Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1 *0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis

Background Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. Methods and Results Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCc1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. Conclusions Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.

Progesterone regulation of implantation-related genes: new insights into the role of oestrogen

Genomic profiling was performed on explants of late proliferative phase human endometrium after 24-h treatment with progesterone (P) or oestradiol and progesterone (17 beta-E-2+P) and on explants of menstrual phase endometrium treated with 17 beta-E-2+P. Gene expression was validated with real-time PCR in the samples used for the arrays, in endometrium collected from early and mid-secretory phase endometrium, and in additional experiments performed on new samples collected in the menstrual and late proliferative phase. The results show that late proliferative phase human endometrium is more responsive to progestins than menstrual phase endometrium, that the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P in vitro, and that genes that are fully dependent on the continuous presence of 17 beta-E-2 during P exposure can be distinguished from those that are P-dependent to a lesser extent. Therefore, 17 beta-E-2 selectively primes implantation-related genes for the effects of P.

Olfactomedin-4 regulation by estrogen in the human endometrium requires epidermal growth factor signaling

Olfactomedin-4 (OLFM-4) is an extracellular matrix protein that is highly expressed in human endometrium. We have examined the regulation and function of OLFM-4 in normal endometrium and in cases of endometriosis and endometrial cancer. OLFM-4 expression levels are highest in proliferative-phase endometrium, and 17 beta-estradiol up-regulates OLFM-4 mRNA in endometrial explant cultures. Using the luciferase reporter under control of the OLFM-4 promoter, it was shown that both 17 beta-estradiol and OH-tamoxifen induce luciferase activity, and epidermal growth factor receptor-1 is required for this estrogenic response. In turn, EGF activates the OLFM-4 promoter, and estrogen receptor-alpha is needed for the complete EGF response. The cellular functions of OLFM-4 were examined by its expression in OLFM-4-negative HEK-293 cells, which resulted in decreased vimentin expression and cell adherence as well as increased apoptosis resistance. In cases of endometriosis and endometrial cancer, OLFM-4 expression correlated with the presence of epidermal growth factor receptor-1 and estrogen receptor-alpha (or estrogen signaling). An increase of OLFM-4 mRNA was observed in the endometrium of endometriosis patients. No change in OLFM-4 expression levels were observed in patients with endometrial cancer relative with controts. In conclusion, cross-talk between estrogen and EGF signaling regulates OLFM-4 expression. The role of OLFM-4 in endometrial tissue remodeling before the secretory phase and during the predisposition and early events in endometriosis can be postulated but requires additional investigation. (Am J Pathol 2010, 177:2495-2508: DOI: 10.2353/ajpath.2010.100026

Explicating the role of sexual coercion and vulnerability: Alcohol expectancies in rape attributions

Despite evidence suggesting that alcohol expectancies may influence people’s rape perceptions, no study to date has measured context-specific expectancies comprehensively. This study represents an initial investigation of the role of sexual coercion and vulnerability alcohol expectancies in young Australian adults’ rape blame attributions. Using a vignette method, it was hypothesised that participants’ stronger expectancy endorsement would predict lesser perpetrator blame and greater victim blame. Participants (N = 210; 34.9% males; 18-25 years) read a hypothetical rape scenario and rated dimensions of blameworthiness attributed to the intoxicated sexual perpetrator and victim. Participants completed the Sexual Coercion and Sexual Vulnerability sub-scales of the Drinking Expectancy Sexual Vulnerabilities Questionnaire for the targets self, men, and women in addition to measures of traditional gender role attitudes and rape myth acceptance. Hierarchical multiple regressions revealed that, as expected, stronger sexual coercion expectancy predicted lower perpetrator blame and greater victim blame. Self-oriented expectancy predicted evaluations of the perpetrator whereas other-oriented expectancy predicted victim evaluations. These effects were robust after controlling for gender role attitudes and rape myth acceptance. Alcohol expectancies appear to be part of a network of beliefs and attitudes which perpetuate biased rape attributions and may be useful to challenge in altering rape perceptions.

Multiple iterations : mapping the trace

This paper explores the concept that individual dancers leave traces in a choreographer’s body of work and similarly, that dancers carry forward residue of embodied choreographies into other working processes. This presentation will be grounded in a study of the multiple iterations of a programme of solo works commissioned in 2008 from choreographers John Jasperse, Jodi Melnick, Liz Roche and Rosemary Butcher and danced by the author. This includes an exploration of the development by John Jasperse of themes from his solo into the pieces PURE (2008) and Truth, Revised Histories, Wishful Thinking and Flat Out Lies (2009); an adaptation of the solo Business of the Bloom by Jodi Melnick in 2008 and a further adaptation of Business of the Bloom by this author in 2012. It will map some of the developments that occurred through a number of further performances over five years of the solo Shared Material on Dying by Liz Roche and the working process of the (uncompleted) solo Episodes of Flight by Rosemary Butcher. The purpose is to reflect back on authorship in dance, an art form in which lineages of influence can often be clearly observed. Normally, once a choreographic work is created and performed, it is archived through video recording, notation and/or reviews. The dancer is no longer called upon to represent the dance piece within the archive and thus her/his lived presence and experiential perspective disappears. The author will draw on the different traces still inhabiting her body as pathways towards understanding how choreographic movement circulates beyond this moment of performance. This will include the interrogation of ownership of choreographic movement, as once it becomes integrated in the body of the dancer, who owns the dance? Furthermore, certain dancers, through their individual physical characteristics and moving identities, can deeply influence the formation of choreographic signatures, a proposition that challenges the sole authorship role of the choreographer in dance production. This paper will be delivered in a presentation format that will bleed into movement demonstrations alongside video footage of the works and auto-ethnographic accounts of dancing experience. A further source of knowledge will be drawn from extracts of interviews with other dancers including Sara Rudner, Rebecca Hilton and Catherine Bennett.

Confirmatory factor analysis and invariance testing of the Young Carer of Parents Inventory (YCOPI)

Objective Research into youth caregiving in families where a parent experiences a significant medical condition has been hampered by a lack of contextually sensitive measures of the nature and breadth of young caregiving experiences. This study examined the factor structure and measurement invariance of such a measure called the Young Carer of Parents Inventory (YCOPI; Pakenham et al., 2006) using confirmatory factor analysis across 3 groups of youth. The YCOPI has 2 parts: YCOPI-A with 5 factors assessing caregiving experiences that are applicable to all caregiving contexts; YCOPI-B with 4 factors that tap dimensions related to youth caregiving in the context of parent illness. Design Two samples (ages 9–20 years) were recruited: a community sample of 2,429 youth from which 2 groups were derived (“healthy” family [HF], n = 1760; parental illness [PI], n = 446), and a sample of 130 youth of a parent with multiple sclerosis). Results With some modification, the YCOPI-A demonstrated a replicable factor structure across 3 groups, and exhibited only partial measurement invariance across the HF and PI groups. The impact of assuming full measurement invariance on latent mean differences appeared small, supporting use of the measure in research and applied settings when estimated using latent factors and controlling for measurement invariance. PI youth reported significantly higher scores than did HF youth on all YCOPI-A subscales. The YCOPI-B requires some modifications, and further development work is recommended. Conclusion The factor structure that emerged and the addition of new items constitutes the YCOPI-Revised. Findings support the use of the YCOPI-Revised in research and applied settings.

Dynamics of industry architecture and firm’s capability development : role of knowledge integration within product innovation

Aligned with the decline of Marshalian view of industry as constituting homogeneous set of firms, the new perspective is emerging by concentrating more on dynamics of sectors as the building block of industrial changes. Based on new assumptions, much of the action in terms of strategy, technology, and knowledge development does not happen either among firms within a stable industry, or through the growth or decline of certain sectors compared to others. Instead, the action happens in terms of the definition, redefinition, drawing, and redrawing of the very nature of these sectors. Technology does not progress and develop within a sector; rather it shapes (and is shaped by) the encompassing architecture of multiple sectors.

The role of human factors in led outdoor activity accidents: literature review and exploratory analysis

While the exact rate of incidence is unknown (due to the paucity of exposure data), it is acknowledged that safety compromising accidents and incidents occur in the led outdoor activity domain, and that they represent an important issue. Despite this, compared to other safety critical domains, very little is currently known about the key causal factors involved in such accidents and incidents. This report presents the findings derived from a review of the literature, the aim of which was to identify the Human Factors-related issues involved in accidents and incidents occurring in this area. In addition, to demonstrate the utility of systems-based, theoretically underpinned accident analysis methodologies for identifying the systemic and human contribution to accidents and incidents occurring in the led outdoor activity domain, three case-study accidents were analysed using two such approaches. In conclusion, the review identified a range of causal factors cited in the literature; however, it was noted that the majority of the research undertaken to date lacks theoretical underpinning and focuses mainly on instructor or activity leader causal factors, as opposed to the wider system failures involved. The accident analysis presented highlighted the utility of systems-based, theoretically underpinned accident analysis methodologies for analysing and learning from accidents and incidents in the led outdoor activity sector. In closing, the need for further research in the area is articulated, in particular focussing on the development of standardised and universally accepted accident and incident reporting systems and databases, the development of data driven, theoretically underpinned causal factor taxonomies, and the development and application of systems-based accident analysis methodologies.

Reshaping housing : the role of prefabricated systems

Prefabricated housing innovations have the potential to reduce the environmental impact of construction through improving efficiency and quality. The current paper systematically summarises the published evidence since 1990 that describes the barriers and drivers affecting the uptake of prefabricated housing innovations. These are discussed in relation to a ‘Project-Based Product Framework’ which considers multiple stakeholders including builders and other intermediaries, suppliers, end-users, the broader policy context and technical issues. The framework facilitated identification of central issues such as the prevalent business and cultural resistance associated with process changes; the potential for efficiency and quality improvements and cost savings; the simultaneous risks and benefits of close supplier-builder relationships, and negative user perceptions towards prefabricated houses. Though there is a lack of evidence regarding the effects of regulations and government policies on prefabrication uptake, there are indications of the positive potential of financial and social incentives. Directions for further research include understanding how to: manage the industry’s transition to prefabricated houses; appropriately compare prefabricated housing to traditional housing on cost, efficiency and quality measures; reconcile the differing perspectives of various stakeholders; quantify and identify the perspectives of the potential end-user population, and manage the interface between the emerging industry and information technology improvements.

The effect of autonomy transparency in human-robot interactions : a preliminary study on operator cognitive workload and situation awareness in multiple heterogeneous UAV management

The autonomous capabilities in collaborative unmanned aircraft systems are growing rapidly. Without appropriate transparency, the effectiveness of the future multiple Unmanned Aerial Vehicle (UAV) management paradigm will be significantly limited by the human agent’s cognitive abilities; where the operator’s CognitiveWorkload (CW) and Situation Awareness (SA) will present as disproportionate. This proposes a challenge in evaluating the impact of robot autonomous capability feedback, allowing the human agent greater transparency into the robot’s autonomous status - in a supervisory role. This paper presents; the motivation, aim, related works, experiment theory, methodology, results and discussions, and the future work succeeding this preliminary study. The results in this paper illustrates that, with a greater transparency of a UAV’s autonomous capability, an overall improvement in the subjects’ cognitive abilities was evident, that is, with a confidence of 95%, the test subjects’ mean CW was demonstrated to have a statistically significant reduction, while their mean SA was demonstrated to have a significant increase.

Néstor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation

Background Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure. Results Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope. Conclusions Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.

Reconceptualizing green infrastructure for climate change adaptation: Barriers to adoption and drivers for uptake by spatial planners

Urban green infrastructure can help cities adapt to climate change. Spatial planning can play an important role in utilizing green infrastructure for adaptation. Yet climate change risks represent a different sort of challenge for planning institutions. This paper aims to address two issues arising from this challenge. First, it defines the concept of green infrastructure within the context of climate adaptation. Second, it identifies and puts into perspective institutional barriers to adopting green infrastructure for climate adaptation, including path dependence. We begin by arguing that there is growing confusion among planners and policy makers about what constitutes green infrastructure. Definitional ambiguity may contribute to inaction on climate change adaptation, because it muddies existing programs and initiatives that are to do with green-space more broadly, which in turn feeds path dependency. We then report empirical findings about how planners perceive the institutional challenge arising from climate change and the adoption of green infrastructure as an adaptive response. The paper concludes that spatial planners generally recognize multiple rationales associated with green infrastructure. However they are not particularly keen on institutional innovation and there is a tendency for path dependence. We propose a conceptual model that explicitly recognizes such institutional factors. This paper contributes to the literature by showing that agency and institutional dimensions are a limiting factor in advancing the concept of green infrastructure within the context of climate change adaptation.

Rejected! The harmful effects of workgroup mistreatment and the moderating role of organisational norms

This program of research investigated the harmful effects of mistreatment by the workgroup, and the role of perceived rejection as a critical mediator linking mistreatment and outcomes. This research program had three primary purposes. First, the research aimed to examine the important role of workgroup mistreatment as an independent predictor of negative outcomes, over and above the influence of supervisor mistreatment. Second, the research aimed to examine the effect of perceived rejection as an explanatory variable linking workgroup mistreatment and outcomes. Finally, the moderating effect of organizational norms on the relationship between workgroup mistreatment and perceived rejection was examined. The relationships of interest were examined over four studies, using multiple methods of data collection, across part-time and full-time working samples. In Study 1 (Chapter 2), the independent role of workgroup mistreatment and the mediating role of perceived rejection were examined. One hundred and forty two part-time working participants took part in the study. The participants completed a questionnaire on workplace behaviors in their organizations. The results of hierarchical regression analyses revealed a strong harmful effect of workgroup mistreatment, independent of mistreatment by the supervisor. In addition, the results showed that perceived rejection fully mediated the relationship between workgroup mistreatment and depression and organizational based self esteem. The study highlighted that perceived rejection acts as a key underlying psychological mechanism involved in the effect of workgroup mistreatment. This study has been published in the Journal of Occupational Health Psychology. Study 2 and Study 3 were presented as one paper in Chapter 3. The aims of these two studies was to explore the effects of workgroup mistreatment on a wider range of individual and organizational level outcomes, and to provide further evidence of the mediating role of perceived rejection as observed in Study 1. The results from both studies demonstrated that workgroup mistreatment had a significant and independent role in predicting negative individual and organizational level outcomes, providing support for the findings of Study 1. In the first study, 189 participants received scenarios manipulating workgroup mistreatment and supervisor mistreatment. The results of hierarchical regression analyses revealed that workgroup mistreatment harmfully affected participants, over and above that of the supervisor. The results also demonstrated that perceived rejection mediated the positive relationships between workgroup mistreatment and depression and organizational deviance, and also the negative relationships between workgroup mistreatment and organizational based self esteem and organizational citizenship behaviors. The second study included an additional aim, to examine the moderating role of supportive organizational norms. Two hundred and twenty nine participants read scenarios that manipulated workgroup mistreatment, supervisor mistreatment and organizational norms. The results of hierarchical regression analyses revealed the significant harmful effects of workgroup mistreatment, over and above the influence of supervisor mistreatment. The results also revealed the mediating role of perceived rejection. The direct effect of positive organizational norms also emerged, consistent with previous research. In addition, the result revealed that employees who experienced supportive organizational norms were more likely to reconcile with their workgroup members after experiencing mistreatment compared to employees who experienced hostile organizational norms. Finally, an unexpected pattern on the key affective variables of depression and organizational based self esteem emerged, such that mistreatment led to more negative outcomes in the supportive norms condition than in the hostile condition, where employees appeared to be desensitized. This paper is currently under review at the Journal of Applied Social Psychology. In Study 4 (Chapter 4), the overall model of workplace mistreatment was tested on a sample of full-time workers in an applied setting. One hundred and seventy two adults took part in the study. Participants were required to evaluate their workplace regarding mistreatment and organizational norms and to report their own psychological, behavioral and organizational outcomes. The results revealed that workgroup mistreatment was associated with increased depression, stress and avoidance, over and above supervisor mistreatment. In addition, the results revealed that perceived rejection acted as an explanatory variable linking workgroup mistreatment to a number of outcomes. Furthermore, the moderating role of hostile organizational norms emerged on depression, stress, reconciliation and avoidance. This paper is currently under review at the Journal of Occupational Health Psychology. Overall, the four studies provided empirical support for the majority of the hypotheses. The effects were demonstrated for a range of psychological, behavioral, and organizational level outcomes, using multiple methods of data collection, across part-time and full-time workers. At the conclusion of the thesis (Chapter 5), an overall summary is provided of the findings across all four studies, practical and theoretical implications and research directions.

The pet factor - Companion animals as a conduit for getting to know people, friendship formation and social support

BACKGROUND: While companion animals have been previously identified as a direct source of companionship and support to their owners, their role as a catalyst for friendship formation or social support networks among humans has received little attention. This study investigated the indirect role of pets as facilitators for three dimensions of social relatedness; getting to know people, friendship formation and social support networks. METHODS: A telephone survey of randomly selected residents in four cities, one in Australia (Perth; n = 704) and three in the U.S. (San Diego, n = 690; Portland, n = 634; Nashville, n = 664) was conducted. All participants were asked about getting to know people within their neighborhood. Pet owners were asked additional questions about the type/s of pet/s they owned, whether they had formed friendships as a result of their pet, and if they had received any of four different types of social support from the people they met through their pet. RESULTS: Pet owners were significantly more likely to get to know people in their neighborhood than non-pet owners (OR 1.61; 95%CI: 1.30, 1.99). When analyzed by site, this relationship was significant for Perth, San Diego and Nashville. Among pet owners, dog owners in the three U.S. cities (but not Perth) were significantly more likely than owners of other types of pets to regard people whom they met through their pet as a friend (OR 2.59; 95%CI: 1.94, 3.46). Around 40% of pet owners reported receiving one or more types of social support (i.e. emotional, informational, appraisal, instrumental) via people they met through their pet. CONCLUSION: This research suggests companion animals can be a catalyst for several dimensions of human social relationships in neighborhood settings, ranging from incidental social interaction and getting to know people, through to formation of new friendships. For many pet owners, their pets also facilitated relationships from which they derived tangible forms of social support, both of a practical and emotionally supportive nature. Given growing evidence for social isolation as a risk factor for mental health, and, conversely, friendships and social support as protective factors for individual and community well-being, pets may be an important factor in developing healthy neighborhoods.