•Autophagy is a catabolic process that degrades and recycles cellular organelles and proteins.•The level of autophagy is increased under stress conditions including chemical stress.•Many ...environmental chemicals have been found to affect autophagy.•Increase of autophagy can increase adaptation into stress and decrease genetic damage.•Inhibition or depletion of autophagy process can either increase or decrease toxicity depending on the context.
Autophagy is a catabolic pathway, which breaks down old and damaged cytoplasmic material into basic biomolecules through lysosome-mediated digestion thereby recycling cellular material. In this way, autophagy prevents the accumulation of damaged cellular components inside cells and reduces metabolic stress and toxicity. The basal level of autophagy is generally low but essential for maintaining the turnover of proteins and other molecules. The level is, however, increased in response to various stress conditions including chemical stress. This elevation in autophagy is intended to restore energy balance and improve cell survival in stress conditions. However, aberrant and/or deficient autophagy may also be involved in the aggravation of chemical-caused insults. Thus, the overall role of autophagy in chemical-induced toxicity is complex and only a limited number of environmental chemicals have been studied from this point of view. Autophagy is associated with many of the chemical-caused cytotoxic mechanisms, including mitochondrial dysfunction, DNA damage, oxidative stress, changes in the endoplasmic reticulum, impairment of lysosomal functions, and inflammation. This mini-review describes autophagy and its involvement in the responses to some common environmental exposures including airborne particulate matter, nanoparticles and tobacco smoke as well as to some common single environmental chemicals.
Many chemicals, including many endocrine disruptors (EDCs) are known to leach out from various plastic consumer products and waste, and are widespread in the environment. EDCs are a large group of ...contaminants that can interfere with hormonal metabolism or function. In addition, there are in the literature implications of contribution by EDCs in tumor progression, the last stage of carcinogenesis driven by cells with a metastatic phenotype. The process of epithelial cells losing their apical-basal polarity and cell-to-cell contacts, and acquiring migration and invasive properties typical of mesenchymal cells is called epithelial-mesenchymal transition (EMT). It is essential for tumor progression. In human cells, plastic-related EDCs, (phthalates, bisphenol A, and the alkylphenols: nonylphenol and octylphenol) reduce epithelial E-cadherin, and increase mesenchymal N-cadherin and extracellular matrix metalloproteinases. These changes are hallmarks of EMT. In xenograft mouse studies, EDCs increase migration of cells and metastatic growth in distant tissues. Their contribution to EMT and tumor progression, the topic of this review, is important from public health perspective, because of the ubiquitous exposure to these EDCs. In this mini-review we also discuss molecular mechanisms associated with EDC-induced EMT and tumor progression.
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•Chemicals leaching out from plastics include endocrine disruptors.•The leaching endocrine disruptors can induce epithelial-mesenchymal transition (EMT).•EMT leads to cell migration and invasion essential in tumor progression and metastasis.•The leached endocrine disruptors probably contribute to tumor progression and metastasis.
Per- and polyfluoroalkyl substances (PFAS) are a large group of synthetic persistent chemicals, which are used in many industrial and commercial applications. Hundreds of different PFAS have been ...identified in the environment and they are commonly found also in human blood. Due to the chemical stability and extensive use, PFAS pose a risk for human health and wildlife. Mounting evidence indicates that PFAS-exposure adversely affects many organs including liver, kidney, and reproductive tissues and induces tumors in laboratory rodents. Epidemiological studies show association between PFAS-exposure and some tumors also in humans. Effects of PFAS-exposure are complex and obviously do not depend only on the concentration and the structure of PFAS, but also on age and sex of the exposed individuals. It has been difficult to show a causal link between PFAS-exposure and tumors. Moreover, molecular mechanisms of the PFAS effects in different tissues are poorly understood. PFAS are not directly mutagenic and they do not induce formation of DNA binding metabolites, and thus are assumed to act more through non-genotoxic mechanisms. In this review, we discuss the involvement of PFAS-compounds in tumor development in tissues where PFAS exposure has been associated with cancer in epidemiological and animal studies (liver, kidney, testicle and breast). We will focus on molecular pathways and mechanisms related to tumor formation following PFAS-exposure.
Studies on the increasing number of transporters found in the placental barrier are gaining momentum, because of their tissue‐specific expression, significance in physiology and disease, and the ...possible utilization of the emerging knowledge in pharmacology. In the placenta, both syncytiotrophoblast and fetal capillary endothelium express transporters. Fetal exposure is determined by the net effect of combination of transporters, their nature and localization in relation to placental cells and their substrate specificity. Although the significance of placental transporters on human fetal drug exposure is almost an unstudied field so far, their potential use to design drugs that do not cross the placenta is already being pursued. It is thus of interest to review the existing knowledge of human placental transporters. Transporters in all groups which take part in drug transport are found in human placenta. Especially, ATP‐binding cassette transporters ABCG2/breast cancer resistance protein, ABCB1/P‐glycoprotein and ABCC2/MRP2 are all expressed at the apical surface of syncytiotrophoblast facing maternal blood and are putatively important protective proteins both for placental tissue and the fetus, because they are efflux transporters and their substrates include many drugs and also environmental chemicals. Such protective effect has been shown in animals, but these results cannot be directly extrapolated to humans due to interspecies differences in placental structure and function. Experimental models utilizing human placental tissue, especially human placental perfusion, offer valuable possibilities, which have been insufficiently studied so far.
Toxicity of diuron metabolites in human cells Mohammed, Ali Mustafa; Huovinen, Marjo; Vähäkangas, Kirsi H.
Environmental toxicology and pharmacology,
August 2020, 2020-Aug, 2020-08-00, 20200801, Volume:
78
Journal Article
Peer reviewed
•Diuron metabolites were toxic in human cancer cell lines BeWo, MCF-7 and Caco-2.•Clear toxicity by MTT assay indicates mitochondrial-mediated toxicity.•In comparison between the cell lines, MCF-7 ...was the most resistant.•Increased ROS may not explain cytotoxicity of diuron metabolites.
Diuron, a highly used herbicide worldwide, is metabolized into several toxic metabolites. DCA (3,4-dichloroaniline), DCPU 3-(3, 4-dichlorophenyl)urea and DCPMU 3-(3,4-dichlorophenyl)-1-methyl urea reduced viability of human placental choriocarcinoma BeWo, human breast adenocarcinoma MCF-7 and human colon adenocarcinoma Caco-2 cells as judged by the MTT assay, where color formation is dependent on functional mitochondria in viable cells. Based on the IC50 values in BeWo cells the order of cytotoxicity was DCA > DCPU > diuron > DCPMU, and in Caco-2 cells DCPMU > DCPU > DCA, diuron. In MCF-7 cells, only DCPU had an IC50 within the range of the concentrations used. In the PI-digitonin viability assay, only the highest concentration (200 μM) of DCPU caused a statistically significant decrease in viability in any cell line. There was no correlation between cytotoxicity and ROS production. This indicates that diuron metabolites are toxic in cells of human origin with mitochondria as the target, but ROS not the likely mechanism.
► Xenobiotic metabolizing enzymes and transporters modify placental transfer of xenobiotics. ► Several in vitro methods for placental toxicity and transfer exist. ► Placental perfusion and cells ...grown on semipermeable membranes provide data on placental transfer. ► Other models provide data on mechanisms affecting transfer such as uptake, efflux and metabolism.
Over the decades several ex vivo and in vitro models which utilize delivered human placenta have been developed to study various placental functions. The use of models originating from human placenta to study transplacental transfer and related mechanisms is an attractive option because human placenta is relatively easily available for experimental studies. After delivery placenta has served its purpose and is usually disposed of. The purpose of this review is to give an overview of the use of human placental models for the studies on human placental transfer and related mechanisms such as transporter functions and xenobiotic metabolism. Human placental perfusion, the most commonly used continuous cell lines, primary cells and tissue culture, as well as subcellular fractions are briefly introduced and their major advantages and disadvantages are discussed.
Toxicity of red mud, a waste from alumina production, was studied using human breast cancer MCF-7 cells. Culture medium was prepared by mixing water for 3 days with the red mud and removing solid ...particles afterwards (red mud water). Culture for 48 h of the cells in this medium in neutral pH decreased the cell viability, as analyzed by the MTT-test, and increased the formation of reactive oxygen species. Thus, neutralization does not eliminate the toxicity of red mud. In preliminary experiments, a combined effect of five metals (Cr, Li, V, Al, As) increased the formation of ROS (reactive oxygen species) statistically significantly. Each element separately did not have a similar effect. In environmental applications, red mud is likely to be used after activation. In this work, the red mud was activated using hydrochloric acid to study the physical and chemical properties before and after the treatment. Activation increased the specific surface area of red mud from 16 m2 g−1 to 148 m2 g−1, which is beneficial in many environmental applications such as in the adsorptive removal of pollutants. After activation, leaching of some elements from the red mud decreased (e.g. Al from 38.0 to 0.56 mg L−1, As from 21.0 to 2.1 μg L−1, V from 172.0 to 29.8 μg L−1) while some increased (e.g. Li from 0.04 to 2.81 mg L−1, Cr from 0.35 to 3.23 mg L−1).
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•Elements leached from red mud decrease the viability of MCF-7 cells.•Elements leached from red mud increase the formation of reactive oxygen species.•Neutralization does not eliminate the toxicity of red mud.•Acid activation increases the specific surface area of red mud.
Micro- and nanoplastics (MNPs) are ubiquitous in the environment and have recently been found in human lungs, blood and placenta. However, data on the possible effects of MNPs on human health is ...extremely scarce. The potential toxicity of MNPs during pregnancy, a period of increased susceptibility to environmental insults, is of particular concern. The placenta provides a unique interface between maternal and fetal circulation which is essential for in utero survival and healthy pregnancy. Placental toxicokinetics and toxicity of MNPs are still largely unexplored and the limited studies performed up to now focus mainly on polystyrene particles. Practical and ethical considerations limit research options in humans, and extrapolation from animal studies is challenging due to marked differences between species. Nevertheless, diverse in vitro and ex vivo human placental models exist e.g., plasma membrane vesicles, mono-culture and co-culture of placental cells, placenta-on-a-chip, villous tissue explants, and placental perfusion that can be used to advance this research area. The objective of this concise review is to recapitulate different human placental models, summarize the current understanding of placental uptake, transport and toxicity of MNPs and define knowledge gaps. Moreover, we provide perspectives for future research urgently needed to assess the potential hazards and risks of MNP exposure to maternal and fetal health.
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•Placenta is crucial for fetal development and pregnancy.•First evidence of microplastics in human placentas emerge, but more data is needed using relevant methodology.•Human in vitro and ex vivo placental models are recapitulated and comprehensively reviewed.•The current understanding of transplacental transport and toxicity of microplastics is summarized.•The most pressing knowledge gaps are identified and perspectives for future research provided.
Toxicity of diuron in human cancer cells Huovinen, Marjo; Loikkanen, Jarkko; Naarala, Jonne ...
Toxicology in vitro,
October 2015, 2015-Oct, 2015-10-00, 20151001, Volume:
29, Issue:
7
Journal Article
Peer reviewed
Open access
•Human MCF-7 and BeWo cells responded differently to diuron treatment.•Trophoblastic BeWo cells were more sensitive to cytotoxicity by diuron.•ROS production was increased in both types of ...cells.•Genotoxic potential of diuron is implicated by the positive Comet-assay in MCF-7 cells.
Diuron is a substituted phenylurea used as a herbicide to control broadleaf and grass weeds and as a biocidal antifouling agent. Diuron is carcinogenic in rat urinary bladder and toxic to the reproductive system of oysters, sea urchins and lizards. The few studies carried out in human cells do not include the genotoxicity of diuron. We have investigated the toxicity of diuron in human breast adenocarcinoma (MCF-7) and human placental choriocarcinoma (BeWo) cells. The production of reactive oxygen species (ROS) was statistically significantly increased in both cell lines but only at the highest 200μM concentration. Diuron clearly reduced the viability of BeWo, but not MCF-7 cells. The relative cell number was decreased in both cell lines indicative of inhibition of cell proliferation. In the Comet assay, diuron increased DNA fragmentation in MCF-7 but not in BeWo cells. The expressions of p53 protein, a marker for cell stress, and p21 protein, a transcriptional target of p53, were increased, but only in MCF-7 cells. In conclusion, our results suggest that diuron is cytotoxic and potentially genotoxic in a tissue-specific manner and that ROS play a role in its toxicity. Thus, exposure to diuron may exert harmful effects on fetal development and damage human health.
•Diuron crosses human placenta with ease suggesting fetal exposure and hence fetotoxicity.•Diuron is metabolized into a toxic metabolite in human placenta from smokers.•Diuron is also metabolized in ...human placenta from non-smokers but only in high doses.•CYP1A1 is responsible for the metabolism of diuron in human placenta.
Diuron is a broad-spectrum phenylurea derived herbicide which is commonly used across the globe. Diuron is toxic to the reproductive system of animals and carcinogenic to rat urothelium, and recently found to be genotoxic in human cells. In in vivo, it is metabolized predominately into 3-(3,4-dichlorophenyl)-1-methyl urea (DCPMU) in humans and 3-(3, 4-dichlorophenyl)urea (DCPU) in animals. Information on diuron toxicokinetics and related toxicity in human placenta is absent. We have investigated the toxicokinetics of diuron in ex vivo human placental perfusion and in in vitro human placental microsomes and human trophoblastic cancer cells (BeWo). Diuron crossed human placenta readily in placental perfusion. Furthermore, diuron was metabolized into DCPMU in perfused placenta and in in vitro incubations using microsomes from placentas of smokers. In incubations with placental microsomes from non-smokers, and in BeWo cells, metabolism to DCPMU was detected but only with the highest used diuron concentration (100 μM). Diuron metabolism was inhibited upon addition of α-naphthoflavone, a CYP1A1 inhibitor, underscoring the role of CYP1A1 in the metabolism. In conclusion, it is evident that diuron crosses human placenta and diuron can be metabolized in the placenta to a toxic metabolite via CYP1A1. This implicates in vivo fetal exposure to diuron if pregnant women are exposed to diuron, which may result in fetotoxicity.
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