No description available.

Manufactured nanoparticles (NPs) are a class of small ( ≤ 100 nm) materials that are being used for a variety of purposes, including industrial lubricants, food additives, antibacterial agents, as well as delivery systems for drug and gene therapies. Their unique characteristics due to their small size as well as their parent materials allow them to be exploited in convenience applications; however, some of these properties also allow them to interact with and invade biological systems. Few studies have been performed to determine the potential harm that NPs can inflict on reproductive and developmental processes in organisms. In this study, Drosophila melanogaster and CD-1 mice were orally exposed to varying doses of titanium dioxide (TiO2) NPs, silver (Ag) NPs, or hydroxyl-functionalized carbon nanotubes (fCNTs) and Drosophila were also exposed to microparticles (MPs) as a control for particle size. The subsequent effect of these materials on reproduction and development were evaluated. Strikingly, each type of NP studied negatively affected either reproduction or development in one or both of the two model systems. TiO2 NPs significantly negative effected both CD-1 mouse development (100 mg/kg or 1000 mg/kg) as well as Drosophila female fecundity (0.005%-0.5% w/v). Ag NPs significantly reduced mouse fetus viability after prenatal exposure to10 mg/kg. Ag NPs also significantly decreased the developmental success of Drosophila when they were directly exposed to these NPs (0.05% - 0.5% w/v) compared to both the vehicle and MP controls. fCNTs significantly increased the presence of morphological defects, resorptions and skeletal abnormalities in CD-1 mice, but had little effect on Drosophila. We speculate that the differences seen in the effects of NP types may be partially due to differences in reproductive physiology as well as each organism’s ability to internalize these NPs. Whereas the differing response of each organism to a NP type was likely due in part to varying durations of exposure. Since NPs are a popular commodity in today’s consumer world, the research presented here accentuates the need for further studies on the detrimental effects that these particles may have on a variety of developing organisms and on female reproductive health. / Thesis (Master, Environmental Studies) -- Queen's University, 2010-09-20 17:57:59.343

Aluminium (Al) and silver (Ag), through human activities, are present in the environment at concentrations sufficient to cause toxicity. The aim of this study was to administer Al and Ag to the short lived model organism Drosophila melanogaster, so that developmental toxicity and potential ameliorative interventions could be examined over a compressed timescale relative to mammalian models. Aluminium was administered to Drosophila in food as either the chloride salt or citrate complex at concentrations of 1, 10 and 100 mM and various developmental parameters were assessed. The lowest concentration to delay pupation relative to the control was 10 mM but this depended upon the food in which it was administered. Higher whole body tissue levels of Al were seen following Al citrate administration compared to AlCl3, but Al citrate was less toxic as this did not did not impair larval viability at 100 mM; 100 mM AlCl3 resulted in 100% mortality. Eclosion success was significantly impaired with either form of Al at 10 mM, but no difference was seen between the forms of Al. When Drosophila were fed AlCl3 over their entire lifespan, a small but significant reduction in the lifespan of male flies was seen. No behavioural toxicity could be demonstrated. Existing studies have demonstrated significant tissue Al concentrations and toxicity whereas these have been minimal in this study. It is suggested that these differences may have a genetic component, with food composition exerting an influence also. Silver, either as AgNO3 or Ag nanoparticles (AgNPs) was administered in concentrations up to 500 micromolar and 10 mM, respectively. Either form of Ag, at 50 micromolar was sufficient to significantly retard pupation rate, although pupation or eclosion success was not impaired until 100 micromolar. The concentration-response relationship for AgNO3 was steep with pupation success dropping to nearly zero by 300 micromolar; Drosophila in this study were far more sensitive to AgNO3 than those in other reports. Animals exposed to AgNPs were still able to pupate at 500 micromolar, but these pupae were almost all non-viable when exposed to 400 micromolar AgNPs. At 1 mM and above, AgNPs, however, showed reduced toxicity compared to lower concentrations. The reasons for this are unclear. Both forms of Ag caused de-pigmentation in adults after larval exposure that may be explainable by inhibition of polyphenol oxidase enzymes by Ag (I) ions. The de-pigmentation was preventable by pre-loading larvae with Cu. Ascorbate prevented the de-pigmentation caused by AgNPs but not AgNO3 suggesting that AgNP toxicity is due to Ag (I) ion release. Oxidation of AgNPs was found to be greatly accelerated by Fe (III) and Cu (II) ions in the presence of Cl- ions. Although some of the results here conflict with the literature, developmental toxicity has been observed here, for both Al and Ag, and the variability across studies may provide an opportunity for dissecting the mechanisms behind Al and Ag toxicity through identification of the traits that confer sensitivity or resistance.

Persistent organic pollutants (POPs) cause significant effects on organisms due to their resistance to environmental degradation and specific toxic responses. Although POPs toxicities were linked to oxidative stress in the previous studies, there are few POPs studies that link them with oxidative stress in zebrafish during development. Aim of this study is to investigate effect of selected POPs on expression of genes involved in oxidative stress response and biotransformation of xenobiotics in zebrafish. Zebrafish embryos in 96 hours’ post-fertilization were exposed to selected POPs and their mixture. To explore the developmental toxicity in zebrafish early stage, we exposed 3,3',4,4',5-pentachlorobiphenyl (PCB), perfluorooctanesulfonic acid (PFOS) and perfluorohexanoic acid (PFHxA) at concentrations of 7.5 μg/L, 50 μM, 50 μM until 96 hours’ post-fertilization. The effects were measured by gene expression quantification technique - quantitative real-time PCR (qPCR). Significant up-regulation in gene expression was detected in embryos treated with mixture of PCB with PFHxA and PCB with PFOS only for cytochrome P450(cyp1a). The results also showed the treatment with selected compound caused significant higher upregulation of cyp1a when we compare the treatment in the individual compounds to the mixture compounds. However, treatments did not cause changes in expression of genes involved in oxidative stress response (glutathione peroxidase 1a(gpx1a), tumor protein p53(tp53), aryl hydrocarbon receptor 2 (ahr2)). The result also suggests that exposure to selected POPs in mixtures or alone is not causing oxidative stress in early stage of embryonal development of zebrafish but activating biotransformation function of the organism. Effect of activation of biotransformation capacity by means of cyp1a upregulation is also higher when POPs are in mixtures over when used as individual substance.

The recent expansion in chemical and manufacturing and innovation has led to a large influx of chemicals to the market, and subsequent release into the environment. Many of these new chemicals, as well as legacy chemicals are untested for their potential developmental toxicity, especially in early embryonic stages. This creates a need for a timely and cost-effective method for screening these chemicals. Furthermore, advances in in vitro methods and human pluripotent cell culturing techniques have revealed some weaknesses in our current animal model-based paradigms. Here we tested an in vitro model for developmental toxicity screening using human embryonic stem cells (hESCs) for environmental chemicals. In this study, hESCs were exposed to three known developmental toxicants that are prevalent in the environment, bisphenol A (BPA), perfluorooctane sulfonate (PFOS), or lead chloride (PbCl₂), at environmentally relevant concentrations of 0-2500 µg/L, 0-2275 µg/L, and 0-6200 µg/L respectively, for 6-days. hESCs were evaluated for dose responses on proliferation level by assaying cell viability, mitochondrial dehydrogenase activity (MDHA), cell confluency, and cell cycle distribution. Differentiation capability was assayed by induction of differentiation into ectoderm, mesoderm, and endoderm; hESCs and differentiated cells were then sequenced for their full transcriptome. Gene expression effects were analyzed by a single cell transcriptome sequencing and analysis of global DNA methylation. Proliferation and methylation effects were tested for all 3 chemicals, while differentiation and single cell sequencing was only tested on PbCl₂. Our results show hESCs were able to identify known and novel proliferation effects of BPA, PFOS, and PbCl₂, reflect differentiation level effects of PbCl₂, and elucidate molecular level drivers of these toxic effects. We also showed that hESCs responded to developmental toxicants at lower doses than in vivo models. In conclusion, our hESC-based model could act as an effective developmental toxicity screening tool for pre- peri- and post-implantation stages of embryo development.

No description available.

PCBs are synthetic organic compounds known for their toxicity to many organisms and are notorious for having large discrepancies between measured and nominal concentrations. Historically thought to be less toxic, non-dioxin-like (NDL) PCBs represent the majority of congeners and are capable of eliciting neurotoxic effects. NDL-PCBs remain understudied, including their effects on aquatic organisms. In the first study, I collected extensive chemistry data and data on neurobehavioral and cardiac endpoints to test the acute effects of exposure to an NDL-PCB mixture on early life stage zebrafish. Neurobehavioral effects observed in the first study indicated a potential for longer term behavioral effects in these fish. In the second study, I collected data on feeding, social, and memory behavior of zebrafish at time points beyond the acute exposure from the first study. Acute and longer-term behavioral endpoints in the first and second studies demonstrated effects from PCB exposure but did not indicate mechanisms. In the third study, I collected untargeted and targeted metabolomic data on amino acid, sugar, anionic compound, and neurotransmitter profiles to determine the specific pathways affected by exposure to an NDL-PCB mixture. These combined data from these studies provide a unique insight into the chemical profile of an NDL-PCB mixture in biological applications and synthesize acute, longer-term, and mechanistic effects on developing zebrafish. These data fully illustrate an adverse outcome pathway from toxicokinetic to population level effects.

Since their emergence in the early 1990s, neonicotinoid use has increased exponentially to make them the world's most prevalent insecticides. Although there is considerable research concerning the lethality of neonicotinoids, their sub-lethal and developmental effects are still being explored, especially with regards to non-mammalian species. The goal of this research was to investigate the effects of the neonicotinoid imidacloprid on the morphological and physiological development of northern bobwhite quail (Colinus virginianus). Bobwhite eggs (n = 650) were injected with imidacloprid concentrations of 0 (sham), 10, 50, 100 and 150 grams per kilogram of egg mass, which was administered at day 0 (pre-incubation), 3, 6, 9, or 12 of growth. Embryos were dissected on day 19 when they were weighed, staged, and examined for any overt structural deformities. Embryonic heart, liver, lungs and kidneys were also weighed and preserved for future use. Treated embryos exhibited increased frequency of severely deformed beaks and legs, as well as larger hearts and smaller lungs at the higher dosing concentrations. Some impacts are more pronounced in specific dosing periods, implying that there may be critical windows of development when embryos are highly susceptible to neonicotinoid exposure. This investigation suggests that imidacloprid could play a significant role in chick survival and declining quail populations in treated regions of the country.

<p>  </p> <p>Perfluoroalkyl substances (PFAS) are synthetic chemicals that are composed of fluorinated aliphatic chains and are widely used in industrial and consumer products. These chemicals are very stable and persist in the environment. Due to concerns linked with longer chain PFAS, shorter chain chemicals are being used as replacements. There are limited human health data regarding the shorter chain chemicals. In addition, these alternatives are persistent in the environment similar to the longer chain PFAS. The main objective of this dissertation was to assess developmental toxicity of the shorter chain PFAS or shorter chain PFAS with chemical modifications represented by perfluorobutanoic acid (PFBA, C4), perfluorohexanoic acid (PFHxA, C6), perfluorobutane sulfonate (PFBS, C4), and perfluoro-2-proxypropanoic acid (GenX, C6). Overall, the results showed that chain length and functional group are determinants of toxicity of PFAS. All tested PFAS induced one or more developmental adverse outcome, but the effects of each chemical are unique, warranting further studies to address the toxicity of the replacement PFAS. </p>

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Selenium (Se) is an essential trace element for man and is known for its role in regulating growth and development of the fetus and newborn. Furthermore, Se is a micronutrient required for normal spermatogenesis and, therefore, essential for normal male reproductive function. However, it is well known that this element, depending of dose, can be highly toxic to several species of animals. Diphenyl diselenide [(PhSe)2] is a Se-compound widely used as intermediate in organic synthesis, as a consequence, the risk of human exposure to this chemical at the workplace may increase. Several studies demonstrated that (PhSe)2 is an organoselenium compound with potential therapeutic use. The present study evaluates the effects of single maternal subcutaneous injection of 50 and 100 mg/kg (PhSe)2 at gestational days (GD) 6, 10 or 17 in Wistar rats (article 1). The highest dose of (PhSe)2 was also administered at GD7-12. External and internal fetal soft-tissue examination was performed at GD20. No mortality was observed in fetuses or dams at any (PhSe)2 treatment. Neither did exposure to (PhSe)2 cause significant changes to fetal body weight, organ weight, or fetal size when dministered at GD6-8, 10-12 or 17. Exposure to 100 mg/kg (PhSe)2 at GD 9 produced significant changes in fetal biometry (crown-rump (CR) length) and body weight. No increase in the proportion of fetuses with external visible abnormalities was observed in groups exposed to (PhSe)2. Skeletal anomalies were observed in fetuses in the GD 9-11 treatment groups and included incomplete ossification of cranial bones, misshapen and incomplete ossification of sternebrae, reduced sternebrae number, wavy and extra ribs, incomplete ossification of fore and hindpaw bones and incomplete ossification of sacral and caudal bones. We conclude that maternal administration of (PhSe)2 during GD 7-12 led to increased incidences of these skeletal variations or anomalies, but did not cause externally visible malformations in rat fetuses. Another focus of this study was the evaluation of the effect of paternal exposure to (PhSe)2 on the development of progeny of Wistar male rats (article 2). Male rats were exposed to (PhSe)2 subcutaneously for 4 weeks (wk) at the dose of 5.0 mg/kg and 8 weeks at the dose of 2.5 mg/kg, prior to mating with unexposed females. No lethality was noted in any group. At term of exposure period, 4-wk-exposed male rats presented significant decrease in the body weight. Sex organ weights were similar in (PhSe)2-exposed and control male groups. The number of implantation sites in females mated with males exposed to (PhSe)2 for 8-wk was significantly higher than those of the respective control group. Male exposure to (PhSe)2, administered for 4- and 8-wk, did not change fetal body weight. Gross examination of fetuses from 4- and 8-wk-exposed groups did not reveal the appearance of external anomalies. Examination of live fetuses for ossification centers did not show any significant difference between groups. No increase in the incidence of skeletal anomalies was observed in fetuses obtained from females impregnated with (PhSe)2-exposed males. The current study indicated that (PhSe)2 given sub-chronically (4 or 8 weeks) to male rats had no adverse effects on their progeny. On the basis of results mentioned above, it is possible conclude that (PhSe)2 is a compound with low developmental toxicity, since adverse effects observed were only manifested at a high level dose. Of particular importance, (PhSe)2 possess its pharmacological properties at doses lower than these tested here. / O selênio (Se) é um elemento traço essencial para humanos e desempenha uma importante função durante a gestação, regulando o crescimento e desenvolvimento de fetos e recém-nascidos. Além disso, o Se é um micronutriente requerido para o processo da espermatogênese e, portanto, essencial para a função reprodutiva em machos. Entretanto, o elemento Se, dependendo da dose, pode ser tóxico para diversas espécies de animais. O disseleneto de difenila [(ØSe)2] é um composto de Se amplamente utilizado como intermediário em reações de síntese orgânica, o que aumenta o risco de intoxicação por exposição ocupacional a este composto. Existem diversos estudos demonstrando que o (ØSe)2 possui propriedades farmacológicas. O presente estudo avaliou os efeitos da administração subcutânea, única, de (ØSe)2 nas doses de 50 ou 100 mg/kg no 6°, 10° ou 17° dia da gestação de ratas Wistar (artigo 1). Os estudos com a maior dose de (ØSe)2 (100 mg/kg) foram estendidos a outros dias da gestação (7° ao 12°). No 20° dia de gestação foi realizada uma laparotomia para a retirada dos fetos e a observação do aparecimento de malformações morfológicas externas e esqueléticas. Não foram observadas mortes maternas e fetais nos grupos expostos ao (ØSe)2. A exposição ao (∅Se)2 não causou alterações significativas nos parâmetros de desenvolvimento avaliados (peso e comprimento fetal), com exceção da exposição a 100 mg/kg de (∅Se)2 no 9° dia de gestação, a qual produziu mudanças significativas na biometria fetal: diminuição do comprimento longitudinal e do peso corporal do feto. Não foi observado um aumento significativo no aparecimento de malformações fetais nos grupos expostos ao (∅Se)2. A exposição ao (∅Se)2 aumentou a incidência de alterações na ossificação do esqueleto dos fetos, principalmente nos grupos tratados no 9°, 10° e 11° dia de gestação sem afetar a sobrevivência dos mesmos. As alterações observadas incluem: ossificação incompleta dos ossos do crânio, das vértebras sacrais e caudais e dos ossos das patas anteriores e posteriores. Além disso, foram observadas alterações nas esternebras das quais, destacam-se: malformação, número reduzido e incompleta ossificação. Um número extra de costelas e costelas onduladas também foi observado. Portanto, com base nos resultados encontrados, concluímos que a exposição materna ao (ØSe)2 leva ao aumento na incidência de alterações esqueléticas nos fetos, sem causar o aparecimento de malformações externas visíveis e sem afetar a sobrevivência dos mesmos. Outro foco deste estudo foi avaliar o grau de toxicidade da exposição sub-crônica ao (ØSe)2 sobre o desenvolvimento da prole de ratos Wistar (artigo 2). Os ratos foram expostos ao composto pela via subcutânea por um período de 4 (na dose de 5,0 mg/kg) ou 8 semanas (2,5 mg/kg) antes do período de acasalamento. Não foram observadas mortes em nenhum dos grupos e, ao final do período de exposição, apenas os animais tratados com o composto por um período de 4 semanas apresentaram uma redução significativa do peso corporal. O peso dos órgãos sexuais masculinos (testículos e epidídimos) não foi alterado pelo tratamento. Foi observado um aumento significativo no número de sítios de implantações nas fêmeas acasaladas com os machos expostos ao (ØSe)2 por um período de 8 semanas. Em relação aos parâmetros fetais, não foram observadas anomalias externas e nem mudanças no peso em ambos os grupos tratados com o (ØSe)2 (4 ou 8 semanas). Não foram observadas diferenças significativas no desenvolvimento do esqueleto dos fetos expostos a este composto. O presente estudo demonstrou que a exposição sub-crônica (4 ou 8 semanas) ao (ØSe)2 não causou efeitos adversos sobre a prole de ratos Wistar. Tendo em vista os dados obtidos no presente estudo, é possível concluir que o composto (ØSe)2 apresenta baixa toxicidade desenvolvimental, uma vez que os efeitos adversos observados neste estudo se manifestam apenas em uma dose muito alta. É importante salientar que o (ØSe)2 desempenha suas propriedades farmacológicas em doses mais baixas do que as testadas neste trabalho.