Family adaptation in families of individuals with Down syndrome from 12 countries.

Our current understanding of adaptation in families of individuals with Down syndrome (DS) is based primarily on findings from studies focused on participants from a single country. Guided by the Resiliency Model of Family Stress, Adjustment, and Adaptation, the purpose of this cross-country investigation, which is part of a larger, mixed methods study, was twofold: (1) to compare family adaptation in 12 countries, and (2) to examine the relationships between family variables and family adaptation. The focus of this study is data collected in the 12 countries where at least 30 parents completed the survey. Descriptive statistics were generated, and mean family adaptation was modeled in terms of each predictor independently, controlling for an effect on covariates. A parsimonious composite model for mean family adaptation was adaptively generated. While there were cross-country differences, standardized family adaptation mean scores fell within the average range for all 12 countries. Key components of the guiding framework (i.e., family demands, family appraisal, family resources, and family problem-solving communication) were important predictors of family adaptation. More cross-country studies, as well as longitudinal studies, are needed to fully understand how culture and social determinants of health influence family adaptation in families of individuals with DS.

SAMHD1 acts at stalled replication forks to prevent interferon induction.

SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS-STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health.

Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.

The Use of Mobile Sensors by Children: A Review of Two Decades of Environmental Education Projects.

Over the past twenty years, the use of electronic mobile sensors by children and youngsters has played a significant role in environmental education projects in Portugal. This paper describes a research synthesis of a set of case studies (environmental education projects) on the use of sensors as epistemic mediators, evidencing the technological, environmental, social, and didactical dimensions of environmental education projects over the last two decades in Portugal. The triggers of the identified changes include: (i) the evolution of sensors, information and communication platforms, and mobile devices; (ii) the increasing relevance of environmental citizenship and participation; (iii) the recognition of the role of multisensory situated information and quantitative information in environmental citizenship; (iv) the cause-effect relation between didactical strategies and environmental education goals; (v) the potential of sensory and epistemic learners' practices in the environment to produce learning outcomes and new knowledge. To support the use of senses and sensors in environmental education projects, the SEAM model was created based on the developed research synthesis.

HBM4EU chromates study - Usefulness of measurement of blood chromium levels in the assessment of occupational Cr(VI) exposure.

Occupational exposures to hexavalent Chromium (Cr(VI)) can occur in welding, hot working stainless steel processing, chrome plating, spray painting and coating activities. Recently, within the human biomonitoring for Europe initiative (HBM4EU), a study was performed to assess the suitability of different biomarkers to assess the exposure to Cr(VI) in various job tasks. Blood-based biomarkers may prove useful when more specific information on systemic and intracellular bioavailability is necessary. To this aim, concentrations of Cr in red blood cells (RBC-Cr) and in plasma (P-Cr) were analyzed in 345 Cr(VI) exposed workers and 175 controls to understand how these biomarkers may be affected by variable levels of exposure and job procedures. Compared to controls, significantly higher RBC-Cr levels were observed in bath plating and paint application workers, but not in welders, while all the 3 groups had significantly greater P-Cr concentrations. RBC-Cr and P-Cr in chrome platers showed a high correlation with Cr(VI) in inhalable dust, outside respiratory protective equipment (RPE), while such correlation could not be determined in welders. In platers, the use of RPE had a significant impact on the relationship between blood biomarkers and Cr(VI) in inhalable and respirable dust. Low correlations between P-Cr and RBC-Cr may reflect a difference in kinetics. This study showed that Cr-blood-based biomarkers can provide information on how workplace exposure translates into systemic availability of Cr(III) (extracellular, P-Cr) and Cr(VI) (intracellular, RBC-Cr). Further studies are needed to fully appreciate their use in an occupational health and safety context.

Cellular and Molecular Mechanisms of Toxicity of Ingested Titanium Dioxide Nanomaterials.

An exponential increase in products containing titanium dioxide nanomaterials (TiO2), in agriculture, food and feed industry, lead to increased oral exposure to these nanomaterials (NMs). Thus, the gastrointestinal tract (GIT) emerges as a possible route of exposure that may drive systemic exposure, if the intestinal barrier is surpassed. NMs have been suggested to produce adverse outcomes, such as genotoxic effects, that are associated with increased risk of cancer, leading to a concern for public health. However, to date, the differences in the physicochemical characteristics of the NMs studied and other variables in the test systems have generated contradictory results in the literature. Processes like human digestion may change the NMs characteristics, inducing unexpected toxic effects in the intestine. Using TiO2 as case-study, this chapter provides a review of the works addressing the interactions of NMs with biological systems in the context of intestinal tract and digestion processes, at cellular and molecular level. The knowledge gaps identified suggest that the incorporation of a simulated digestion process for in vitro studies has the potential to improve the model for elucidating key events elicited by these NMs, advancing the nanosafety studies towards the development of an adverse outcome pathway for intestinal effects.

Overview of Adverse Outcome Pathways and Current Applications on Nanomaterials.

Nanomaterials (NMs) have important and useful applications in chemical industry, electronics, pharmaceuticals, food and others. Their rapid proliferation presents a dilemma to regulators regarding hazard identification and increased concerns for public health.The Adverse Outcome Pathways (AOPs) are innovative central elements of a toxicological knowledge framework, developed for supporting chemical risk assessment based on mechanistic reasoning. AOPs describe a sequence of causally linked events at different levels of biological organisation, triggered by exposure to a stressor (like chemicals or NMs) leading to an adverse health effect in humans or wildlife. The integrative analysis of the cellular and molecular mechanisms of nanotoxicity towards the identification of connected adverse outcomes drives a sequential line - an AOP landscape definition. Each defined AOP is available for crossing data, linking known and unknown landscapes, reducing the reliance on animal studies, associated costs and ethical issues. NMs have unique properties, with specific associated toxicological challenges, which may represent unknown AOP landscapes.In this chapter, an overview of AOPs as important novel strategic tools in nanotoxicology is presented, highlighting the current applications in hazard identification and human health risk assessment.

Hazard Assessment of Benchmark Metal-Based Nanomaterials Through a Set of In Vitro Genotoxicity Assays.

For safety assessment of nanomaterials (NMs), in vitro genotoxicity data based on well-designed experiments is required. Metal-based NMs are amongst the most used in consumer products. In this chapter, we report results for three metal-based NMs, titanium dioxide (NM-100), cerium dioxide (NM-212) and silver (NM-302) in V79 cells, using a set of in vitro genotoxicity assays covering different endpoints: the medium-throughput comet assay and its modified version (with the enzyme formamidopyrimidine DNA glycosylase, Fpg), measuring DNA strand beaks (SBs) and oxidized purines, respectively; the micronucleus (MN) assay, assessing chromosomal damage; and the Hprt gene mutation test. The results generated by this test battery showed that all NMs displayed genotoxic potential. NM-100 induced DNA breaks, DNA oxidation damage and point mutations but not chromosome instability. NM-212 increased the level of DNA oxidation damage, point mutations and increased the MN frequency at the highest concentration tested. NM-302 was moderately cytotoxic and induced gene mutations, but not DNA or chromosome damage. In conclusion, the presented in vitro genotoxicity testing strategy allowed the identification of genotoxic effects caused by three different metal-based NMs, raising concern as to their impact on human health. The results support the use of this in vitro test battery for the genotoxicity assessment of NMs, reducing the use of more expensive, time-consuming and ethically demanding in vivo assays, in compliance with the 3 R's.

New "Omics" Approaches as Tools to Explore Mechanistic Nanotoxicology.

In the last years, "omics" approaches have been applied to study the toxicity of nanomaterials (NM) with the aim of obtaining insightful information on their biological effects. One of the most developed "omics" field, transcriptomics, expects to find unique profiles of differentially-expressed genes after exposure to NM that, besides providing evidence of their mechanistic mode of action, may also be used as biomarkers for biomonitoring purposes. Moreover, several NM have been associated with epigenetic alterations, i.e., changes in the regulation of gene expression caused by differential DNA methylation, histone tail modification and microRNA expression. Epigenomics research focusing on DNA methylation is increasingly common and the role of microRNAs is being better understood, either promoting or suppressing biological pathways. Moreover, the proteome is a highly dynamic system that changes constantly in response to a stimulus. Therefore, proteomics can identify changes in protein abundance and/or variability that lead to a better understanding of the underlying mechanisms of action of NM while discovering biomarkers. As to genomics, it is still not well developed in nanotoxicology. Nevertheless, the individual susceptibility to NM mediated by constitutive or acquired genomic variants represents an important component in understanding the variations in the biological response to NM exposure and, consequently, a key factor to evaluate possible adverse effects in exposed individuals. By elucidating the molecular changes that are involved NM toxicity, the new "omics" studies are expected to contribute to exclude or reduce the handling of hazardous NM in the workplace and support the implementation of regulation to protect human health.

Biomarkers of effect as determined in human biomonitoring studies on hexavalent chromium and cadmium in the period 2008-2020.

A number of human biomonitoring (HBM) studies have presented data on exposure to hexavalent chromium [Cr(VI)] and cadmium (Cd), but comparatively few include results on effect biomarkers. The latter are needed to identify associations between exposure and adverse outcomes (AOs) in order to assess public health implications. To support improved derivation of EU regulation and policy making, it is of great importance to identify the most reliable effect biomarkers for these heavy metals that can be used in HBM studies. In the framework of the Human Biomonitoring for Europe (HBM4EU) initiative, our study aim was to identify effect biomarkers linking Cr(VI) and Cd exposure to selected AOs including cancer, immunotoxicity, oxidative stress, and omics/epigenetics. A comprehensive PubMed search identified recent HBM studies, in which effect biomarkers were examined. Validity and applicability of the markers in HBM studies are discussed. The most frequently analysed effect biomarkers regarding Cr(VI) exposure and its association with cancer were those indicating oxidative stress (e.g., 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), glutathione (GSH)) and DNA or chromosomal damage (comet and micronucleus assays). With respect to Cd and to some extent Cr, ß-2-microglobulin (B2-MG) and N-acetyl-ß-D-glucosaminidase (NAG) are well-established, sensitive, and the most common effect biomarkers to relate Cd or Cr exposure to renal tubular dysfunction. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1 could serve as sensitive biomarkers of acute kidney injury in response to both metals, but need further investigation in HBM studies. Omics-based biomarkers, i.e., changes in the (epi-)genome, transcriptome, proteome, and metabolome associated with Cr and/or Cd exposure, are promising effect biomarkers, but more HBM data are needed to confirm their significance. The combination of established effect markers and omics biomarkers may represent the strongest approach, especially if based on knowledge of mechanistic principles. To this aim, also mechanistic data were collected to provide guidance on the use of more sensitive and specific effect biomarkers. This also led to the identification of knowledge gaps relevant to the direction of future research.

Measurement of Family Management in Families of Individuals With Down Syndrome: A Cross-Cultural Investigation.

Down syndrome (DS) is the most common genetic cause of intellectual disability worldwide. The purpose of this analysis was to determine the internal consistency reliability of eight language versions of the Family Management Measure (FaMM) and compare family management of DS across cultures. A total of 2,740 parents of individuals with DS from 11 countries completed the FaMM. The analysis provided evidence of internal consistency reliability exceeding .70 for four of six FaMM scales for the entire sample. Across countries, there was a pattern of positive family management. Cross-cultural comparisons revealed parents from Brazil, Spain, and the United States had the most positive family management and respondents from Ireland, Italy, Japan, and Korea had the least positive. The rankings were mixed for the four remaining countries. These findings provide evidence of overall strong internal consistency reliability of the FaMM. More cross-cultural research is needed to understand how social determinants of health influence family management in families of individuals with DS.

Circulating tumour DNA in metastatic breast cancer to guide clinical trial enrolment and precision oncology: A cohort study.

BACKGROUND: Metastatic breast cancer (mBC) is a heterogenous disease with increasing availability of targeted therapies as well as emerging genomic markers of therapeutic resistance, necessitating timely and accurate molecular characterization of disease. As a minimally invasive test, analysis of circulating tumour DNA (ctDNA) is well positioned for real-time genomic profiling to guide treatment decisions. Here, we report the results of a prospective testing program established to assess the feasibility of ctDNA analysis to guide clinical management of mBC patients. METHODS AND FINDINGS: Two hundred thirty-four mBC patients (median age 54 years) were enrolled between June 2015 and October 2018 at the Peter MacCallum Cancer Centre, Melbourne, Australia. Median follow-up was 15 months (range 1-46). All patient samples at the time of enrolment were analysed in real time for the presence of somatic mutations. Longitudinal plasma testing during the course of patient management was also undertaken in a subset of patients (n = 67, 28.6%), according to clinician preference, for repeated molecular profiling or disease monitoring. Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1. In parallel, subsets of samples were also analysed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]). The sensitivity of ddPCR and targeted panel sequencing to identify actionable mutations was compared. Results were discussed at a multidisciplinary breast cancer meeting prior to treatment decisions. ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing. LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1. Increasing ctDNA levels were associated with inferior overall survival, whether assessed by ddPCR, targeted sequencing, or LC-WGS. Overall, the ctDNA results changed clinical management in 40 patients including the direct recruitment of 20 patients to clinical trials. Limitations of the study were that it was conducted at a single site and that 31.3% of participants were lost to follow-up. CONCLUSION: In this study, we found prospective ctDNA testing to be a practical and feasible approach that can guide clinical trial enrolment and patient management in mBC.

Extremism and common mental illness: cross-sectional community survey of White British and Pakistani men and women living in England.

BACKGROUND: Mental illnesses may explain vulnerability to develop extremist beliefs that can lead to violent protest and terrorism. Yet there is little evidence. AIMS: To investigate the relationship between mental illnesses and extremist beliefs. METHOD: Population survey of 618 White British and Pakistani people in England. Extremism was assessed by an established measure of sympathies for violent protest and terrorism (SVPT). Respondents with any positive scores (showing sympathies) were compared with those with all negative scores. We calculated associations between extremist sympathies and ICD-10 diagnoses of depression and dysthymia, and symptoms of anxiety, personality difficulties, autism and post-traumatic stress. Also considered were demographics, life events, social assets, political engagement and criminal convictions. RESULTS: SVPT were more common in those with major depression with dysthymia (risk ratio 4.07, 95% CI 1.37-12.05, P = 0.01), symptoms of anxiety (risk ratio 1.09, 95% CI 1.03-1.15, P = 0.002) or post-traumatic stress (risk ratio 1.03, 95% CI 1.01-1.05, P = 0.003). At greater risk of SVPT were: young adults (<21 versus ≥21: risk ratio 3.05, 95% CI 1.31-7.06, P = 0.01), White British people (versus Pakistani people: risk ratio 2.24, 95% CI 1.25-4.02, P = 0.007) and those with criminal convictions (risk ratio 2.23, 95% CI 1.01-4.95, P = 0.048). No associations were found with life events, social assets and political engagement. CONCLUSION: Depression, dysthymia and symptoms of anxiety and post-traumatic stress are associated with extremist sympathies.

Weight misperception and psychological symptoms from adolescence to young adulthood: longitudinal study of an ethnically diverse UK cohort.

BACKGROUND: To evaluate the association between weight misperception and psychological symptoms in the Determinants of young Adults Social well-being and Health (DASH) longitudinal study. METHODS: A longitudinal sample of 3227 adolescents, in 49 secondary schools in London, aged 11-16 years participated in 2002/2003 and were followed up in 2005/2006. A sub-sample (N = 595) was followed up again at ages 21-23 years in 2012/2013. An index of weight misperception was derived from weight perception and measured weight. Psychological well- being was measured using the Strengths and Difficulties Questionnaire at 11-16 years and the General Health Questionnaire at 21-23 years. Associations with weight misperception was assessed using regression models, adjusted for socio-economic and lifestyle factors. RESULTS: White British males and females were more likely than ethnic minority peers to report accurate perceptions of measured weight. At 11-13y, 46% females and 38% males did not have an accurate perception of their measured weight. The comparable figures at 14-16y were 42 and 40%. Compared with male adolescents, more females perceived themselves as overweight or were unsure of their weight but measured normal weight, and this was more pronounced among Indians, Pakistanis and Bangladeshis. At 14-16y, more males perceived themselves as underweight but measured normal weight, and this was more pronounced among Indians. Compared with those who had an accurate perception of their normal weight, a higher likelihood of probable clinically-relevant psychological symptoms was observed among those who measured normal weight but perceived themselves to be underweight (females Odds Ratio (OR) = 1.87 95% CI 1.03-3.40; males OR = 2.34 95% CI 1.47-3.71), overweight (females only OR = 2.06 95% CI 1.10-3.87), or unsure of their weight (males only OR = 1.61 95% CI 1.04-2.49). Among females, the association was driven by internalising rather than externalising symptoms. An accurate perception of overweight was associated with higher psychological symptoms in adolescence and early 20s. Ethnic specific effects were not evident. CONCLUSION: Weight misperception may be an important determinant of psychological symptoms in young people, with an accurate perception of normal weight status being protective. Culturally targeted interventions should be considered to promote healthy perceptions of body image.

The symptomatology of psychological trauma in the aftermath of war (1945-1980): UK army veterans, civilians and emergency responders.

BACKGROUND: UK veterans suffering from a psychological or psychiatric illness as a consequence of service in the Second World War were entitled to a war pension. Their case files, which include regular medical assessments, are a valuable resource to investigate the nature, distribution and duration of symptoms. METHODS: A standardised form was used to collect data from pension records of a random sample of 500 UK army veterans from the first presentation in the 1940s until 1980. Data were also gathered from 50 civilians and 54 emergency responders with a pension for post-traumatic illness following air-raids. RESULTS: The 10 most common symptoms reported by veterans were anxiety, depression, sleep problems, headache, irritability/anger, tremor/shaking, difficulty completing tasks, poor concentration, repeated fears and avoidance of social contact. Nine of the 10 were widely distributed across the veteran population when symptoms were ranked by the number of subjects who reported them. Nine symptoms persisted significantly longer in the veteran sample than in emergency responders. These included seven of the most common symptoms, together with two others: muscle pain and restlessness. The persistence of these symptoms in the veteran group suggests a post-traumatic illness linked to lengthy overseas service in combat units. CONCLUSIONS: The nature and duration of symptoms exhibited by veterans may be associated with their experience of heightened risks. Exposure to severe or prolonged trauma seems to be associated with chronic multi-symptom illness, symptoms of post-traumatic stress and somatic expressions of pain that may delay or complicate the recovery process.

In vitro exposure to the next-generation plasticizer diisononyl cyclohexane-1,2-dicarboxylate (DINCH): cytotoxicity and genotoxicity assessment in human cells.

Plasticizers are currently present in many consumer products, particularly food packaging, children's toys, and medical devices. There are concerns regarding potential leaching to environment or food, thus increasing the risk of human exposure by inhalation, ingestion and/or dermal absorption potentially leading to adverse health consequences. Hexamoll diisononyl cyclohexane-1,2-dicarboxylate (Hexamoll® DINCH®), a non-phthalate plasticizer, has been used as a safer alternative to hazardous phthalates. In contrast to phthalates, evidence indicates that DINCH did not produce endocrine disruption, reproductive dysfunctions, genotoxicity or mutagenicity. However, there are limited data available regarding safety assessment, especially with respect to genotoxicity in human cells. The aim of this study was to assess DINCH cytotoxic and genotoxic effects in human liver and kidney cell lines following several exposure periods. For this purpose, the MTT cell viability, micronucleus, conventional and formamidopyrimidine DNA glycosylase (FPG)-modified comet assays were employed to detect cell death and genotoxicity, respectively. Data demonstrated that DINCH induced cytotoxicity in kidney cells exposed for 48hr, but not in liver cells. No marked chromosomal damage was noted after short-term or longer following treatment of both cell lines. However, DINCH produced oxidative DNA damage in liver cells exposed for 3 h, which decreased after a more prolonged incubation period. The occurrence of oxidative lesions, even transiently, indicates that mutation fixation may occur leading to adverse effects in liver. Therefore, these findings suggest that DINCH may be hazardous to humans and that further investigation is necessary to warrant its safety.

Canine Mammary Tumors: Comparison of Classification and Grading Methods in a Survival Study.

Histopathology remains the cornerstone for diagnosing canine mammary tumors (CMTs). Recently, 2 classification systems (the World Health Organization [WHO] classification of 1999 and the proposal of 2011) and 2 grading methods based on the human Nottingham grade have been used by pathologists. Despite some evidence that the histological subtype and grade are prognostic factors, there is no comprehensive comparative study of these classification and grading systems in the same series of CMTs. In this study, the 2 classifications and the 2 grading methods were simultaneously applied to a cohort of 134 female dogs with CMTs. In 85 animals with malignant tumors, univariable and multivariable survival analyses were performed. Using the 2 systems, the proportion of benign (161/305, 53%) and malignant (144/305, 47%) tumors was similar and no significant differences existed in categorization of benign tumors. However, the 2011 classification subdivided malignant tumors in more categories-namely, those classified as complex, solid, and tubulopapillary carcinomas by the WHO system. Histological subtype according to both systems was significantly associated with survival. Carcinomas arising in benign tumors, complex carcinomas, and mixed carcinomas were associated with a better prognosis. In contrast, carcinosarcomas and comedocarcinomas had a high risk of tumor-related death. Slight differences existed between the 2 grading methods, and grade was related to survival only in univariable analysis. In this cohort, age, completeness of surgical margins, and 2 index formulas adapted from human breast cancer studies (including tumor size, grade, and vascular/lymph node invasion) were independent prognostic factors.

Correction: The Subclonal Architecture of Metastatic Breast Cancer: Results from a Prospective Community-Based Rapid Autopsy Program "CASCADE".

[This corrects the article DOI: 10.1371/journal.pmed.1002204.].

Fibrous shape underlies the mutagenic and carcinogenic potential of nanosilver while surface chemistry affects the biosafety of iron oxide nanoparticles.

Nowadays engineered nanomaterials (ENMs) are increasingly used in a wide range of commercial products and biomedical applications. Despite this, the knowledge of human potential health risk as well as comprehensive biological and toxicological information is still limited. We have investigated the capacity of two frequently used metallic ENMs, nanosilver and magnetite nanoparticles (MNPs), to induce thymidine kinase (Tk +/-) mutations in L5178Y mouse lymphoma cells and transformed foci in Bhas 42 cells. Two types of nanosilver, spherical nanoparticles (AgNM300) and fibrous (AgNM302) nanorods/wires, and MNPs differing in surface modifications [MNPs coated with sodium oleate (SO-MNPs), MNPs coated with SO + polyethylene glycol (SO-PEG-MNPs) and MNPs coated with SO + PEG + poly(lactide-co-glycolic acid) SO-PEG-PLGA-MNPs] were included in this study. Spherical AgNM300 showed neither mutagenic nor carcinogenic potential. In contrast, silver nanorods/wires (AgNM302) increased significantly the number of both gene mutations and transformed foci compared with the control (untreated) cells. Under the same treatment conditions, neither SO-MNPs nor SO-PEG-PLGA-MNPs increased the mutant frequency compared with control cells though an equivocal mutagenic effect was estimated for SO-PEG-MNPs. Although SO-MNPs and SO-PEG-MNPs did not show any carcinogenic potential, SO-PEG-PLGA-MNPs increased concentration dependently the number of transformed foci in Bhas 42 cells compared with the control cells. Our results revealed that fibrous shape underlies the mutagenic and carcinogenic potential of nanosilver while surface chemistry affects the biosafety of MNPs. Considering that both nanosilver and MNPs are prospective ENMs for biomedical applications, further toxicological evaluations are warranted to assess comprehensively the biosafety of these nanomaterials.

In vitro hepatotoxicity of 'Legal X': the combination of 1-benzylpiperazine (BZP) and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) triggers oxidative stress, mitochondrial impairment and apoptosis.

N-Benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) are two synthetic phenylpiperazine analogues that have been frequently commercialized in combination as an alternative to ecstasy ('Legal X'). Despite reports of several clinical complications following the use of these drugs in association, few studies have been conducted so far to elucidate their combined toxicity. The present study was aimed at clarifying the cytotoxic effects of mixtures of BZP and TFMPP in vitro. Human-derived HepaRG cells and primary rat hepatocytes were exposed to the drugs, individually or combined at different mixture ratios, and cytotoxicity was assessed by the MTT assay. Mixture additivity expectations were calculated by the independent action and the concentration addition (CA) models and compared with the experimental outcomes. To delineate the mechanisms underlying the elicited effects, a range of stress endpoints was evaluated, including oxidative stress, energetic imbalance, and metabolic interactions. It was observed that primary rat hepatocytes are more sensitive than HepaRG cells to the toxicity of BZP (EC50 2.20 and 6.60 mM, respectively) and TFMPP (EC50 0.14 and 0.45 mM, respectively). For all BZP-TFMPP combinations tested, CA was the most appropriate model to predict the mixture effects. TFMPP proved to act additively with BZP to produce significant hepatotoxicity (p < 0.01). Remarkably, substantial mixture effects were observed even when each drug was present at concentrations that were harmless individually. In primary hepatocytes, a small deviation from additivity (antagonism) was observed toward the upper range of the concentration-response curve. GC/MS data suggest that a metabolic interaction may be at a play, as the mixture favors the metabolism of both substances, to a significant extent in the case of BZP (p < 0.05). Also, our results demonstrate the influence of oxidative stress and energetic imbalance on these effects (increase in RNS and ROS production, decrease in intracellular GSH/GSSG, ATP depletion and mitochondrial Δψm disruption). The present work clearly demonstrates that potentially harmful interactions among BZP and TFMPP are expected when these drugs are taken concomitantly.