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Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review.
DeBaun MR
(2014) Expert Rev Hematol 7: 767-73
MeSH Terms: Anemia, Sickle Cell, Animals, Antisickling Agents, Humans, Hydroxyurea, Hypogonadism, Infertility, Male, Male, Spermatogenesis
Show Abstract · Added October 7, 2014
Hydroxyurea therapy, a chemotherapeutic agent, is the only US FDA approved therapy for the prevention of vaso-occlusive pain in sickle cell disease (SCD). The National Institutes of Health has sponsored two Phase III randomized, placebo-controlled trials, initially in adults, and subsequently in children with sickle cell anemia (SCA). Despite the overwhelming evidence that hydroxyurea therapy is beneficial to children and adults with SCA, individuals with SCA and their families express reservations about its use, in part because of the concerns about fertility, particularly in men. As adolescent boys with SCD are now expected to reach their reproductive years, a new concern is emerging about the role of hydroxyurea therapy as a barrier to their progeny. This review will systemically evaluate compromised fertility in men with SCD, and the evidence that hydroxyurea therapy is associated with further decreasing fertility in men with SCD.
1 Communities
1 Members
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9 MeSH Terms
Two waves of de novo methylation during mouse germ cell development.
Molaro A, Falciatori I, Hodges E, Aravin AA, Marran K, Rafii S, McCombie WR, Smith AD, Hannon GJ
(2014) Genes Dev 28: 1544-9
MeSH Terms: Animals, Cellular Reprogramming, DNA Methylation, Epigenesis, Genetic, Male, Mice, RNA, Small Interfering, Retroelements, Spermatocytes, Spermatogenesis, Transcription, Genetic
Show Abstract · Added February 15, 2016
During development, mammalian germ cells reprogram their epigenomes via a genome-wide erasure and de novo rewriting of DNA methylation marks. We know little of how methylation patterns are specifically determined. The piRNA pathway is thought to target the bulk of retrotransposon methylation. Here we show that most retrotransposon sequences are modified by default de novo methylation. However, potentially active retrotransposon copies evade this initial wave, likely mimicking features of protein-coding genes. These elements remain transcriptionally active and become targets of piRNA-mediated methylation. Thus, we posit that these two waves play essential roles in resetting germ cell epigenomes at each generation.
© 2014 Molaro et al.; Published by Cold Spring Harbor Laboratory Press.
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11 MeSH Terms
Regulation of dynein localization and centrosome positioning by Lis-1 and asunder during Drosophila spermatogenesis.
Sitaram P, Anderson MA, Jodoin JN, Lee E, Lee LA
(2012) Development 139: 2945-54
MeSH Terms: Animals, Animals, Genetically Modified, Cell Cycle Proteins, Centrosome, Drosophila Proteins, Drosophila melanogaster, Dynactin Complex, Dyneins, Humans, Male, Microtubule-Associated Proteins, Models, Biological, Phenotype, Spermatids, Spermatocytes, Spermatogenesis
Show Abstract · Added March 5, 2014
Dynein, a microtubule motor complex, plays crucial roles in cell-cycle progression in many systems. The LIS1 accessory protein directly binds dynein, although its precise role in regulating dynein remains unclear. Mutation of human LIS1 causes lissencephaly, a developmental brain disorder. To gain insight into the in vivo functions of LIS1, we characterized a male-sterile allele of the Drosophila homolog of human LIS1. We found that centrosomes do not properly detach from the cell cortex at the onset of meiosis in most Lis-1 spermatocytes; centrosomes that do break cortical associations fail to attach to the nucleus. In Lis-1 spermatids, we observed loss of attachments between the nucleus, basal body and mitochondria. The localization pattern of LIS-1 protein throughout Drosophila spermatogenesis mirrors that of dynein. We show that dynein recruitment to the nuclear surface and spindle poles is severely reduced in Lis-1 male germ cells. We propose that Lis-1 spermatogenesis phenotypes are due to loss of dynein regulation, as we observed similar phenotypes in flies null for Tctex-1, a dynein light chain. We have previously identified asunder (asun) as another regulator of dynein localization and centrosome positioning during Drosophila spermatogenesis. We now report that Lis-1 is a strong dominant enhancer of asun and that localization of LIS-1 in male germ cells is ASUN dependent. We found that Drosophila LIS-1 and ASUN colocalize and coimmunoprecipitate from transfected cells, suggesting that they function within a common complex. We present a model in which Lis-1 and asun cooperate to regulate dynein localization and centrosome positioning during Drosophila spermatogenesis.
1 Communities
2 Members
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16 MeSH Terms
Deregulated hepatic metabolism exacerbates impaired testosterone production in Mrp4-deficient mice.
Morgan JA, Cheepala SB, Wang Y, Neale G, Adachi M, Nachagari D, Leggas M, Zhao W, Boyd K, Venkataramanan R, Schuetz JD
(2012) J Biol Chem 287: 14456-66
MeSH Terms: Animals, Aryl Hydrocarbon Hydroxylases, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Cytochrome P450 Family 2, Gene Expression Regulation, Enzymologic, Humans, Leydig Cells, Liver, Male, Mice, Mice, Knockout, Multidrug Resistance-Associated Proteins, Receptors, LH, Spermatogenesis, Steroid Hydroxylases, Testosterone, Up-Regulation
Show Abstract · Added March 20, 2014
The physiological role of multidrug resistance protein 4 (Mrp4, Abcc4) in the testes is unknown. We found that Mrp4 is expressed primarily in mouse and human Leydig cells; however, there is no current evidence that Mrp4 regulates testosterone production. We investigated its role in Leydig cells, where testosterone production is regulated by cAMP, an intracellular messenger formed when the luteinizing hormone (LH) receptor is activated. Because Mrp4 regulates cAMP, we compared testosterone levels in Mrp4(-/-) and Mrp4(+/+) mice. Young Mrp4(-/-) mice had significantly impaired gametogenesis, reduced testicular testosterone, and disruption of Leydig cell cAMP homeostasis. Both young and adult mice had impaired testosterone production. In Mrp4(-/-) primary Leydig cells treated with LH, intracellular cAMP production was impaired and cAMP-response element-binding protein (CREB) phosphorylation was strongly attenuated. Notably, expression of CREB target genes that regulate testosterone biosynthesis was reduced in Mrp4(-/-) Leydig cells in vivo. Therefore, Mrp4 is required for normal Leydig cell testosterone production. However, adult Mrp4(-/-) mice are fertile, with a normal circulating testosterone concentration. The difference is that in 3-week-old Mrp4(-/-) mice, disruption of gonadal testosterone production up-regulates hepatic Cyp2b10, a known testosterone-metabolizing enzyme. Therefore, defective testicular testosterone production de-regulates hepatic Cyp-mediated testosterone metabolism to disrupt gametogenesis. These findings have important implications for understanding the side effects of therapeutics that disrupt Mrp4 function and are reported to alter androgen production.
1 Communities
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18 MeSH Terms
Preconception omega-3 fatty acid supplementation of adult male mice with a history of developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure prevents preterm birth in unexposed female partners.
McConaha ME, Ding T, Lucas JA, Arosh JA, Osteen KG, Bruner-Tran KL
(2011) Reproduction 142: 235-41
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Dietary Supplements, Environmental Pollutants, Fatty Acids, Omega-3, Female, Fish Oils, Gene Expression Regulation, Developmental, Hydroxyprostaglandin Dehydrogenases, Male, Mice, Mice, Inbred C57BL, Paternal Exposure, Placenta, Polychlorinated Dibenzodioxins, Pregnancy, Pregnancy Proteins, Premature Birth, RNA, Messenger, Receptors, Progesterone, Spermatogenesis, Toll-Like Receptor 4
Show Abstract · Added May 29, 2014
We have recently reported that adult male C57BL/6 mice exposed in utero to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) confer an increased risk of preterm birth (PTB) to unexposed females. Risk of PTB was coincident with decreased placental progesterone receptor (Pgr) mRNA expression and increased toll-like receptor 4 (Tlr4) mRNA expression, suggesting that toxicant exposure induced a heightened inflammatory response at the maternal-fetal interface. Since omega-3 fatty acids exhibit anti-inflammatory activity, in this study, we provided TCDD-exposed males a fish oil-enriched diet prior to mating. Although PTB was common in control females mated to TCDD-exposed males on the standard diet, fish oil supplementation of TCDD-exposed males eliminated PTB in unexposed partners. We also determined the influence of preconception, paternal fish oil supplementation on the placental inflammatory response in late pregnancy (E18.5) by examining the expression of Pgr and Tlr4 mRNA as well as the expression of 15-hydroxyprostaglandin dehydrogenase (PGDH). PGDH catabolizes the inflammatory PGE2 to an inactive form; thus, reduced expression of this enzyme would promote tissue inflammation. Compared with control pregnancies, examination of E18.5 placentas arising from TCDD-exposed males on the standard diet revealed a significant increase in Tlr4 mRNA expression corresponding to a reduction in Pgr mRNA and PGDH protein expression. In contrast, fish oil supplementation of toxicant-exposed males led to normalization of placental expression of both Pgr and Tlr4 mRNA and a marked increase in PGDH expression. These studies suggest that a paternal preconception diet that includes omega-3 fatty acids prevents the toxicant-associated increase in the placental inflammatory response at late gestation, preventing PTB.
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22 MeSH Terms
Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.
Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai AC, Nair KS, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SW, Maas RL
(2011) Science 331: 1571-6
MeSH Terms: Animals, Cataract, Cell Line, Chick Embryo, Crystallins, Cytoplasmic Granules, Embryonic Development, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Glaucoma, Humans, Hypospadias, Lens, Crystalline, Male, Mice, Mutation, Organogenesis, Protein Biosynthesis, RNA, Messenger, RNA-Binding Proteins, Ribonucleoproteins, Spermatogenesis
Show Abstract · Added February 15, 2016
The precise transcriptional regulation of gene expression is essential for vertebrate development, but the role of posttranscriptional regulatory mechanisms is less clear. Cytoplasmic RNA granules (RGs) function in the posttranscriptional control of gene expression, but the extent of RG involvement in organogenesis is unknown. We describe two human cases of pediatric cataract with loss-of-function mutations in TDRD7 and demonstrate that Tdrd7 nullizygosity in mouse causes cataracts, as well as glaucoma and an arrest in spermatogenesis. TDRD7 is a Tudor domain RNA binding protein that is expressed in lens fiber cells in distinct TDRD7-RGs that interact with STAU1-ribonucleoproteins (RNPs). TDRD7 coimmunoprecipitates with specific lens messenger RNAs (mRNAs) and is required for the posttranscriptional control of mRNAs that are critical to normal lens development and to RG function. These findings demonstrate a role for RGs in vertebrate organogenesis.
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23 MeSH Terms
A novel predicted bromodomain-related protein affects coordination between meiosis and spermiogenesis in Drosophila and is required for male meiotic cytokinesis.
Bergner LM, Hickman FE, Wood KH, Wakeman CM, Stone HH, Campbell TJ, Lightcap SB, Favors SM, Aldridge AC, Hales KG
(2010) DNA Cell Biol 29: 487-98
MeSH Terms: Amino Acid Sequence, Animals, Chromosomal Proteins, Non-Histone, Cloning, Molecular, Conserved Sequence, Cytokinesis, Drosophila Proteins, Drosophila melanogaster, Female, Genes, Insect, Infertility, Male, Insect Proteins, Male, Meiosis, Mitochondria, Molecular Sequence Data, Mutation, Protein Structure, Tertiary, Spermatogenesis, Testis
Show Abstract · Added August 14, 2014
Temporal coordination of meiosis with spermatid morphogenesis is crucial for successful generation of mature sperm cells. We identified a recessive male sterile Drosophila melanogaster mutant, mitoshell, in which events of spermatid morphogenesis are initiated too early, before meiotic onset. Premature mitochondrial aggregation and fusion lead to an aberrant mitochondrial shell around premeiotic nuclei. Despite successful meiotic karyokinesis, improper mitochondrial localization in mitoshell testes is associated with defective astral central spindles and a lack of contractile rings, leading to meiotic cytokinesis failure. We mapped and cloned the mitoshell gene and found that it encodes a novel protein with a bromodomain-related region. It is conserved in some insect lineages. Bromodomains typically bind to histone acetyl-lysine residues and therefore are often associated with chromatin. The Mitoshell bromodomain-related region is predicted to have an alpha helical structure similar to that of bromodomains, but not all the crucial residues in the ligand-binding loops are conserved. We speculate that Mitoshell may participate in transcriptional regulation of spermatogenesis-specific genes, though perhaps with different ligand specificity compared to traditional bromodomains.
0 Communities
1 Members
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20 MeSH Terms
Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P.
Coffee RL, Tessier CR, Woodruff EA, Broadie K
(2010) Dis Model Mech 3: 471-85
MeSH Terms: Animals, Animals, Genetically Modified, Brain, Conserved Sequence, Drosophila Proteins, Drosophila melanogaster, Evolution, Molecular, Fertility, Fragile X Mental Retardation Protein, Humans, Male, Mutation, Nerve Net, Neuromuscular Junction, Neurons, RNA-Binding Proteins, Spermatogenesis, Synapses, Testis
Show Abstract · Added March 29, 2017
Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.
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19 MeSH Terms
Asunder is a critical regulator of dynein-dynactin localization during Drosophila spermatogenesis.
Anderson MA, Jodoin JN, Lee E, Hales KG, Hays TS, Lee LA
(2009) Mol Biol Cell 20: 2709-21
MeSH Terms: Animals, Animals, Genetically Modified, Cell Cycle Proteins, Cell Nucleus, Chromosome Segregation, Drosophila Proteins, Drosophila melanogaster, Dynactin Complex, Dyneins, Fertility, Green Fluorescent Proteins, HeLa Cells, Humans, Immunoblotting, Infertility, Male, Male, Meiosis, Microscopy, Fluorescence, Microtubule-Associated Proteins, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Spermatids, Spermatocytes, Spermatogenesis, Spindle Apparatus, Transfection
Show Abstract · Added March 5, 2014
Spermatogenesis uses mitotic and meiotic cell cycles coordinated with growth and differentiation programs to generate functional sperm. Our analysis of a Drosophila mutant has revealed that asunder (asun), which encodes a conserved protein, is an essential regulator of spermatogenesis. asun spermatocytes arrest during prophase of meiosis I. Strikingly, arrested spermatocytes contain free centrosomes that fail to stably associate with the nucleus. Spermatocytes that overcome arrest exhibit severe defects in meiotic spindle assembly, chromosome segregation, and cytokinesis. Furthermore, the centriole-derived basal body is detached from the nucleus in asun postmeiotic spermatids, resulting in abnormalities later in spermatogenesis. We find that asun spermatocytes and spermatids exhibit drastic reduction of perinuclear dynein-dynactin, a microtubule motor complex. We propose a model in which asun coordinates spermatogenesis by promoting dynein-dynactin recruitment to the nuclear surface, a poorly understood process required for nucleus-centrosome coupling at M phase entry and fidelity of meiotic divisions.
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2 Members
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26 MeSH Terms
Comprehensive analysis of reproductive ADAMs: relationship of ADAM4 and ADAM6 with an ADAM complex required for fertilization in mice.
Han C, Choi E, Park I, Lee B, Jin S, Kim DH, Nishimura H, Cho C
(2009) Biol Reprod 80: 1001-8
MeSH Terms: ADAM Proteins, Animals, Antibody Specificity, Female, Fertilins, Fertilization, Immunohistochemistry, Male, Membrane Glycoproteins, Mice, Mice, Inbred ICR, Mice, Knockout, Multiprotein Complexes, Protein Processing, Post-Translational, Sperm Maturation, Spermatogenesis, Spermatozoa, Testis
Show Abstract · Added April 7, 2010
A Disintegrin And Metalloprotease (ADAM) family members expressed in male reproductive tissues are divided phylogenetically into three major groups. In the present study, we analyzed six ADAMs in one of the groups (ADAMs 4, 6, 24, 26, 29, and 30) of which function is largely unknown. Our results showed that most of the ADAMs undergo unique processing during sperm maturation and are located at the surface of sperm head. We found that the levels of ADAM4 and ADAM6 are dramatically reduced in Adam2 and Adam3 knockout sperm defective in various fertilization processes. We observed premature processing of ADAM4 in the Adam3-null mice. Furthermore, we obtained a result showing complex formation of ADAM6 with ADAM2 and ADAM3 in testis. Taken together, these results disclose involvement of ADAM4 and ADAM6 in a reproductive ADAM system that functions in fertilization.
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18 MeSH Terms