Effects Of Environmental Chemicals Research Articles

Analysis of reference doses of chemicals introduced with drinking water

At present, many researchers highlight that the risk assessment methodology is rather static in Russian regulatory documents. This goes for both the essence of chemical exposures and reference doses stipulated for chemicals introduced into the body with drinking water. In this study, we aimed to analyze reference doses of chemicals introduced into the body with drinking water. Our research object was represented by the basic list of indicators that describe drinking water safety as per its chemical structure. Comparative analysis of reference doses of chemicals and their evidence base relied on the valid regulatory documents, Information System for Risk Assessment open-access electronic database on effects of environmental chemicals on health, and background research articles. The results obtained by assessing combined effects of chemicals on human health were generalized and visualized in MS Excel and a tool for working with graphs. The overall time period when reference doses of the analyzed chemicals were last revised was between 1987 and 2012. Not all health effects suggested in the Russian Guide on risk assessment are used as a basis for calculating reference doses of chemicals; hence, not all of them can be agreed upon on the international level at present since they do not rely on background research. Changes in reference doses occurred for chlorinated organic compounds (bromdichloromethane, tetrachloroethylene, tetrachloromethane, and trichloroethylene), lithium, cadmium, cobalt, iron, and copper. We identified certain limitations in establishing an oral reference dose of iron and ammonia, which are conventionally considered from organoleptic perception. Due to various reasons, we did not find any adequate data obtained by toxicological studies that would substantiate reference doses for copper, magnesium, ammonia, lead, silicon, bromine, and chromium under oral introduction with drinking water. We recommend considering our research data on reference doses when planning a study with its focus on impacts exerted by drinking water quality on public health and employing the risk assessment methodology to analyze oral chemical exposure.

Effects of environmental chemicals on EGFR signaling via protein modification

Effects of environmental chemicals on EGFR signaling via protein modification

Systems toxicology approach explores target-pathway relationship and adverse health impacts of ubiquitous environmental pollutant bisphenol A

ABSTRACT The effects of environmental chemicals on health outcomes may be underestimated due to deficiency of knowledge regarding the actions of compounds on toxico-pathogenic mechanisms underlying biological systems outcomes. In this regard, the current study aimed to explore the potential target-pathway-disease relationship attributed to bisphenol A (BPA) responses in target tissues. Computational methods including reverse pharmacophore mapping approach, structural similarity based search and kinome wide interaction profiling were employed with molecular docking validation. Gene ontology (GO) enrichment analysis and protein-protein interaction (PPI) network based illustrations were utilized to prioritize target-pathway and disease relationships. Data illustrated that BPA possessed multi-target nature since this chemical potentially interacted with various protein targets where many of these were validated through docking. Potential BPA targets were significantly enriched to various cellular signaling pathways including steroid biosynthesis, peroxisome proliferator-activated receptor gamma (PPARℽ) and cancer. Further, hypertension was prioritized as disease target. In addition, BPA targeted 17 cell signaling kinases encompassed in the human kinome. In addition, inflammatory (5-LO) and apoptosis regulators (Bcl-X and Bcl-2) were also explored as novel targets. Evidence indicates that the multi-target nature and plausible mechanisms underlying BPA actions in a system wide manner aids toward understanding of adverse effects. This observation may lead us to more precise method to elucidate the toxico-pathogenic mechanisms of BPA with an environmental health perspective.

Untargeted Metabolomics Reveals that Multiple Reproductive Toxicants are Present in the Endometrium

BACKGROUND AND AIM: Recent epidemiological research focused on the effects of environmental chemicals on the female reproductive system shows mixed results, which may be partially due to differences in exposure assessment, residual confounding from diet or lifestyle factors, or co-exposures to other chemicals. These challenges highlight the need for more precise exposure assessment at the end-organ of interest to accurately understand the adverse reproductive effects of environmental exposures. Our aim was to perform untargeted metabolomic analysis of menstrual blood, a novel biospecimen, to identify environmental toxins present in the endometrium. METHODS: Whole menstrual effluent samples were collected from four women using a menstrual cup. To evaluate the effect of sample processing times, one portion of menstrual effluent was immediately frozen at -20°C for 24hrs and the second portion was kept at 4°C for 24hrs; both samples were then stored at -80°C. Samples were analyzed using untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS). To survey the presence of environmental exposures, LC-HRMS chemical profiles were matched to the ToxCast chemical database, which includes 4,557 commonly used commercial chemicals. Select compounds were confirmed using MS/MS and comparison to reference standards. Principal component analysis (PCA) was used to identify differences within and between individuals’ menstrual blood metabolomic profiles, and the influence of the sample processing method. RESULTS:We identified 261 high confidence matches to environmental chemicals, including suspected reproductive toxicants such as phenols, parabens, phthalates, and organochlorides. PCA showed analysis of menstrual blood samples was highly reproducible, with much higher variability between participants than between an individual’s analytical replicates. CONCLUSIONS:Our results show chemical exposures linked to reproductive toxicity and endocrine disruption are present in the endometrium. In addition, our results demonstrate that menstrual blood can be successfully collected and provides a suitable biofluid for untargeted profiling to assess environmental exposures associated with potential adverse reproductive outcomes. KEYWORDS: metabolomics, exposome, biomarkers of exposure, endocrine disrupting chemicals, reproductive outcomes

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide

The European Union’s REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Environmental Carcinogenesis at the Single-Cell Level.

Elucidating the mechanisms behind how exposure to environmental chemicals can lead to cancer is not easy due to the complex natures of these compounds and the challenges to establish biologically relevant experimental models to study them. Environmental chemicals often present selective mechanisms of action on different cell types and can be involved in the modulation of targeted cells and their microenvironment, including immune cells. Currently, the limitations of traditional epidemiologic correlation analyses, in vitro cell-based assays, and animal models are that they are unable to comprehensively examine cellular heterogeneity and the tissue-selective influences. To this end, we propose utilizing single-cell RNA-sequencing (scRNA-seq) to more effectively capture the subtle and complex effects of environmental chemicals and how their exposure could lead to cancer. scRNA-seq's capabilities for studying gene expression level data at a significantly higher resolution relative to bulk RNA-sequencing (RNA-seq) enable studies to evaluate how environmental chemicals regulate gene transcription on different cell types as well as how these compounds impact signaling pathways and interactions between cells in the tissue microenvironment. These studies will be valuable for evaluating environmental chemicals' carcinogenic properties at the individual cell level.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."

Computational modelling for the sustainable management of chemicals

This commentary explores the contribution of computational toxicology to chemical safety assessment in the context of the broad policy challenges faced by the European Union. The state of the European Environment is considered from the perspective of chemical contributions to the burden of disease and ecosystem damage. This sets the scene for highlighting research and innovation opportunities to further develop computational approaches for assessing the human health and environmental effects of chemicals. Emphasis is placed on focus topics that are particularly relevant to the political priorities of the new European Commission. In particular, two of the six priorities are discussed - “The European Green Deal” and “A Europe fit for a Digital Age”. The former includes the zero pollution ambition for a toxic-free environment, including the need to develop safe and sustainable chemicals, while the latter includes the challenges and opportunities posed by Artificial Intelligence. This commentary is based on a presentation given at the 19th meeting of The Italian Society of Toxicology (SITOX), held in Bologna, Italy, in February 2020.

Perfluorooctane sulfonate alters gut microbiota-host metabolic homeostasis in mice

Perfluorooctane sulfonate (PFOS) is a persistent environmental chemical whose biological effects are mediated by multiple mechanisms. Recent evidence suggests that the gut microbiome may be directly impacted by and/or alter the fate and effects of environmental chemicals in the host. Thus, the aim of this study was to determine whether PFOS influences the gut microbiome and its metabolism, and the host metabolome. Four groups of male C57BL/6 J mice were fed a diet with or without 0.003 %, 0.006 %, or 0.012 % PFOS, respectively. 16S rRNA gene sequencing, metabolomic, and molecular analyses were used to examine the gut microbiota of mice after dietary PFOS exposure. Dietary PFOS exposure caused a marked change in the gut microbiome compared to controls. Dietary PFOS also caused dose-dependent changes in hepatic metabolic pathways including those involved in lipid metabolism, oxidative stress, inflammation, TCA cycle, glucose, and amino acid metabolism. Changes in the metabolome correlated with changes in genes that regulate these pathways. Integrative analyses also demonstrated a strong correlation between the alterations in microbiota composition and host metabolic profiles induced by PFOS. Further, using isolated mouse cecal contents, PFOS exposure directly affected the gut microbiota metabolism. Results from these studies demonstrate that the molecular and biochemical changes induced by PFOS are mediated in part by the gut microbiome, which alters gene expression and the host metabolome in mice.

Effects of Environmental Chemicals on the Course of Autoimmune Thyroiditis

Introduction. The relevance of the research is attributed to the increased incidence of autoimmune thyroiditis in children, especially those dwelling in contaminated areas. Our objective was to study effects of environmental exposures to industrial chemicals on the course of autoimmune thyroiditis. Materials and methods. In order to establish the relationship between specific features of the course of autoimmune thyroiditis and adverse environmental exposures, we conducted a comparative study of incidence rates of thyroid diseases including thyroiditis, cytotoxicity testing, thyroid status assessment, antioxidant activity assays, and thyroid ultrasound. The observation group consisted of 98 children living the area with the developed metallurgical industry while the comparison group included 23 children living in a recreation area. The groups were matched by age and socio-economic characteristics. Results. We established that thyroiditis incidence rates in the industrially polluted area were almost thrice as high as those in the relatively clean area. The observation group was characterized by smoothed sexual differentiation, earlier development of the autoimmune thyroiditis, higher (up to 1.6 times) frequency of typical diffuse structural changes, and increased thyroid gland. Blood levels of metals having a direct cytotoxic effect on the thyroid gland were 2.0 to 6.7 times higher than normal in the cases compared to their matched controls. The correlation and regression analysis established contribution of chemicals to the increased incidence of autoimmune thyroiditis in children (zinc), antibodies to thyroid gland tissue (lead), thyroid-stimulating hormone (nickel), and decreased resistive indices (lead). Conclusion. High blood levels of lead, nickel and zinc were among the factors having an adverse effect on the course of AIT and thyroid function.

Age and seasonal variation in testis and baculum morphology in East Greenland polar bears (Ursus maritimus) in relation to high concentrations of persistent organic pollutants

Persistent organic pollutants (POPs) are found in high concentrations in the Artic. Polar bears (Ursus maritimus) are one of the most exposed mammals in the Arctic and are thereby vulnerable to reproductive disruption. The aim of this study was to investigate male polar bear reproduction based on a detailed evaluation of testis histology and to assess possible effects of environmental chemicals on male polar bear reproduction. Reproductive groups that were identified based on histology were as follows: actively reproductive (REP), non-reproductive either with degenerated testes (DEG), undeveloped seminiferous tubules (UND), or morphology in-transition (INT). Categorization into these groups was supported by significant differences in testis and baculum measurements among REP, DEG, and UND, as well as differences in the area and diameter of seminiferous tubules among REP, DEG, and UND. These results show that it is possible to identify the reproductive stage in polar bears even if capture date and or age is lacking. Based on testis morphology we suggest that adult male polar bears from East Greenland have active spermatogenesis in February to June, and inactive degenerated testes in August to January. January to February was the main period of reproductive transition, characterised by a shift between inactive and active spermatogenesis. Baculum and testis size measurements decreased significantly with increasing concentrations of the chlordane metabolite oxychlordane, suggesting a potential impact on male reproductive success. Half of the investigated polar bears in REP group displayed signs of disorganization of the spermatogenesis which might be a sign of disrupted reproduction. However, no correlations with levels of the investigated POPs were detected. Reproductive organ measurements in polar bears differed significantly between REP and DEG groups, which cannot be explained by age, and therefore should be considered when investigating the effect of POPs on male reproduction.

For making a declaration of countermeasures against the falling birth rate from the Japanese Society for Hygiene: summary of discussion in the working group on academic research strategy against an aging society with low birth rate

In 1952, the Japanese Society for Hygiene had once passed a resolution at its 22nd symposium on population control, recommending the suppression of population growth based on the idea of cultivating a healthier population in the area of eugenics. Over half a century has now passed since this recommendation; Japan is witnessing an aging of the population (it is estimated that over 65-year-olds made up 27.7% of the population in 2017) and a decline in the birth rate (total fertility rate 1.43 births per woman in 2017) at a rate that is unparalleled in the world; Japan is faced with a “super-aging” society with low birth rate. In 2017, the Society passed a resolution to encourage all scientists to engage in academic researches to address the issue of the declining birth rate that Japan is currently facing. In this commentary, the Society hereby declares that the entire text of the 1952 proposal is revoked and the ideas relating to eugenics is rejected. Since the Society has set up a working group on the issue in 2016, there have been three symposiums, and working group committee members began publishing a series of articles in the Society’s Japanese language journal. This commentary primarily provides an overview of the findings from the published articles, which will form the scientific basis for the Society’s declaration. The areas we covered here included the following: (1) improving the social and work environment to balance between the personal and professional life; (2) proactive education on reproductive health; (3) children’s health begins with nutritional management in women of reproductive age; (4) workplace environment and occupational health; (5) workplace measures to counter the declining birth rate; (6) research into the effect of environmental chemicals on sexual maturity, reproductive function, and the children of next generation; and (7) comprehensive research into the relationship among contemporary society, parental stress, and healthy child-rearing. Based on the seven topics, we will set out a declaration to address Japan’s aging society with low birth rate.

Using bisphenol A and its analogs to address the feasibility and usefulness of the CALUX-PPARγ assay to identify chemicals with obesogenic potential

Environmental chemical exposures have been implicated in the obesity epidemic as potential mis-regulators of a variety of metabolic pathways. As agonism of the peroxisome proliferator-activated nuclear hormone receptor γ (PPARγ) is one of the suspected mechanisms involved, a PPARγ screening assay may have relevance for the biodetection of such effects of environmental chemicals. To test this hypothesis, we established the PPARγ2-CALUX® assay in-house and tested it against a number of known and suspected PPARγ modulators. Furthermore, we added a rat liver S9 metabolizing system to the protocol to introduce metabolic competence to the assay. Our results confirmed the responsiveness of the cell line to the known PPARγ agonists and antagonists: rosiglitazone, tributyltin, 15-deoxy-Δ12,14-prostaglandin J2, GW9662 and diclofenac. These data are in agreement with previous studies in various models. Seven bisphenol analogs tested induced little to no agonist activity, but all demonstrated antagonistic properties. These findings were contrary to both our assumptions and literature reports. Addition of the S9-metabolizing system to each of these tests did not alter any of the measured activities. Taken together, it seems probable that there are additional obesogenic effects of these chemicals which would not be detected by this assay.

Characterizing the effects of missing data and evaluating imputation methods for chemical prioritization applications using ToxPi

BackgroundThe Toxicological Priority Index (ToxPi) is a method for prioritization and profiling of chemicals that integrates data from diverse sources. However, individual data sources (“assays”), such as in vitro bioassays or in vivo study endpoints, often feature sections of missing data, wherein subsets of chemicals have not been tested in all assays. In order to investigate the effects of missing data and recommend solutions, we designed simulation studies around high-throughput screening data generated by the ToxCast and Tox21 programs on chemicals highlighted by the Agency for Toxic Substances and Disease Registry’s (ATSDR) Substance Priority List (SPL), which helps prioritize environmental research and remediation resources.ResultsOur simulations explored a wide range of scenarios concerning data (0-80% assay data missing per chemical), modeling (ToxPi models containing from 160-700 different assays), and imputation method (k-Nearest-Neighbor, Max, Mean, Min, Binomial, Local Least Squares, and Singular Value Decomposition). We find that most imputation methods result in significant changes to ToxPi score, except for datasets with a small number of assays. If we consider rank change conditional on these significant changes to ToxPi score, we find that ranks of chemicals in the minimum value imputation, SVD imputation, and kNN imputation sets are more sensitive to the score changes.ConclusionsWe found that the choice of imputation strategy exerted significant influence over both scores and associated ranks, and the most sensitive scenarios were those involving fewer assays plus higher proportions of missing data. By characterizing the effects of missing data and the relative benefit of imputation approaches across real-world data scenarios, we can augment confidence in the robustness of decisions regarding the health and ecological effects of environmental chemicals

Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway.

Background:Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression.Objective:We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved.Methods:Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay.Results:To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways.Conclusions:We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer. https://doi.org/10.1289/EHP2698

A method for reducing environmental pollution by using essential oils in rodent pest management program.

Strong-smelling plant extracts, such as essential oils, have a variety of feeding effects on mammals. Considering current concerns over long-term health issues and environmental effects of chemicals, plant-based products with repellent or antifungal activities may represent good solutions for improvement of rodent pest control programs. The present study was therefore focused on examining the effects of bergamot, lavender, and thyme essential oils as additional bait components on daily intakes of cereal-based baits by wild house mice. Lavender essential oil, containing linalool and linalyl acetate as main components, and thyme essential oil with a prevailing thymol component had no effects on house mice diet. Bergamot essential oil, whose main components were linalool, limonene, and linalyl acetate, showed a repellent effect on house mouse diet.

Associations between urinary polycyclic aromatic hydrocarbon metabolites and serum testosterone in U.S. adult males: National Health and nutrition examination survey 2011–2012

Effects of environmental chemicals on human reproductive health and sex hormone levels have been reported for several years, but compared to other environmental chemicals, such as heavy metals, PCBs, triclosan, Phthalate, the links between polycyclic aromatic hydrocarbons (PAHs) and sex hormone levels have not been studied widely. Therefore, our purpose of research was to study the associations between urinary PAH metabolites and serum total testosterone (T) levels among men. The data was obtained from the independent cross-section wave (2011-2012) of the National Health and Nutrition Examination Survey (NHANES), including demographic, socioeconomic, dietary, health-related questions, examinations and laboratory test. All analyses were performed by R software (version 3.2.3), including one-way analysis of variance, multivariable linear regression, stratified analysis and heterogeneity test. Of 1102 American adults aged 20 and above included in the statistical analysis, we found that urinary 3-hydroxyfluorene and 2-hydroxyfluorene were significantly positively associated with serum T levels (β=40.62, 95%CI=21.78-59.46, P=2.56×10-5; β=35.17, 95%CI=13.18-57.15, P=1.75×10-3, respectively). The associations between urinary PAH metabolites and serum T levels signified a major public health problem over the world. Prospective work is needed to investigate the potential long-term health consequences of these findings.

Mediating Roles of PPARs in the Effects of Environmental Chemicals on Sex Steroids

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that are widely involved in various physiological functions. They are widely expressed through the reproductive system. Their roles in the metabolism and function of sex steroids and thus the etiology of reproductive disorders receive great concern. Various kinds of exogenous chemicals, especially environmental pollutants, exert their adverse impact on the reproductive system through disturbing the PPAR signaling pathway. Chemicals could bind to PPARs and modulate the transcription of downstream genes containing PPRE (peroxisome proliferator response element). This will lead to altered expression of genes related to metabolism of sex steroids and thus the abnormal physiological function of sex steroids. In this review, various kinds of environmental ligands are summarized and discussed. Their interactions with three types of PPARs are classified by various data from transcript profiles, PPRE reporter in cell line, in silico docking, and gene silencing. The review will contribute to the understanding of the roles of PPARs in the reproductive toxicology of environmental chemicals.

Institutes in the Lead: Identifying Environmental Factors in Breast Cancer.

Institutes in the Lead: Identifying Environmental Factors in Breast Cancer.

Integrating human, animal, and mechanistic data to support hazard conclusions in a systematic review of health effects of environmental chemicals

Integrating human, animal, and mechanistic data to support hazard conclusions in a systematic review of health effects of environmental chemicals

Phthalates in neonatal health: friend or foe?

Exposure to environmental chemicals has adverse effects on the health and survival of humans. Emerging evidence supports the idea that exposure to endocrine-disrupting compounds (EDCs) can perturb an individual's physiological set point and as a result increase his/her propensity toward several diseases. The purpose of this review is to provide an update on di-(2-ethylhexyl) phthalate, the primary plasticizer found in plastic medical devices used in neonatal intensive care units, its effects on the fetus and newborn, epidemiological studies, pharmacokinetics, toxicity and epigenetic implications. We searched the PubMed databases to identify relevant studies. Phthalates are known EDCs that primarily are used to improve the flexibility of polyvinyl chloride plastic products and are called plasticizers in lay terms. Neonates and infants are particularly vulnerable to the effects of phthalates, beginning with maternal exposure and placental transfer during gestation and during infancy following birth. In line with the developmental origins of adult disease, a focus on the effects of environmental chemicals in utero or early childhood on the genesis of adult diseases through epigenome modulation is timely and important. The epigenetic effects of phthalates have not been fully elucidated, but accumulating evidence suggests that they may be associated with adverse health effects, some of which may be heritable. Phthalate exposure during pregnancy and the perinatal period is particularly worrisome in health-care settings. Although the clinical significance of phthalate exposure has been difficult to assess with epidemiologic studies, the evidence that physiological changes occur due to exposure to phthalates is growing and points toward the need for more investigation at a molecular, specifically epigenetic level.