input into the environment has raised concerns regarding the eventual risk posed by such compounds to human and environmental health. A major group of pharmaceuticals in terms of environmental impact are the antineoplastic agents (AAs). Herein, we followed a systematic review method to retrieve antineoplastic agents (AAs') ecotoxicological information regarding freshwater species. In this analysis, data from diverse taxonomic groups, from microorganisms to vertebrate species, looked at different levels of biological organization, including cell lines. Furthermore, this review gathers ecotoxicological parameters (EC50 and LC50) for imatinib (IM), cisplatin (CisPt), and 5-fluorouracil (5-FU) in species sensitivity distribution (SSD) curves and estimates the hazard concentration (HC5) considering the protection of 95% of the ecological community. Lastly, we suggest how we can improve AAs' Environmental Risk Assessment (ERA), considering potential adoptable toxicity endpoints, test duration, AAs metabolites testing, and AAs mixture exposure.

Environmental Hazard of Anticancer Drugs: State of the Art and Future Perspective for Marine Organisms.

Pharmaceutical compounds represent a class of emerging contaminants present in the environment. Their intense (and increasing) use in human and veterinary medicine leads to their discharge, mainly via human excretion, into wastewater treatment plants where their removal is inefficient. A specific class of pharmaceuticals used to fight cancer, known as antineoplastic or anticancer drugs, has gained increased attention regarding their possible environmental hazard due to their pharmacological properties, which include the nonselective targeting of DNA replication mechanisms and cell division processes, potentially inducing cell apoptosis. To date, there is limited information concerning the effects of anticancer drugs and/or their metabolites in species inhabiting freshwater environments, let alone marine and estuarine compartments. In the present review, we aimed to assemble information regarding the impact that anticancer drugs have on biological traits of marine species, to identify gaps in the current environmental hazard assessment, and to make recommendations to promote an efficient environmental hazard assessment of anticancer drugs in the marine environment. Environ Toxicol Chem 2022;41:1793-1807. © 2022 SETAC.

Polyethylene glycol acute and sub-lethal toxicity in neotropical Physalaemus cuvieri tadpoles (Anura, Leptodactylidae).

Although many polymers are known by their toxicity, we know nothing about the impact of polyethylene glycol (PEG) on anurofauna. Its presence in different products and disposal in aquatic environments turn assessments about its impact on amphibians an urgent matter. Accordingly, we tested the hypothesis that short-time exposure (72 h) of tadpoles belonging to the species Physalaemus cuvieri (Anura, Leptodactylidae) to PEG induces oxidative stress and neurotoxicity on them. We observed that polymer uptake in P. cuvieri occurred after exposure to 5 and 10 mg/L of PEG without inducing changes in their nitrite levels neither at the levels of substances reactive to thiobarbituric acid. However, hydrogen peroxide and reactive oxygen species production was higher in animals exposed to PEG, whose catalase and superoxide dismutase levels were not enough to counterbalance the production of these reactive species. Therefore, this finding suggests physiological changes altering REDOX homeostasis into oxidative stress. In addition, the increased activity of acetylcholinesterase and butyrylcholinesterase, and reduction in superficial neuromasts, confirmed PEG's neurotoxic potential. To the best of our knowledge, this is the first report on PEG's biological impact on a particular amphibian species. The study has broadened the understanding about ecotoxicological risks associated with water pollution by these polymers, as well as motivated further investigations on its impacts on amphibians' health and on the dynamics of their natural populations.

Ceria Nanoparticles Decrease UVA-Induced Fibroblast Death Through Cell Redox Regulation Leading to Cell Survival, Migration and Proliferation.

Exposure to ultraviolet radiation is a major contributor to premature skin aging and carcinogenesis, which is mainly driven by overproduction of reactive oxygen species (ROS). There is growing interest for research on new strategies that address photoaging prevention, such as the use of nanomaterials. Cerium oxide nanoparticles (nanoceria) show enzyme-like activity in scavenging ROS. Herein, our goal was to study whether under ultraviolet A rays (UVA)-induced oxidative redox imbalance, a low dose of nanoceria induces protective effects on cell survival, migration, and proliferation. Fibroblasts cells (L929) were pretreated with nanoceria (100 nM) and exposed to UVA radiation. Pretreatment of cells with nanoceria showed negligible cytotoxicity and protected cells from UVA-induced death. Nanoceria also inhibited ROS production immediately after irradiation and for up to 48 h and restored the superoxide dismutase (SOD) activity and GSH level. Additionally, the nanoceria pretreatment prevented apoptosis by decreasing Caspase 3/7 levels and the loss of mitochondrial membrane potential. Nanoceria significantly improved the cell survival migration and increased proliferation, over a 5 days period, as compared with UVA-irradiated cells, in wound healing assay. Furthermore, it was observed that nanoceria decreased cellular aging and ERK 1/2 phosphorylation. Our study suggests that nanoceria might be a potential ally to endogenous, antioxidant enzymes, and enhancing the redox potentials to fight against UVA-induced photodamage and consequently modulating the cells survival, migration, and proliferation.

Structural Characterization and Biological Evaluation of 18-Nor-ent-labdane Diterpenoids from Grazielia gaudichaudeana.

The phytochemical investigation of Grazielia gaudichaudeana aerial parts yielded 15 compounds, including diterpenes, triterpenes, sterols and flavonoids. With exception to ent-kaurenoic acid diterpenes, the compounds isolated are being described for the first time in this species. Some unusual 1 H-NMR chemical shifts of 18-nor-ent-labdane (7-9) led us carry out a conformational analysis by theoretical calculations in order to support the experimental data. Moreover, due to the limitation of studies focused on pharmacological potential of Grazielia gaudichaudeana, the present study was carried out to investigate the antioxidant, antiproliferative, antiviral, antileishmanial and antimicrobial activities from the extract, fractions and isolated compounds obtained from this species. Ethyl acetate fraction showed significant activity in the antiproliferative assay, with GI50 range of 3.9 to 27.2 µg mL-1 . Dichloromethane fraction, rich in diterpenoids, inhibited all human tumor cell lines tested, and the nor-labdane 7 showed potent cytotoxic activity against glioma and ovary cancer cell lines.

In vitro evaluation of the protective effects of plant extracts against amyloid-beta peptide-induced toxicity in human neuroblastoma SH-SY5Y cells.

Alzheimer's disease (AD) is the most common form of dementia and has no cure. Therapeutic strategies focusing on the reduction of oxidative stress, modulation of amyloid-beta (Aß) toxicity and inhibition of tau protein hyperphosphorylation are warranted to avoid the development and progression of AD. The aim of this study was to screen the crude extracts (CEs) and ethyl-acetate fractions (EAFs) of Guazuma ulmifolia, Limonium brasiliense, Paullinia cupana, Poincianella pluviosa, Stryphnodendron adstringens and Trichilia catigua using preliminary in vitro bioassays (acetylcholinesterase inhibition, antioxidant activity and total polyphenol content) to select extracts/fractions and assess their protective effects against Aß25-35 toxicity in SH-SY5Y cells. The effect of the EAF of S. adstringens on mitochondrial membrane potential, lipid peroxidation, superoxide production and mRNA expression of 10 genes related to AD was also evaluated and the electropherogram fingerprints of EAFs were established by capillary electrophoresis. Chemometric tools were used to correlate the in vitro activities of the samples with their potential to be evaluated against AD and to divide extracts/fractions into four clusters. Pretreatment with the EAFs grouped in cluster 1 (S. adstringens, P. pluviosa and L. brasiliense) protected SH-SY5Y cells from Aß25-35-induced toxicity. The EAF of S. adstringens at 15.62 µg/mL was able completely to inhibit the mitochondrial depolarization (69%), superoxide production (49%) and Aß25-35-induced lipid peroxidation (35%). With respect to mRNA expression, the EAF of S. adstringens also prevented the MAPT mRNA overexpression (expression ratio of 2.387x) induced by Aß25-35, which may be related to tau protein hyperphosphorylation. This is the first time that the neuroprotective effects of these fractions have been demonstrated and that the electropherogram fingerprints for the EAFs of G. ulmifolia, L. brasiliense, P. cupana, P. pluviosa and S. adstringens have been established. The study expands knowledge of the in vitro protective effects and quality control of the evaluated fractions.

Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System.

Despite ongoing efforts, the available treatments for Chagas' disease are still unsatisfactory, especially in the chronic phase of the disease. Our previous study reported the strong trypanocidal activity of the dibenzylideneacetones A3K2A1 and A3K2A3 against Trypanosoma cruzi (Z. Ud Din, T. P. Fill, F. F. de Assis, D. Lazarin-Bidóia, V. Kaplum, F. P. Garcia, C. V. Nakamura, K. T. de Oliveira, and E. Rodrigues-Filho, Bioorg Med Chem 22:1121-1127, 2014, http://dx.doi.org/10.1016/j.bmc.2013.12.020). In the present study, we investigated the mechanisms of action of these compounds that are involved in parasite death. We showed that A3K2A1 and A3K2A3 induced oxidative stress in the three parasitic forms, especially trypomastigotes, reflected by an increase in oxidant species production and depletion of the endogenous antioxidant system. This oxidative imbalance culminated in damage in essential cell structures of T. cruzi, reflected by lipid peroxidation and DNA fragmentation. Consequently, A3K2A1 and A3K2A3 induced vital alterations in T. cruzi, leading to parasite death through the three pathways, apoptosis, autophagy, and necrosis.

Co-exposure of ZnO nanoparticles and UV radiation to Daphnia magna and Danio rerio: Combined effects rather than protection.

The application of nanoparticles (NPs) in consumer products has been increasing over the past few years. Their release into the environment is likely to happen at any stage of production or during the use of products containing NPs. Zinc oxide NPs (ZnO-NP) are among the most-used NPs on the market due to its intrinsic properties, such as ultraviolet (UV) absorption. The aim of the present study was to assess the combined effects of ZnO-NP and UV radiation on 2 freshwater species: Daphnia magna and Danio rerio. The initial hypothesis was that the presence of ZnO-NP in the aquatic media would decrease the damaging effects of UV radiation for both species. The endpoints assessed for D. magna were immobilization, feeding inhibition, and reproduction output. For D. rerio, egg development was studied during 96 h and mortality, hatching delay, and abnormal development were the endpoints recorded. Combined exposures were designed based on the single toxicity of both stressors and analyzed based on the independent action concept and exploring possible deviations for synergism/antagonism, dose level, and dose ratio. Combined exposures with D. magna induced synergism on reproduction, decreasing the number of neonates produced more than expected based on both stressors' individual toxicity. Single exposures of D. rerio embryos to both stressors induced negative effects. The combined exposures caused a dose-ratio deviation pattern on mortality and hatching, with a synergism observed when ZnO-NP was the dominant stressor, changing to antagonism when UV radiation dominated the combined exposure. Regarding the results attained, studying ZnO toxicity under laboratory conditions may underestimate the risks when considering the potential interaction on effects when combined with UV radiation.

The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process.

Chagas' disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas' disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death.

Environmental- and growth stage-related differences in the susceptibility of terrestrial isopods to UV radiation.

Global environmental changes are nowadays one of the most important issues affecting terrestrial ecosystems. One of its most significant expressions is the increasing ultraviolet radiation (UVR) arising from the human-induced depletion in ozone layer. Therefore, to investigate the effects of UVR on the terrestrial isopod Porcellionides pruinosus a multiple biomarker approach was carried out. Two experiments were performed in order to analyze the importance of the exposure environment and the growth stage on the UV-induced damages. First, adult individuals were exposed to UVR in three exposure environments (soil, soil with leaves, and plaster). Thereafter, three growth stages using soil as the exposure condition were tested. Integrated biomarker responses (IBR) suggested that UV effects were higher in plaster, and mostly identified by changes in acetylcholinesterase and glutathione-S-transferases activities, lipid peroxidation rates, and total energy available. The effects in soil and soil with leaves were not so clear. In the growth stages' experiment, juveniles and pre-adults were found to be more affected than adults, with the greatest differences between irradiated and non-irradiated isopods occurring in energy-related parameters. Our findings suggest that soil surface-living macrofauna may be prone to deleterious effects caused by UVR, highlighting the importance of taking the media of exposure and growth stage in account.

Is ultraviolet radiation a synergistic stressor in combined exposures? The case study of Daphnia magna exposure to UV and carbendazim.

The toxicological assessment of chemical compounds released to the environment is more accurate when mixtures of chemicals and/or interactions between chemicals and natural stressors are considered. Ultraviolet radiation can be taken as a natural stressor since the levels of UV are increasing due to the decrease of its natural filter, the stratospheric ozone concentration. Therefore, a combination of chemical exposures and increasing UV irradiance in aquatic environments is likely to occur. In the current study, combined effects of carbendazim and ultraviolet radiation were evaluated, using selected life traits as endpoints on Daphnia magna. To design combined exposures, first single chemical and natural stressor bioassays were performed: a reproduction test with carbendazim and a reproduction, feeding inhibition and Energy budget test with ultraviolet radiation. Following single exposures, the combinations of stressors included exposures to UV radiation and carbendazim for a maximum exposure time of 4h, followed by a post-exposure period in chemically contaminated medium for a maximum of 15 days, depending on the endpoint, where the effects of the combined exposures were investigated. Statistical analyses of the data set were performed using the MixTox tool and were based on the conceptual model of Independent Action (IA) and possible deviations to synergism or antagonism, dose-ratio or dose-level response pattern. Both ultraviolet radiation and carbendazim as single stressors had negative impacts on the measured life traits of daphnids, a decrease on both feeding rates and reproduction was observed. Feeding rates and reproduction of D. magna submitted to combined exposures of ultraviolet radiation and carbendazim showed a dose-ratio deviation from the conceptual model as the best description of the data set, for both endpoints. For feeding inhibition, antagonism was observed when the UV radiation was the dominant item in combination, and for reproduction, synergism was observed when UV radiation dominated the exposure. From these results, the combined exposure of ultraviolet radiation and chemical compounds should also be considered for risk assessment as this study has shown that more severe effect than expected by single chemical assessment might be observed.