RESUMO
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. Environ Toxicol Chem 2023;42:1212-1228. © 2023 Crown copyright and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.
Assuntos
Inteligência Artificial , Poluição Ambiental , Humanos , Ecotoxicologia , Agricultura , Europa (Continente)RESUMO
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 TiO(2)). 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 TiO(2) 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.
Assuntos
Dano ao DNA , Hepatócitos/efeitos dos fármacos , Modelos Biológicos , Mutagênicos/toxicidade , Nanopartículas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Interleucina-8/biossíntese , Nanopartículas/química , Nanotecnologia , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Propriedades de SuperfícieRESUMO
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.
Assuntos
Criptorquidismo/embriologia , Gônadas/embriologia , Hipospadia/embriologia , Diferenciação Sexual , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Criptorquidismo/metabolismo , Criptorquidismo/patologia , Embrião de Mamíferos/metabolismo , Feminino , Gônadas/efeitos dos fármacos , Hipospadia/metabolismo , Hipospadia/patologia , Masculino , Ratos , Ratos Wistar , Receptores Androgênicos/metabolismo , Caracteres Sexuais , Diferenciação Sexual/efeitos dos fármacos , Testosterona/farmacologiaRESUMO
This review focuses on outlining the toxicity of titanium dioxide (TiO(2)) particulates in vitro and in vivo, in order to understand their ability to detrimentally impact on human health. Evaluating the hazards associated with TiO(2 )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 TiO(2), due to the fact that the greatest number of studies by far have evaluated the toxicity of TiO(2), in comparison to other metal oxide particulates. This derives from historical reasons (whereby the size dependency of particulate toxicity was first realised for TiO(2)) and due to its widespread application within consumer products (such as sunscreens). The pulmonary and dermal hazards of TiO(2 )have been a particular focus of the available studies, due to the past use of TiO(2 )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 TiO(2 )particulate toxicity will also be discussed and it is apparent that, in the main, the oxidant driven inflammatory, genotoxic and cytotoxic consequences associated with TiO(2 )exposure, are inherently linked, and are evident both in vivo and in vitro. The attributes of TiO(2 )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 TiO(2 )forms, to TiO(2 )particulates in general, requires consideration. At this time it is inappropriate to consider the findings for one TiO(2 )form as being representative for TiO(2 )particulates as a whole, due to the vast number of available TiO(2 )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.
RESUMO
Fetal androgen action is an important determinant of Sertoli cell (SC) number at birth. Androgens "program" reproductive tract development in rats between embryonic d (e) 15.5 and e17.5 ("male programming window"), and this is reflected for life by anogenital distance (AGD). We investigated if androgen regulation of SC number/proliferation was also programmed by androgens in this window. Pregnant rats were treated in various fetal time windows with vehicle (control) or 500 mg/kg.d di(n-butyl) phthalate (DBP), which suppresses fetal intratesticular testosterone (ITT). ITT and SC number/proliferation index were determined at e17.5 or e21.5; AGD was also determined at e21.5. In controls, SC number increased 11-fold and ITT by 10-fold from e17.5-e21.5. In animals exposed daily to DBP from e13.5, SC number was reduced by approximately 50% at e21.5, but increased 6-fold, as did ITT, from e17.5-e21.5; DBP had no effect on ITT at e15.5, reduced ITT by 50% at e17.5, and by more than 75% at e19.5-21.5. DBP exposure just in the male programming window did not alter SC number at e17.5 or 21.5 but reduced AGD. DBP treatment beyond e19.5 caused major reductions in SC number/proliferation index and ITT at e21.5. Only DBP treatments that included the male programming window led to reduced AGD at e21.5, but SC number was clearly not programmed in this window. Nevertheless, testis weight correlated highly (P<0.001) with AGD at e21.5, and postnatal d 25 and 90 in animals exposed in utero to vehicle or DBP (e13.5-e21.5). Thus, AGD may predict adult testis size but probably not through a direct relationship with SC number.
Assuntos
Androgênios/metabolismo , Células de Sertoli/citologia , Testículo/citologia , Testículo/embriologia , Testosterona/metabolismo , Fatores Etários , Animais , Contagem de Células , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Dibutilftalato/farmacologia , Feminino , Imuno-Histoquímica , Masculino , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Maturidade Sexual/fisiologia , Testículo/metabolismoRESUMO
A testicular dysgenesis-like syndrome is induced in rats by fetal exposure to di(n-butyl) phthalate (DBP). A key feature of this is the formation of focal dysgenetic areas comprising malformed seminiferous cords/tubules and intratubular Leydig cells (ITLC), but how and why these arise remains unclear. The present study has used combinations of cell-specific markers and immunohistochemistry to address this. The results show that focal dysgenetic areas and ITLC first appear postnatally at 4-10 days of age, but this only occurs in treatment groups in which formation of fetal Leydig cell aggregation is induced between e17.5 and e21.5. Extreme variability in the formation and size of the Leydig cell aggregates probably accounts for the equally extreme variation in occurrence and size of focal dysgenetic areas postnatally. DBP-induced fetal Leydig cell aggregation traps Sertoli and other cells within the aggregates, but it is unclear why this happens nor why cords fail to form prenatally in these cell mixtures but do elsewhere in the fetal testis. The present studies show that differentiation of the fetal Leydig cells is drastically delayed at e15.5 after DBP exposure, which may be indicative of a wider delay in testis cell development and organisation, and this might account for some of the unexplained findings.
Assuntos
Modelos Animais de Doenças , Doenças Testiculares/patologia , Testículo/crescimento & desenvolvimento , Animais , Imuno-Histoquímica , Masculino , Ratos , Ratos WistarRESUMO
Neutrophil surveillance is central to nanoparticle clearance. Silver nanoparticles (AgNP) have numerous uses, however conflicting evidence exists as to their impact on neutrophils and whether they trigger damaging inflammation. Neutrophil's importance in innate defence and regulating immune networks mean it's essential we understand AgNP's impact on neutrophil function. Human neutrophil viability following AgNP or Ag Bulk treatment was analysed by flow cytometry and AnV/PI staining. Whilst AgNP exposure did not increase the total number of apoptotic neutrophils, the number of late apoptotic neutrophils was increased, suggesting AgNP increase transit through apoptosis. Mature (CD16bright/CD62Lbright), immature (CD16dim/CD62Lbright) and apoptotic (CD16dim/CD62Ldim) neutrophil populations were evident within isolated neutrophil preparations. AgNP exposure significantly reduced CD62L staining of CD16bright/CD62Lbright neutrophils, and increased CD16 staining of CD16dim/CD62Lbright populations, suggesting AgNPs trigger neutrophil activation and maturation, respectively. AgNP exposure dramatically increased IL-8, yet not classical pro-inflammatory cytokine release, suggesting AgNP triggers neutrophil activation, without pro-inflammation or damaging, necrotic cell death. For the first time, we show AgNPs differentially affect distinct sub-populations of circulating human neutrophils; activating mature neutrophils with the emergence of CD16bright/CD62Ldim neutrophils. This may stimulate particle clearance without harmful inflammation, challenging previous assumptions that silver nanomaterials induce neutrophil toxicity and damaging inflammatory responses.
Assuntos
Interleucina-8/metabolismo , Neutrófilos/citologia , Prata/efeitos adversos , Regulação para Cima , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Selectina L/metabolismo , Nanopartículas Metálicas/efeitos adversos , Ativação de Neutrófilo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Receptores de IgG/metabolismoRESUMO
This study sought to establish whether reduced androgen levels/action in the fetal rat testis induced by di(n-butyl) phthalate (DBP) contributes to dysgenetic features, namely reduced Sertoli cell number, occurrence of multinucleated gonocytes (MNG), and Leydig cell aggregation. Pregnant rats were administered treatments or cotreatments designed to manipulate testosterone levels [DBP, testosterone propionate (TP)] or action [flutamide, 7,12-dimethyl-benz[a]anthracene (DMBA)]. The aforementioned end points were analyzed and related to intratesticular testosterone (ITT) levels and peripheral androgen action (anogenital distance). Dysgenetic features were also evaluated in mice with inactivation of the androgen receptor (testicular feminized or ARKO mice). Exposure to DBP alone, or combined with flutamide, DMBA, or TP, resulted in reduced Sertoli cell number and ITT levels, as did exposure to TP alone; coadministration of DBP + TP caused the most severe reduction in both parameters. A positive correlation between ITT levels and Sertoli cell number was found (r = 0.791; P = 0.019). Similarly, exposure to DBP alone, or as a cotreatment, significantly increased occurrence of MNG and Leydig cell aggregation, and these were negatively correlated with ITT levels. Exposure to flutamide or DMBA alone had no significant effect on these dysgenetic end points. These findings suggest that reduced ITT decreases fetal Sertoli cell numbers and might be involved in Leydig cell aggregation and MNG. However, of these three end points, only Sertoli cell number was affected significantly in ARKO/testicular feminized mice with absent androgen action. Therefore, induction of MNG and Leydig cell aggregation might result from DBP-induced effects other than suppression of ITT levels.
Assuntos
Disgenesia Gonadal/patologia , Disgenesia Gonadal/fisiopatologia , Testículo/anormalidades , Testosterona/deficiência , Testosterona/fisiologia , 9,10-Dimetil-1,2-benzantraceno/farmacologia , Antagonistas de Androgênios/farmacologia , Animais , Peso Corporal , Carcinógenos/farmacologia , Dibutilftalato/farmacologia , Feminino , Feminização/patologia , Feminização/fisiopatologia , Flutamida/farmacologia , Células Gigantes/patologia , Células Intersticiais do Testículo/patologia , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Células de Sertoli/patologia , Testículo/patologiaRESUMO
BACKGROUND: In the year 2000 Corus closed its steel plant operations in Redcar, NE of England temporarily for refurbishment of its blast furnace. This study investigates the impact of the closure on the chemical composition and biological activity of PM10 collected in the vicinity of the steel plant. METHODS: The metal content of PM10 samples collected before during and after the closure was measured by ICP-MS in order to ascertain whether there was any significant alteration in PM10 composition during the steel plant closure. Biological activity was assessed by instillation of 24 hr PM10 samples into male Wistar rats for 18 hr (n = 6). Inflammation was identified by the cellular and biochemical profile of the bronchoalveolar lavage fluid. Metal chelation of PM10 samples was conducted using Chelex beads prior to treatment of macrophage cell line, J774, in vitro and assessment of pro-inflammatory cytokine expression. RESULTS: The total metal content of PM10 collected before and during the closure period were similar, but on reopening of the steel plant there was a significant 3-fold increase (p < 0.05) compared with the closure and pre-closure samples. Wind direction prior to the closure was predominantly from the north, compared to south westerly during the closure and re-opened periods. Of metals analysed, iron was most abundant in the total and acid extract, while zinc was the most prevalent metal in the water-soluble fraction. Elevated markers of inflammation included a significant increase (p < 0.01) in neutrophil cell numbers in the bronchoalveolar lavage of rats instilled with PM10 collected during the reopened period, as well as significant increases in albumin (p < 0.05). Extracts of PM10 from the pre-closure and closure periods did not induce any significant alterations in inflammation or lung damage. The soluble and insoluble extractable PM10 components washed from the reopened period both induced a significant increase in neutrophil cell number (p < 0.05) when compared to the control, and these increases when added together approximately equalled the inflammation induced by the whole sample. PM10 from the re-opened period stimulated J774 macrophages to generate TNF-alpha protein and this was significantly prevented by chelating the metal content of the PM10 prior to addition to the cells. CONCLUSION: PM10-induced inflammation in the rat lung was related to the concentration of metals in the PM10 samples tested, and activity was found in both the soluble and insoluble fractions of the particulate pollutant.
Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental/efeitos adversos , Nanoestruturas/toxicidade , Exposição Ocupacional/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Aço/toxicidade , Animais , Masculino , Metalurgia , Tamanho da Partícula , Ratos , Ratos Wistar , Medição de Risco/métodos , Fatores de Risco , Aço/análise , Reino UnidoRESUMO
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 exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such 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.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Dibutilftalato/toxicidade , Células Germinativas/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Testículo/efeitos dos fármacos , Animais , Feto/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Testículo/embriologia , Transplante HeterólogoRESUMO
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.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Exposição Materna/efeitos adversos , Nanopartículas , Material Particulado/toxicidade , Animais , Feminino , Idade Gestacional , Humanos , Modelos Animais , Material Particulado/sangue , Material Particulado/farmacocinética , Circulação Placentária , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Medição de Risco , Testes de Toxicidade/métodosRESUMO
Effects on the liver C3A cell line treated with a panel of engineered nanomaterials (NMs) consisting of two zinc oxide particles (ZnO; coated 100 nm and uncoated 130 nm), two multi-walled carbon nanotubes (MWCNTs), one silver (Ag < 20 nm), one 7 nm anatase, two rutile TiO2 nanoparticles (10 and 94 nm) and two derivatives with positive and negative covalent functionalisation of the 10 nm rutile were evaluated. The silver particles elicited the greatest level of cytotoxicity (24 h LC50 - 2 µg/cm(2)). The silver was followed by the uncoated ZnO (24 h LC50 - 7.5 µg/cm(2)) and coated ZnO (24 h LC50 - 15 µg/cm(2)) particles with respect to cytotoxicity. The ZnO NMs were found to be about 50-60% soluble which could account for their toxicity. By contrast, the Ag was <1% soluble. The LC50 was not attained in the presence of any of the other engineered NMs (up to 80 µg/cm(2)). All NMs significantly increased IL-8 production. Meanwhile, no significant change in TNF-α, IL-6 or CRP was detected. Urea and albumin production were measured as indicators of hepatic function. These markers were only altered by the coated and uncoated ZnO, which significantly decreased albumin production.
Assuntos
Citocinas/metabolismo , Hepatócitos/efeitos dos fármacos , Nanoestruturas/toxicidade , Albuminas/metabolismo , Análise de Variância , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Prata/toxicidade , Titânio/toxicidade , Ureia/metabolismo , Óxido de Zinco/toxicidadeRESUMO
This critical review of the available human health safety data, relating to carbon nanotubes (CNTs), was conducted in order to assess the risks associated with CNT exposure. Determining the toxicity related to CNT exploitation is of great relevance and importance due to the increased potential for human exposure to CNTs within occupational, environmental and consumer settings. When this information is combined with knowledge on the likely exposure levels of humans to CNTs, it will enable risk assessments to be conducted to assess the risks posed to human health. CNTs are a diverse group of materials and vary with regards to their wall number (single and multi-walled CNTs are evident), length, composition, and surface chemistry. The attributes of CNTs that were identified as being most likely to drive the observed toxicity have been considered, and include CNT length, metal content, tendency to aggregate/agglomerate and surface chemistry. Of particular importance, is the contribution of the fibre paradigm to CNT toxicity, whereby the length of CNTs appears to be critical to their toxic potential. Mechanistic processes that are critical to CNT toxicity will also be discussed, with the findings insinuating that CNTs can exert an oxidative response that stimulates inflammatory, genotoxic and cytotoxic consequences. Consequently, it may transpire that a common mechanism is responsible for driving CNT toxicity, despite the fact that CNTs are a diverse population of materials. The similarity of the structure of CNTs to that of asbestos has prompted concern surrounding the exposure of humans, and so the applicability of the fibre paradigm to CNTs will be evaluated. It is also necessary to determine the systemic availability of CNTs following exposure, to determine where potential targets of toxicity are, and to thereby direct in vitro investigations within the most appropriate target cells. CNTs are therefore a group of materials whose useful exploitable properties prompts their increased production and utilization within diverse applications, so that ensuring their safety is of vital importance.
Assuntos
Nanotubos de Carbono/química , Nanotubos de Carbono/toxicidade , Testes de Toxicidade , Animais , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Células Cultivadas , Exposição Ambiental/efeitos adversos , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Modelos Biológicos , Especificidade de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Propriedades de Superfície , Distribuição TecidualRESUMO
This review provides a comprehensive critical review of the available literature purporting to assess the toxicity of carbon fullerenes. This is required as prior to the widespread utilization and production of fullerenes, it is necessary to consider the implications of exposure for human health. Traditionally, fullerenes are formed from 60 carbon atoms, arranged in a spherical cage-like structure. However, manipulation of surface chemistry and molecular makeup has created a diverse population of fullerenes, which exhibit drastically different behaviors. The cellular processes that underlie observed fullerene toxicity will be discussed and include oxidative, genotoxic, and cytotoxic responses. The antioxidant/cytoprotective properties of fullerenes (and the attributes responsible for driving these phenomena) have been considered and encourage their utilization within the treatment of oxidant-mediated disease. A number of studies have focused on improving the water solubility of fullerenes in order to enable their exploitation within biological systems. Manipulating fullerene water solubility has included the use of surface modifications, solvents, extended stirring, and mechanical processes. However, the ability of these processes to also impact on fullerene toxicity requires assessment, especially when considering the use of solvents, which particularly appear to enhance fullerene toxicity. A number of the discussed investigations were not conducted to reveal if fullerene behavior was due to their nanoparticle dimensions but instead addressed the biocompatibility and toxicity of fullerenes. The hazards to human health, associated with fullerene exposure, are uncertain at this time, and further investigations are required to decipher such effects before an effective risk assessment can be conducted.
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Antioxidantes/toxicidade , Fulerenos/toxicidade , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Fulerenos/química , Fulerenos/metabolismo , Humanos , Camundongos , Nanopartículas/efeitos adversos , Nanopartículas/química , Nanotecnologia , Ratos , Medição de Risco , SolubilidadeRESUMO
Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg . d dibutyl phthalate (DBP), 0.1 mg/kg . d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg . d DBP and exacerbated the effects of 100 mg/kg . d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.
Assuntos
Dexametasona/farmacologia , Dibutilftalato/farmacologia , Glucocorticoides/farmacologia , Exposição Materna , Testículo/crescimento & desenvolvimento , Testosterona/biossíntese , Animais , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Gravidez , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/metabolismoRESUMO
Pregnancy exposure to di(n-butyl) phthalate (DBP) in rats induces a testicular dysgenesislike syndrome (TDS) in male offspring. Earlier studies suggested altered Sertoli cell development/maturation may result, especially in testes that become cryptorchid. This study quantitatively assessed Sertoli cell numerical and functional development in DBP-exposed rats and compared (unilaterally) cryptorchid and scrotal testes. Pregnant rats were gavaged with 500 mg/kg/day DBP or corn oil from embryonic (E) Days 13.5 to 21.5. Male offspring were sampled on E21.5 or Postnatal Day 6, 10, 15, 25, or 90. Sertoli cell number in DBP-exposed males was reduced by approximately 50% at E21.5 but recovered to normal by Days 25-90, accompanied by significant changes in plasma inhibin B and testosterone levels. Sertoli cell maturational development in DBP-exposed males, assessed using five protein markers (anti-müllerian hormone, cytokeratin, androgen receptor, CDKN1B, and Nestin), was largely normal, with some evidence of delayed maturation. However, in adulthood, Sertoli cells (SC) in areas lacking germ cells (Sertoli cell-only [SCO] tubules) often exhibited immature features, especially in cryptorchid testes. Sertoli cells in DBP-exposed animals supported fewer germ cells during puberty, but this normalized in scrotal testes by adulthood. Scrotal and especially cryptorchid testes from DBP-exposed animals exhibited abnormalities (SCO tubules, focal dysgenetic areas) at all postnatal ages. Cryptorchid testes from DBP-exposed animals exhibited more Sertoli cell abnormalities at Day 25 compared with scrotal testes, perhaps indicating more severe underlying Sertoli cell malfunction in these testes. Our findings support the concept of altered Sertoli cell development in TDS, especially in cryptorchid testes, but show that maturational defects in Sertoli cells in adulthood most commonly reflect secondary dedifferentiation in absence of germ cells.
Assuntos
Criptorquidismo/patologia , Disgenesia Gonadal/patologia , Células de Sertoli/patologia , Testículo/anormalidades , Testículo/patologia , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Contagem de Células , Criptorquidismo/induzido quimicamente , Dibutilftalato/toxicidade , Modelos Animais de Doenças , Hormônio Foliculoestimulante/sangue , Disgenesia Gonadal/induzido quimicamente , Inibinas/sangue , Masculino , Tamanho do Órgão , Plastificantes/toxicidade , Proteínas/análise , Proteínas/metabolismo , Ratos , Ratos Wistar , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/fisiologia , Espermatogônias/citologia , Espermatogônias/fisiologia , Síndrome , Testosterona/sangueRESUMO
BACKGROUND: Particulate air pollution (PM(10)) consists of a mixture of components, including nanoparticles and metals. Studies from our laboratory have demonstrated that transition metals can potentiate the ability of nanoparticles to induce lung inflammation and that the zinc content of PM(10) was largely responsible for their potential to induce inflammation. These results are also relevant to zinc-containing engineered nanoparticles. OBJECTIVES: To investigate the potential of ZnCl(2) and FeCl(3) to interact with nanoparticle carbon black in cell-free and biological systems to generate ROS, express pro-inflammatory mediators and cytotoxic ability. METHODS: ROS production was examined using DCFH-DA. J774 cells were treated for 4 h with 14 nm CB and/or ZnCl(2) before measuring TNF-alpha by ELISA. Cytoskeletal changes were investigated using confocal microscopy. Flow cytometry was used to examine apoptotic/necrotic cells and phagocytic ability. RESULTS: In a cell-free system the particles generated significant ROS, whereas ZnCl(2) did not. Treatment of cells with 100 microM ZnCl(2), but not FeCl(3), increased TNF-alpha. Treatment with 14 nm CB alone induced TNF-alpha, which was synergistically enhanced by ZnCl(2). No interactions were observed in cells treated with 14 nm CB and FeCl(3). Cytoskeletal changes were observed with increasing concentrations of ZnCl(2). These results were confirmed by flow cytometry indicating that ZnCl(2) induced markers of apoptosis and necrosis. The phagocytic ability of cells was also significantly decreased. Nanoparticle carbon black alone did not induce changes in apoptosis/necrosis or the phagocytosis activity of the cells. CONCLUSION: Despite an inability to induce ROS production, ZnCl(2) stimulated TNF-alpha production which was synergistically enhanced by 14 nm carbon black. The ability of zinc to induce morphological changes and cell death was not altered by nanoparticle treatment.