K Boekelheide

..In utero exposure of the fetus to a stressor can lead to disease in later life. Epigenetic mechanisms are likely mediators of later-life expression of early-life events...

..The ultimate purpose of this discussion is to help researchers and regulators understand the challenges they face in the development and integration of new and existing biomarkers to determine adverse responses...

..A filterlysis protocol was optimized to purify rat testicular homogenates for automated HRSH counts. Automated counting systems yield unbiased data and can be applied to detect changes in the testis after low-dose toxicant exposure...

..This unique model identified a role for p53 in the perinatal apoptosis of DBP-induced MNGs and provided insight into the long-term effects of gestational DBP exposure within a p53-null environment...

..Similar to an accident, predisposing "latent failures" identified within categories of the toxicant response database will be associated with the "active failure" of an adverse effect...

..Species differences exist in the testicular response to radiation, GnRH antagonist therapy, or both, so that rescue protocols that were successful in rodents might not work in primates...

..Cell proliferation and apoptosis are key processes regulating development of the testis, and alterations in these processes may underlie testicular dysgenesis...

..The different models of Sertoli cell injury indicate that spermatogenesis is susceptible to disruption, and that targeting critical Sertoli cell functions can lead to rapid and massive germ cell death...

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..The goal is to evaluate the technical and conceptual approaches used to assess 2,5-HD-induced testicular injury, to highlight unanswered questions, and to identify fruitful avenues of future research...

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..An increase in the ratio of soluble to membrane stem cell factor mRNA levels was present in aged rats and partially reversed following leuprolide therapy...

..The large number and variety of cadherin superfamily members found in testis supports a critical function for cadherin-mediated cell-cell adhesion in spermatogenesis...

..Further analysis demonstrated this staining to be associated with the Golgi complex in both germ and Sertoli cells...

..Ongoing experiments are designed to address the role of the Leydig cell in post-injury recovery, and to further characterize the molecular events contributing to the different states of persistent atrophy...

..Collectively, these data indicate that celsr cadherins have a cell type-specific expression pattern, and celsr2 may mediate Sertoli cell-germ cell adhesion outside of classic cadherin-based adhesion junctions...

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..In this review, the role of RKIP-1 in cellular signaling, and especially its functions revealed using a mouse knockout model, are discussed...

..From these data, we conclude that p120 is a component of most, if not all, desmosome-like junctions, and that desmosome-like junctions between different cell types contain a unique molecular composition...

..There was no evidence of other histopathological alterations. These data identify RSH as a sensitive histopathological marker of testicular toxicity for subacute HD exposure...

..These data show that the various testicular cell-cell junctions are molecularly unique and dynamic complexes...

..The murine S14-1 Sertoli cell line should be useful for both in vitro studies of Sertoli cell function and in vivo studies of Sertoli cell malignancy...

..Overall, these studies indicate an important role for RKIP in reproduction as a modulator of capacitation but not in the regulation of testicular injury...

..In addition, this work is fundamental to a planned investigation of the histopathologic and gene expression changes associated with testicular toxicant co-exposures, which may occur both occupationally and environmentally...

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..These results demonstrate a resistance to testicular injury conferred by the K48R mutation, suggesting that ubiquitin-mediated protein degradation is involved in the processing or modulation of testicular insults...

..Given the reduced life span and increased incidence of lymphoma in FasL -/- p53 +/- mice, these mice could be useful in carcinogenicity testing, particularly for understanding mechanisms of compounds that are nongenotoxic...

..These data indicate that, despite acting in an antiapoptotic manner in many tissue types, NF-kappaB is proapoptotic in modulating the germ cell response to ionizing radiation...

..Taken together, these data demonstrate a need for early spermatogonial expression of Cre recombinase, as an alternative to meiotic Cre expression, for the creation of germ cell-specific knockout mice...

..These results indicate that apoptosis and up-regulation of Fas following radiation are both p53-dependent events. Although Fas is necessary, in part, for radiation-induced p53-dependent apoptosis, FasL is not...

..A significant correlation (r(s) = 0.665, P < .02, n = 16) was found between testosterone levels and percent soluble SCF, which suggests that, in humans, there may be a regulatory interaction between soluble SCF and testosterone...

..In this report, we suggest a potential mechanism involving corpora luteal regression to explain this defect in parturition in FasL-/-p53-/- female mice...

..These findings will aid in ensuring proficient histopathological analysis of testes in toxicity studies...

..CONCLUSION: Study findings suggested an association between PXE and testicular microlithiasis. It is possible that the testicular microlithiasis in male subjects who have PXE is related to the underlying PXE abnormality...

..43% in controls) and striatum volume (10% decrease vs. 40% in controls). These data indicate that CP transplants might be useful for preventing the degeneration of neurons in HD...

..Together, these data indicate that Supv3L1 is important for the maintenance of the skin barrier. In addition, loss of Supv3L1 function leads to accelerated aging-like phenotypes...

..These results suggest that NF-kappaB is involved in the testicular response to MEHP-induced injury...

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..The phenotype of the sir2alpha null animals suggests that the SIR2alpha protein is essential for normal embryogenesis and for normal reproduction in both sexes...

..This response in the mouse occurs without a measurable decrease in testicular testosterone, suggesting that altered seminiferous cord formation and gonocyte multinucleation may not be mechanistically linked to lowered testosterone...

..Our data indicate that fetal Sertoli cells are targeted by exposure in utero to DBP and suggest that abnormal interactions between Sertoli and germ cells during fetal life play a role in the development of MNG...

..This project will develop a xenograft bioassay consisting of fetal testes implanted in a rodent host to directly assess human susceptibility to endocrine disrupting chemicals, including the plasticizer di-n-butyl phthalate. ..

..Together, these complimentary approaches will critically examine key steps in the pathogenetic sequence by which microtubule disrupters alter the supportive capacity of Sertoli cells resulting in loss of germ cells and infertility. ..

..Together, these complimentary approaches will elucidate the key molecular mechanisms responsible for irreversible testicular injury. ..

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..Tissue culture and immunologic techniques will be developed to allow early assessment of additional compounds which may induce testicular atrophy by Sertoli cell cytoskeletal disruption...

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..This project will develop a xenograft bioassay consisting of fetal testes implanted in a rodent host to directly assess human susceptibility to endocrine disrupting chemicals, including the plasticizer di-n-butyl phthalate. ..