Engineered Nanomaterial Impact in the Liver following Exposure via an Intravenous Route–The Role of Polymorphonuclear Leukocytes and Gene Expression in the Organ

Background and methods: Following exposure via a number of routes (inhalation, ingestion or injection), someNanomaterials (NMs) translocate to secondary tissues, prominently the liver. This study investigated the effects of anarray of NMs, varying in their physicochemical characteristics, consisting of two types of Zinc Oxide (ZnO), two MultiwalledCarbon Nanotubes (MWCNT), one silver (Ag) and one titanium dioxide (TiO2) on the liver, following Intravenous(IV) exposure of C57/BL6 mice. The animals were exposed to either a single dose of NM (128 μg/ml–100 μl) or threedoses of (64 μg/ml–100 μl), every 24 hr. Animals were dissected 6, 24, 48 and 72 hr after the single IV injection, or 72hr after the triple injection regime.Results and conclusions: A Myeloperoxidase (MPO) assay was utilised to quantify neutrophil influx into thetissue. However, as MPO is also found in other granulocytes in smaller quantities, the neutrophils in the liver tissue werealso labelled, using a specific neutrophil cell surface marker (Ly-6B.2). A wide array of NMs (including ZnO, Ag, TiO2and MWCNT) induced a neutrophil influx into the liver, as early as 6 hr post IV exposure. However, the neutrophils wereonly involved in the initial phases of the immune response against the NMs, as the leukocyte numbers had returned tocontrol levels after 48 hr. Finally, analysis of mRNA expression in mice livers showed alterations in levels of C3, IL6,IL10, CXCL2 and ICAM-1

An in vitro liver model - assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials

Background:Following exposure via inhalation, intratracheal instillation or ingestion some nanomaterials (NM) have been shown to translocate to the liver. Since oxidative stress has been implicated as a possible mechanism for NM toxicity this study aimed to investigate the effects of various materials (five titanium dioxide (TiO2), two zinc oxide (ZnO), two multi-walled carbon nanotubes (MWCNT) and one silver (Ag) NM) on oxidative responses of C3A cell line as a model for potential detrimental properties of nanomaterials on the liver.Results:We noted a dose dependant decrease in the cellular glutathione content following exposure of the C3A cells to Ag, the ZnO and the MWCNTs. Intracellular ROS levels were also measured and shown to increase significantly following exposure of the C3A to the low toxicity NMs (MWCNT and TiO2). The antioxidant Trolox in part prevented the detrimental effect of NMs on cell viability, and decreased the NM induced IL8 production after exposure to all but the Ag particulate. Following 4?hr exposure of the C3A cells to sub-lethal levels of the NMs, the largest amount of DNA damage was induced by two of the TiO2 samples (7?nm and the positively charged 10?nm particles).Conclusions:All ten NMs exhibited effects on the hepatocyte cell line that were at least in part ROS/oxidative stress mediated. These effects included mild genotoxicity and IL8 production for all NM except the Ag possibly due to its highly cytotoxic nature

Identification of the mechanisms that drive the toxicity of TiO2 particulates: the contribution of physicochemical characteristics

This review focuses on outlining the toxicity of titanium dioxide (TiO₂) particulates in vitro and in vivo, in order to understand their ability to detrimentally impact on human health. Evaluating the hazards associated with TiO₂ particles is vital as it enables risk assessments to be conducted, by combining this information with knowledge on the likely exposure levels of humans. This review has concentrated on the toxicity of TiO₂, due to the fact that the greatest number of studies by far have evaluated the toxicity of TiO₂, in comparison to other metal oxide particulates. This derives from historical reasons (whereby the size dependency of particulate toxicity was first realised for TiO₂) and due to its widespread application within consumer products (such as sunscreens). The pulmonary and dermal hazards of TiO₂ have been a particular focus of the available studies, due to the past use of TiO₂ as a (negative) control when assessing the pulmonary toxicity of particulates, and due to its incorporation within consumer products such as sunscreens. Mechanistic processes that are critical to TiO₂ particulate toxicity will also be discussed and it is apparent that, in the main, the oxidant driven inflammatory, genotoxic and cytotoxic consequences associated with TiO₂ exposure, are inherently linked, and are evident both in vivo and in vitro. The attributes of TiO₂ that have been identified as being most likely to drive the observed toxicity include particle size (and therefore surface area), crystallinity (and photocatalytic activity), surface chemistry, and particle aggregation/agglomeration tendency. The experimental set up also influences toxicological outcomes, so that the species (or model) used, route of exposure, experiment duration, particle concentration and light conditions are all able to influence the findings of investigations. In addition, the applicability of the observed findings for particular TiO₂ forms, to TiO₂ particulates in general, requires consideration. At this time it is inappropriate to consider the findings for one TiO₂ form as being representative for TiO₂ particulates as a whole, due to the vast number of available TiO₂ particulate forms and large variety of potential tissue and cell targets that may be affected by exposure. Thus emphasising that the physicochemical characteristics are fundamental to their toxicity

Magnetic properties of ilmenite-hematite single crystals from the Ecstall pluton near Prince Rupert, British Columbia

Paleomagnetic studies of the 91 Ma Ecstall pluton and other Cretaceous plutons of British Columbia imply large northward tectonic movements (>2000 km) may have occurred during the tectonic evolution of western North America. However, more recent studies have shown that the eastern edge of the Ecstall pluton experienced considerable mineralogical changes as younger Eocene plutons, such as the ∼58 Ma Quottoon Pluton, were emplaced along its margins. We investigated changes in the rock magnetic properties associated with this reheating event by examining isolated grains of intergrown ilmenite and hematite, the primary paleomagnetic recorder in the Ecstall pluton. Measurements of hysteresis properties, low-temperature remanence, and room temperature isothermal remanent magnetization acquisition and observations from magnetic force microscopy and off-axis electron holography indicate that samples fall into three groups. The groups are defined by the presence of mineral microstructures that are related to distance from the Quotoon plutonic complex. The two groups closest to the Quottoon Pluton contain magnetite within hematite and ilmenite lamellae. Reheating of the Ecstall pluton led to an increase in coercivity and magnetization, as well as to development of mixed phase hysteresis. These results indicate that shallow paleomagnetic directions from the western Ecstall pluton are not affected by reheating and are therefore likely to record original field conditions at the time of pluton emplacement. In the absence of structural deformation, these shallow inclinations are consistent with large-scale northward translation suggested by the Baja–British Columbia hypothesis

Comparative Effects of Di(n-Butyl) Phthalate Exposure on Fetal Germ Cell Development in the Rat and in Human Fetal Testis Xenografts

Background: Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored.Objectives: We sought to identify the effects of phthalate exposur on human fetal germ cellsin a dynamic model and to establish whether the rat is an appropriate model for investigatingsuch effects.Methods: We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n‑butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins.Results: In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes(MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell–germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution.Conclusions: Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects

Racial differences in influenza vaccination among older americans 1996–2000: longitudinal analysis of the Health and Retirement Study (HRS) and the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey

BACKGROUND: Influenza is a common and serious public health problem among the elderly. The influenza vaccine is safe and effective. METHODS: The purpose of the study was to determine whether frequencies of receipt vary by race, age group, gender, and time (progress from 1995/1996 to 2000), and whether any racial differences remain in age groups covered by Medicare. Subjects were selected from the Health and Retirement Study (HRS) (12,652 Americans 50–61 years of age (1992–2000)) and the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey (8,124 community-dwelling seniors aged 70+ years (1993–2000)). Using multivariate logistic regression, adjusting for potential confounders, we estimated the relationship between race, age group, gender, time and the main outcome measure, receipt of influenza vaccination in the last 2 years. RESULTS: There has been a clear increase in the unadjusted rates of receipt of influenza vaccination for all groups from 1995/1996 to 2000. However, the proportions immunized are 10–20% higher among White than among Black elderly, with no obvious narrowing of the racial gap from 1995/1996 to 2000. There is an increase in rates from age 50 to age 65. After age 70, the rate appears to plateau. In multivariate analyses, the racial difference remains after adjusting for a series of socioeconomic, health, and health care related variables. (HRS: OR = 0.63 (0.55–0.72), AHEAD: OR = 0.55 (0.44–0.66)) CONCLUSIONS: There is much work left if the Healthy People 2010 goal of 90% of the elderly immunized against influenza annually is to be achieved. Close coordination between public health programs and clinical prevention efforts in primary care is necessary, but to be truly effective, these services must be culturally appropriate

Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism

Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation

Nicotinic acetylcholine receptor β2 subunit gene implicated in a systems-based candidate gene study of smoking cessation

Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms (SNPs) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented with tagSNPs within each gene. We used global tests of main effects and treatment interactions, adjusting the P-values for multiple correlated tests. An SNP (rs2072661) in the 3′ UTR region of the β2 nicotinic acetylcholine receptor subunit (CHRNB2) has an impact on abstinence rates at the end of treatment (adjusted P = 0.01) and after a 6-month follow-up period (adjusted P = 0.0002). This latter P-value is also significant with adjustment for the number of genes tested. Independent of treatment at 6-month follow-up, individuals carrying the minor allele have substantially decreased the odds of quitting (OR = 0.31; 95% CI 0.18–0.55). Effect of estimates indicate that the treatment is more effective for individuals with the wild-type (OR = 2.14, 95% CI 1.20–3.81) compared with individuals carrying the minor allele (OR = 0.83, 95% CI 0.32–2.19), although this difference is only suggestive (P = 0.10). Furthermore, this SNP demonstrated a role in the time to relapse (P = 0.0002) and an impact on withdrawal symptoms at target quit date (TQD) (P = 0.0009). Overall, while our results indicate strong evidence for CHRNB2 in ability to quit smoking, these results require replication in an independent sample

A perspective on the developmental toxicity of inhaled nanoparticles.

This paper aimed to clarify whether maternal inhalation of engineered nanoparticles (NP) may constitute a hazard to pregnancy and fetal development, primarily based on experimental animal studies of NP and air pollution particles. Overall, it is plausible that NP may translocate from the respiratory tract to the placenta and fetus, but also that adverse effects may occur secondarily to maternal inflammatory responses. The limited database describes several organ systems in the offspring to be potentially sensitive to maternal inhalation of particles, but large uncertainties exist about the implications for embryo–fetal development and health later in life. Clearly, the potential for hazard remains to be characterized. Considering the increased production and application of nanomaterials and related consumer products a testing strategy for NP should be established. Due to large gaps in data, significant amounts of groundwork are warranted for a testing strategy to be established on a sound scientific basis

A Horizon Scan to Support Chemical Pollution–Related Policymaking for Sustainable and Climate‐Resilient Economies

While chemicals are vital to modern society through materials, agriculture, textiles, new technology, medicines, and consumer goods, their use is not without risks. Unfortunately, our resources seem inadequate to address the breadth of chemical challenges to the environment and human health. Therefore, it is important we use our intelligence and knowledge wisely to prepare for what lies ahead. The present study used a Delphi‐style approach to horizon‐scan future chemical threats that need to be considered in the setting of chemicals and environmental policy, which involved a multidisciplinary, multisectoral, and multinational panel of 25 scientists and practitioners (mainly from the United Kingdom, Europe, and other industrialized nations) in a three‐stage process. Fifteen issues were shortlisted (from a nominated list of 48), considered by the panel to hold global relevance. The issues span from the need for new chemical manufacturing (including transitioning to non‐fossil‐fuel feedstocks); challenges from novel materials, food imports, landfills, and tire wear; and opportunities from artificial intelligence, greater data transparency, and the weight‐of‐evidence approach. The 15 issues can be divided into three classes: new perspectives on historic but insufficiently appreciated chemicals/issues, new or relatively new products and their associated industries, and thinking through approaches we can use to meet these challenges. Chemicals are one threat among many that influence the environment and human health, and interlinkages with wider issues such as climate change and how we mitigate these were clear in this exercise. The horizon scan highlights the value of thinking broadly and consulting widely, considering systems approaches to ensure that interventions appreciate synergies and avoid harmful trade‐offs in other areas. We recommend further collaboration between researchers, industry, regulators, and policymakers to perform horizon scanning to inform policymaking, to develop our ability to meet these challenges, and especially to extend the approach to consider also concerns from countries with developing economies