Proteomic alterations underlie an association with teratozoospermia in obese mice sperm.

BACKGROUND: Obesity is a worldwide crisis impairing human health. In this condition, declines in sperm quality stem from reductions in sperm concentration, motility and increase in sperm deformity. The mechanism underlying these alterations remains largely unknown. This study, determined if obesity-associated proteomic expression patterns in mice sperm parallel those in spermatozoa obtained from obese humans. METHODS: An obese mouse model was established via feeding a high-fat diet (HFD). Histological analysis identified testicular morphology and a computer assisted semen analyzer (CASA) evaluated sperm parameters. Proteome analysis was performed using a label-free quantitative LC-MS/MS system. Western blot, immunohistochemical and immunofluorescent analyses characterized protein expression levels and localization in testis, sperm and clinical samples. RESULTS: Bodyweight gains on the HFD induced hepatic steatosis. Declines in sperm motility accompanied sperm deformity development. Differential proteomic analysis identified reduced cytoskeletal proteins, centrosome and spindle pole associated protein 1 (CSPP1) and Centrin 1 (CETN1), in sperm from obese mice. In normal weight mice, both CSPP1 and CETN1 were localized in the spermatocytes and spermatids. Their expression was appreciable in the post-acrosomal region parallel to the microtubule tracks of the manchette structure in spermatids, which affects spermatid head shaping and morphological maintenance. Moreover, CSPP1 was localized in the head-tail coupling apparatus of the mature sperm, while CETN1 expression was delimited to the post-acrosomal region within the sperm head. Importantly, sperm CSPP1 and CETN1 abundance in both the overweight and obese males decreased in comparison with that in normal weight men. CONCLUSION: These findings show that regionally distinct expression and localization of CETN1 and CSPP1 is strongly related to spermiogenesis and sperm morphology maintaining. Obesity is associated with declines in the CETN1 and CSPP1 abundance and compromise of both sperm morphology in mice and relevant clinical samples. This parallelism between altered protein expression in mice and humans suggests that these effects may contribute to poor sperm quality including increased deformity.

Do some epithelial ovarian cancers originate from a fallopian tube ciliate cell lineage?

There is a general agreement that a large subpopulation of serous ovarian cancers arise from the fallopian tube mucosal epithelium. However, there is still some debate as to whether the cancers originate from a secretory or ciliate cell lineage. One well established method for determining the origin of a cell line is to document the expression of genes and proteins that are cell type specific. Lineage or tissue specific patterns of gene expression are evidence of direct decent from a given cell type within a tissue. It has recently been established that the Tumor Protein TAp73 gene (TP73) is expressed in basal epithelial cells that develop into multiciliate cells. TP73 expression is therefore a marker for basal stem cells that are predestined to differentiate into cells with motile cilia and its expression is maintained in fully differentiated multiciliate cells. Interestingly TP73 expression has also been observed in a high percentage of epithelial ovarian cancers. With this in mind, it is hypothesized that a high percentage of epithelial ovarian cancers which express TP73 originate from a ciliate cell lineage.

Germline deletion of Cetn1 causes infertility in male mice.

Centrins are calmodulin-like Ca(2+)-binding proteins that can be found in all ciliated eukaryotic cells from yeast to mammals. Expressed in male germ cells and photoreceptors, centrin 1 (CETN1) resides in the photoreceptor transition zone and connecting cilium. To identify its function in mammals, we deleted Cetn1 by homologous recombination. Cetn1(-/-) mice were viable and showed no sign of retina degeneration suggesting that CETN1 is nonessential for photoreceptor ciliogenesis or structural maintenance. Phototransduction components localized normally to the Cetn1(-/-) photoreceptor outer segments, and loss of CETN1 had no effect on light-induced translocation of transducin to the inner segment. Although Cetn1(-/-) females and Cetn1(+/-) males had normal fertility, Cetn1(-/-) males were infertile. The Cetn1(-/-) testes size was normal, and spermatogonia as well as spermatocytes developed normally. However, spermatids lacked tails suggesting severe defects at the late maturation phase of spermiogenesis. Viable sperm cells were absent and the few surviving spermatozoa were malformed. Light and electron microscopy analyses of Cetn1(-/-) spermatids revealed failures in centriole rearrangement during basal body maturation and in the basal-body-nucleus connection. These results confirm an essential role for CETN1 in late steps of spermiogenesis and spermatid maturation.