Hypospadias and endocrine disruption: is there a connection?

Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 250 newborns or roughly 1 in 125 live male births. It is the result of arrested development of the urethra, foreskin, and ventral surface of the penis where the urethral opening may be anywhere along the shaft, within the scrotum, or in the perineum. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias, the majority of which have been classified as idiopathic. In this paper we briefly describe the normal development of the male external genitalia and review the prevalence, etiology, risk factors, and epidemiology of hypospadias. The majority of hypospadias are believed to have a multifactorial etiology, although a small percentage do result from single gene mutations. Recent findings suggest that some hypospadias could be the result of disrupted gene expression. Discoveries about the antiandrogenic mechanisms of action of some contemporary-use chemicals have provided new knowledge about the organization and development of the urogenital system and may provide additional insight into the etiology of hypospadias and direction for prevention

PCBs Exert an Estrogenic Effect through Repression of the Wnt7a Signaling Pathway in the Female Reproductive Tract

Polychlorinated biphenyls (PCBs) have been proposed to have a weak estrogenic activity and therefore pose a risk as potential environmental endocrine disruptors to the perinatal development of the female reproductive tract. Perinatal exposure to high concentrations of the potent synthetic estrogen diethylstilbestrol (DES) induces abnormal development of the female reproductive tract via a mechanism that acts through the down-regulation of Wnt7a (wingless-type MMTV integration site family, member 7A). To test the hypothesis that PCBs act as weak estrogens, we injected neonatal mice with a commercial PCB mixture (Aroclor 1254) or with low levels of DES and measured effects of exposure on Wnt7a expression and uterine morphology. We report here that neonatal PCB or low-level DES exposure resulted in the down-regulation of Wnt7a expression. In addition, both PCB and low-level DES exposure induced changes in the uterine myometrium and gland formation. These data reveal that weak estrogens such as the PCBs act through a Wnt7a-dependent pathway and suggest that Wnt7a regulation is a sensitive biomarker for testing weak estrogenic candidate compounds. The morphologic changes that were elicited by PCBs and DES were different immediately after exposure, suggesting that Wnt7a-independent pathways are also activated by one or both of these compounds. Although Wnt7a down-regulation is transient after estrogenic exposure, subsequent morphologic changes became more pronounced during postnatal and adult life, suggesting that the female reproductive tract is permanently reprogrammed after exposure even to weak estrogenic compounds. In addition, Wnt7a heterozygous mice were more sensitive to PCB exposure, revealing an important genetic predisposition to risks of environmental endocrine disruptors

Enhanced high-dispersion coronagraphy with KPIC phase II: design, assembly and status of sub-modules

The Keck Planet Imager and Characterizer (KPIC) is a purpose-built instrument for high-dispersion coronagraphy in the K and L bands on Keck. This instrument will provide the first high resolution (R>30,000) spectra of known directly imaged exoplanets and low-mass brown dwarf companions visible in the northern hemisphere. KPIC is developed in phases. Phase I is currently at Keck in the early operations stage, and the phase II upgrade will deploy in late 2021. The goal of phase II is to maximize the throughput for planet light and minimize the stellar leakage, hence reducing the exposure time needed to acquire spectra with a given signal-to- noise ratio. To achieve this, KPIC phase II exploits several innovative technologies that have not been combined this way before. These include a 1000-element deformable mirror for wavefront correction and speckle control, a set of lossless beam shaping optics to maximize coupling into the fiber, a pupil apodizer to suppress unwanted starlight, a pupil plane vortex mask to enable the acquisition of spectra at and within the diffraction limit, and an atmospheric dispersion compensator. These modules, when combined with the active fiber injection unit present in phase I, will make for a highly efficient exoplanet characterization platform. In this paper, we will present the final design of the optics and opto-mechanics and highlight some innovative solutions we implemented to facilitate all the new capabilities. We will provide an overview of the assembly and laboratory testing of the sub-modules and some of the results. Finally, we will outline the deployment timeline

Testosterone metabolism in Neomysis integer following exposure to benzo(a)pyrene

Author Posting. © Elsevier B.V., 2006. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 144 (2006): 405-412, doi:10.1016/j.cbpb.2006.04.001.Cytochromes P450 (CYPs) are important enzymes involved in the regulation of hormone synthesis and in the detoxification and/or activation of xenobiotics. CYPs are found in virtually all organisms, from archae, and eubacteria to eukaryota. A number of endocrine disruptors are suspected of exerting their effects through disruption of normal CYP function. Consequently, alterations in steroid hormone metabolism through changes in CYP could provide an important tool to evaluate potential effects of endocrine disruptors. The aim of this study was to investigate the potential effects of the known CYP modulator, benzo(a)pyrene (B(a)P), on the testosterone metabolism in the invertebrate Neomysis integer (Crustacea; Mysidacea). N. integer were exposed for 96h to 0.43, 2.39, 28.83, 339.00 and 1682.86μg B(a)P L-1 and a solventcontrol, and subsequently their ability to metabolize testosterone was assessed. Identification and quantification of the produced phase I and phase II testosterone metabolites was performed using liquid chromatography coupled with multiple mass spectrometry (LC-MS2). Significant changes were observed in the overall ability of N. integer to metabolize testosterone when exposed to 2.39, 28.83, 339.00 and 1682.86μg B(a)P L-1 as compared to the control animals.This research was supported by a research grant of the Ghent University Research Fund (BOF, 011.072.02). Dr. Tim Verslycke was supported by a Postdoctoral Fellowship of the Belgian American Educational Foundation

Human cerebral malaria and Plasmodium falciparum genotypes in Malawi

<p>Abstract</p> <p>Background</p> <p>Cerebral malaria, a severe form of <it>Plasmodium falciparum </it>infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype.</p> <p>Methods</p> <p>The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria.</p> <p>Results</p> <p>Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients.</p> <p>Conclusions</p> <p>Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.</p

Status of the Keck Planet Imager and Characterizer phase II development

The Keck Planet Imager and Characterizer comprises of a series of upgrades to the Keck II adaptive optics system and instrument suite to improve the direct imaging and high resolution spectroscopy capabilities of the facility instruments NIRC2 and NIRSPEC, respectively. Phase I of KPIC includes a NIR pyramid wavefront sensor and a Fiber Injection Unit (FIU) to feed NIRSPEC with a single mode fiber, which have already been installed and are currently undergoing commissioning. KPIC will enable High Dispersion Coronagraphy (HDC) of directly imaged exoplanets for the first time, providing potentially improved detection significance and spectral characterization capabilities compared to direct imaging. In favorable cases, Doppler imaging, spin measurements, and molecule mapping are also possible. This science goal drives the development of phase II of KPIC, which is scheduled to be deployed in early 2020. Phase II optimizes the system throughput and contrast using a variety of additional submodules, including a 952 element deformable mirror, phase induced amplitude apodization lenses, an atmospheric dispersion compensator, multiple coronagraphs, a Zernike wavefront sensor, and multiple science ports. A testbed is being built in the Exoplanet Technology Lab at Caltech to characterize and test the design of each of these submodules before KPIC phase II is deployed to Keck. This paper presents an overview of the design of phase II and report on results from laboratory testing