Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.

TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration

Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H.

Critical success factors in urban brownfield regeneration: an analysis of ‘hardcore’ sites in Manchester and Osaka during the economic recession (2009–10)

Hardcore, or long-term derelict and vacant brownfield sites which are often contaminated, form a significant proportion of brownfield land in many cities, not only in the UK but also in other countries. The recent economic recession has placed the economic viability of such sites in jeopardy. This paper compares the approaches for bringing back hardcore brownfield sites into use in England and Japan by focusing on ten case studies in Manchester and Osaka, using an `agency'-based frame- work. The findings are set in the context of (i) national brownfield and related policy agendas; (ii) recent trends in land and property markets in both England and Japan; and (iii) city-level comparisons of brownfields in Manchester and Osaka. The research, which was conducted during 2009 ^ 10, suggests that hardcore brownfield sites have been badly affected by the recent recession in both Manchester and Osaka. Despite this, not only is there evidence that hardcore sites have been successfully regenerated in both cities, but also that the critical success factors (CSFs) operating in bringing sites back into use share a large degree of commonality. These CSFs include the presence of strong potential markets, seeing the recession as an opportunity, long-term vision, strong branding, strong partnerships, integrated development, and getting infrastructure into place. Finally, the paper outlines the policy implications of the research.

Housing supply and brownfield regeneration in a post-Barker world: is there enough brownfield land in England and Scotland?

The findings of the Barker review, which examined the reasons for the undersupply of UK housing, have important implications for the devolved constituents of the UK, including Scotland. This paper traces the emergence of the brownfi eld regeneration policy agenda across the UK and examines how the Barker review connects with this brownfi eld policy focus. The paper compares housing and brownfi eld policies and practices in England and Scotland, places them in an international context and elicits wider lessons for devolved governance in relation to housing policy, in terms of ‘centrist–local’ tensions. Estimates based on published data suggest that Barker’s emphasis on increased housing supply cannot easily be reconciled with the current emphasis on brownfi eld development and is likely to require a return to greenfield development in both countries.

The property development industry and sustainable urban brownfield regeneration in England: an analysis of case studies in Thames Gateway and Greater Manchester

The property development industry is a key actor in UK brownfield regeneration projects. UK policy has attempted to interlink ‘sustainable development’ and ‘sustainable brownfield’ policy agendas, which have found an additional focus through the UK government’s ‘Sustainable Communities Plan’, part of a growing international emphasis on sustainable development. This paper examines the emergence of these agendas and related policies, and the role of the property development industry in the regeneration of six differing brownfield sites, based in Thames Gateway and Greater Manchester. Using a conceptual framework, the paper investigates aspects of the sustainability of these projects and highlights key lessons from them for both the UK and overseas. The research is based on structured interviews with a variety of stakeholders, including developers, planners, consultants and community representatives to highlight emerging best practice and related policy implications.

Dietary quebracho tannins are not absorbed, but increase the antioxidant capacity of liver and plasma in sheep

A total of sixteen lambs were divided into two groups and fed two different diets. Of these, eight lambs were fed a control diet (C) and eight lambs were fed the C diet supplemented with quebracho tannins (C+T). The objective of the present study was to assess whether dietary quebracho tannins can improve the antioxidant capacity of lamb liver and plasma and if such improvement is due to a direct transfer of phenolic compounds or their metabolites, to the animal tissues. Feed, liver and plasma samples were purified by solid-phase extraction (SPE) and analysed by liquid chromatography–MS for phenolic compounds. Profisitinidin compounds were identified in the C+T diet. However, no phenolic compounds were found in lamb tissues. The liver and the plasma from lambs fed the C+T diet displayed a greater antioxidant capacity than tissues from lambs fed the C diet, but only when samples were not purified with SPE. Profisetinidin tannins from quebracho seem not to be degraded or absorbed in the gastrointestinal tract. However, they induced antioxidant effects in animal tissues.

Stock measurement and regeneration policy approaches to ‘hardcore’ brownfield sites: England and Japan compared

This paper discusses key contextual differences and similarities in a comparative study on brownfield regeneration in England and Japan. Over the last decade, the regeneration of large-scale ‘flagship’ projects has been a primary focus in England, and previous research has discussed policy issues and key barriers at these sites. However, further research is required to explore specific barriers associated with problematic ‘hardcore’ sites suffering from long-term dereliction due to site-specific obstacles such as contamination and fragmented ownership. In comparison with England, brownfield regeneration is a relatively new urban agenda in Japan. Japan has less experience in terms of promoting redevelopment of brownfield sites at national level and the specific issues of ‘hardcore’ sites have been under-researched. The paper reviews and highlights important issues in comparing the definitions, national policy frameworks and the current stock of brownfields.

Integrating Sustainability into Brownfield Regeneration: Rhetoric or Reality? – An Analysis of the UK Development Industry

In the UK and elsewhere the use of the term ‘sustainable brownfield regeneration’ has resulted from the interweaving of two key policy themes, comprising ‘sustainable development’ and ‘brownfield regeneration’. This paper provides a critical overview of brownfield policy within the context of the emerging sustainable development agenda in the UK, and examines the development industry's role and attitudes towards key aspects of sustainable development and brownfield regeneration. The paper analyses results from a survey of commercial and residential developers carried out in mid‐2004, underpinned by structured interviews with eleven developers in 2004–2005, which form part of a two‐and‐half‐year EPSRC‐funded project. The results suggest that despite the increasing focus on sustainability in government policy, the development industry seems ill at ease with precisely how sustainable development can be implemented in brownfield schemes. These and other findings, relating to sustainability issues (including the impact of climate change on future brownfield development), have important ramifications for brownfield regeneration policy in the UK. In particular, the research highlights the need for better metrics and benchmarks to be developed to measure ‘sustainable brownfield regeneration’. There also needs to be greater awareness and understanding of alternative clean‐up technologies to ‘dig and dump’.

An analysis of the UK development industry's role in brownfield regeneration

Purpose – This study aims to provide a review of brownfield policy and the emerging sustainable development agenda in the UK, and to examine the development industry’s (both commercial and residential) role and attitudes towards brownfield regeneration and contaminated land. Design/methodology/approach – The paper analyses results from a two-stage survey of commercial and residential developers carried out in mid-2004, underpinned by structured interviews with 11 developers. Findings – The results suggest that housebuilding on brownfield is no longer the preserve of specialists, and is now widespread throughout the industry in the UK. The redevelopment of contaminated sites for residential use could be threatened by the impact of the EU Landfill Directive. The findings also suggest that developers are not averse to developing on contaminated sites, although post-remediation stigma remains an issue. The market for warranties and insurance continues to evolve. Research limitations/implications – The survey is based on a sample which represents nearly 30 per cent of UK volume housebuilding. Although the response in the smaller developer groups was relatively under-represented, non-response bias was not found to be a significant issue. More research is needed to assess the way in which developers approach brownfield regeneration at a local level. Practical implications – The research suggests that clearer Government guidance in the UK is needed on how to integrate concepts of sustainability in brownfield development and that EU policy, which has been introduced for laudable aims, is creating tensions within the development industry. There may be an emphasis towards greenfield development in the future, as the implications of the Barker review are felt. Originality/value – This is a national survey of developers’ attitudes towards brownfield development in the UK, following the Barker Review, and highlights key issues in UK and EU policy layers. Keywords Brownfield sites, Contamination Paper type Research paper