Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.This study assessed whether exposure of male rats to two estrogenic, environmental chemicals, 4-octylphenol (OP) and butyl benzyl phthalate (BBP) during gestation or during the first 21 days of postnatal life, affected testicular size or spermatogenesis in adulthood (90-95 days of age). Chemicals were administered via the drinking water or concentrations of 10-1000 micrograms/l (OP) or 1000 micrograms/l (BBP), diethylstilbestrol (DES; 100 micrograms/l) and an octylphenol polyethoxylate (OPP; 1000 micrograms/l), which is a weak estrogen or nonestrogenic in vitro, were administered as presumptive positive and negative controls, respectively. Controls received the vehicle (ethanol) in tap water. In study 1, rats were treated from days 1-22 after births in studies 2 and 3, the mothers were treated for approximately 8-9 weeks, spanning a 2-week period before mating throughout gestation and 22 days after giving birth. With the exception of DES, treatment generally had no major adverse effect or body weight: in most instances, treated animals were heavier than controls at day 22 and at days 90-95. Exposure to OP, OPP, or BBP at a concentration of 1000 micrograms/1 resulted in a small (5-13%) but significant (p < 0.01 or p < 0.0001) reduction in mean testicular size in studies 2 and 3, an effect that was still evident when testicular weight was expressed relative to body, weight or kidney weight. The effect of OPP is attributed to its metabolism in vivo to OP. DES exposure caused similar reductions in testicular size but also caused reductions in body weight, kidney weight, and litter size. Ventral prostate weight was reduced significantly in DES-treated rats and to minor extent in OP-treated rats. Comparable but more minor effects of treatment with DES or OP on testicular size were observed in study 1. None of the treatments had any adverse effect on testicular morphology or on the cross-sectional area of the lumen or seminiferous epithelium at stages VII-VIII of the spermatogenic cycle, but DES, OP, and BBP caused reductions of 10-21% (p < 0.05 to p < 0.001) in daily sperm production. Humans are exposed to phthalates, such as BBP, and to alkylphenol polyethoxylates, such as OP, but to what extent is unknown. More detailed studies are warranted to assess the possible risk to the development of the human testis from exposure to these and other environmental estrogens

Unravelling the role of mitochondrial dysfunction in core myopathies

Core myopathies are a diverse group of congenital muscle diseases, which typically present with proximal muscle weakness, hypotonia and delayed motor milestones. Biopsies from affected individuals display ‘core’ areas that lack mitochondrial staining; despite cores being a pathological hallmark for these diseases, their formation and development is not well understood. In this thesis I have explored the involvement of mitochondrial dysfunction in core myopathy pathology by studying different models with mutations of proteins involved in intracellular calcium (Ca2+) homeostasis. The first model discussed is a new mouse sub-line carrying the I4898T mutation in RYR1. RYR1 codes for a Ca2+ release channel on the sarcoplasmic reticulum (SR) called Ryanodine Receptor 1 (RyR1), and given that mitochondria localise close to the SR, a faulty RyR1 is likely to upset the Ca2+ balance that is required for mitochondrial function. In contrast to studies of other RyR1 I4898T models, I did not observe reduced SR-stimulated Ca2+ release in myotubes or myofibres isolated from the heterozygous mice. Consequently, no defects in mitochondrial localisation, respiration or biogenesis were identified. The second model discussed is fibroblasts from a patient with a mutation in STAC3, which codes for an adaptor protein that is thought to be involved in excitation-contraction coupling. While histamine-induced Ca2+ signals were elevated in the patient fibroblasts, resting mitochondrial membrane potential was reduced. As STAC3 is predominantly expressed in skeletal muscle, these results are difficult to interpret and highlight the need for a future skeletal muscle model. The final model consists of fibroblasts from individuals that have loss-offunction mutations in MICU1, which codes for a Ca2+ sensor that regulates the opening of the Mitochondrial Ca2+ Uniporter. The mitochondria in these MICU1-deficient fibroblasts are fragmented, exhibit accelerated mitochondrial Ca2+ uptake and are Ca2+ -loaded at rest. While mitochondrial membrane potential and respiration appear normal, there is evidence for a futile Ca2+ cycle across the mitochondrial membrane, which illustrates the bioenergetic cost of mitochondrial Ca2+ accumulation

Learning to laugh : children and being human in early modern thought

This essay explores the construction of the human in early modern English thought, and uses discussions of the nature and use of laughter as a distinguishing feature of humanity from classical arguments as well as early modern ones. Using these classical, reformed English discussions of education and of the nature of children reveals an anxiety about the status of the child. Laughing appropriately - using tile mind and not merely the body - is a key feature of being human, and as such, the child's lack of "true' laughter reveals that child's status to be never always-already human. "Human' is a created rather than merely a natural status

Inositol Trisphosphate Receptor Mediated Ca2+ Signalling Stimulates Mitochondrial Function and Gene Expression in Core Myopathy Patients

Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterise global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation

Services just for men? Insights from a national study of the well men services pilots.

Men continue to have a lower life expectancy in most countries compared to women. Explanations of this gendered health inequality tend to focus on male risk taking, unhealthy lifestyle choices and resistance to seeking help from health services. In the period 2005-2008 the Scottish Government funded a nationwide community health promotion programme aimed at improving men's health, called Well Men Service Pilots (henceforth WMS)

Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection

Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections

The preliminary lattice QCD calculation of κ\kappa meson decay width

We present a direct lattice QCD calculation of the $\kappa$ meson decay width with the s-wave scattering phase shift for the isospin $I=1/2$ pion-kaon ($\pi K$) system. We employ a special finite size formula, which is the extension of the Rummukainen-Gottlieb formula for the $\pi K$ system in the moving frame, to calculate the scattering phase, which indicates a resonance around $\kappa$ meson mass. Through the effective range formula, we extract the effective $\kappa \to \pi K$ coupling constant $g_{\kappa \pi K} = 4.54(76)$ GeV and decay width $\Gamma = 293 \pm 101$ MeV. Our simulations are done with the MILC gauge configurations with $N_f=2+1$ flavors of the "Asqtad" improved staggered dynamical sea quarks on a $16^3\times48$ lattice at $(m_\pi + m_K) / m_\kappa \approx 0.8$ and lattice spacing $a \approx 0.15$ fm.Comment: To make it concise. arXiv admin note: text overlap with arXiv:1110.1422, but much of v1 text overlap with articles by same and other authors remove