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Susan Benoff

Publications and source records attributed to Susan Benoff.

8 recordsLinked to original sources
PubMed2007

Voltage-dependent calcium channels in mammalian spermatozoa revisited.

The last few years have seen an explosion in the number of voltage-dependent ion channel sequences detected in sperm and testes. The complex structural paradigm of these channels is now known to include a pore-forming alpha1 subunit(s) whose electrophysiological properties are modulated by an intracellular beta subunit, a disulfide-linked complex of a membrane-spanning delta subunit with an extracellular alpha2 subunit, and a transmembrane gamma subunit. Many of these are alternatively spliced. Furthermore, the known number of genes coding each subtype has expanded significantly (10 alpha1, 4 beta, 4 alpha2delta, 8 gamma). Recently, the CatSper gene family has been characterized based on similarity to the voltage-dependent calcium channel alpha1 subunit. From among this multiplicity, a wide cross-section is active in sperm, including many splice variants. For example, expression of the various alpha1 subunits appears strictly localized in discrete domains of mature sperm, and seems to control distinct physiological roles such as cellular signaling pathways. These include alpha1 alternative splicing variants that are regulated by ions passed by channels in developing sperm. Various combinations of ion channel sequence variants have been studies in research models and in a variety of human diseases, including male infertility. For example, rats that are genetically resistant to testes damage by lead seem to respond to lead ions by increasing alpha1 alternative splicing. In contrast, in varicocele-associated male infertility, the outcome from surgical correction correlates with suppression of alpha1 alternative splicing, Ion channel blockers remain attractive model contraceptive drugs because of their ability to modulate cholesterol levels. However, the large number of sperm ion channel variants shared with other cell types make ion channels less attractive targets for male contraceptive development than a few years ago. In this review, the genetics, structure and function of voltage-dependent calcium channels and related CatSper molecules will be discussed, and several practical clinical applications associated with these channels will be reported.

Alternative Splicing↗
PubMed2006

Varicoceles.

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Humans↗
PubMed2005

The safety of ultrasonically guided testis aspiration biopsies and efficacy of use to predict varicocelectomy outcome.

BACKGROUND: We hypothesized that infertile men with varicoceles have molecular/genetic defects that interact with varicoceles to induce infertility. Studies directly on testis tissue appeared to be a way to link histology, markers for molecular/genetic defects and spermatogenesis, but testis biopsies may induce morbidity. In this report, we present safety and efficacy data on ultrasonically guided, single stick, percutaneous aspiration. METHODS: Biopsies were performed on 115 infertile men with varicoceles and five men with obstructive azoospermia. Morbidity was examined by pre- and post-biopsy ultrasound, efficacy by ability of two markers to predict >50% increase in sperm density post-operatively. All patients had three pre- and three post-operative semen analyses. RESULTS: 78.3% of patients had no ultrasonic testicular defects immediately post-biopsy. By 2 months, 100% had no defects. Biopsy markers [testicular cadmium (<0.453 ng/mg tissue) and an intact calcium channel mRNA sequence] predicted >50% increase in sperm density with 82.9 and 90.5% accuracy, respectively. CONCLUSIONS: Ultrasonically controlled, percutaneous aspiration testis biopsies are safe. Specimens so acquired can assist study of molecular/genetic markers associated with spermatogenesis in infertile men with varicoceles. Tissue cadmium level, calcium channel sequence and other markers may predict outcome of varicocele surgery.

Biomarkers↗
PubMed2005

Deletions in L-type calcium channel alpha1 subunit testicular transcripts correlate with testicular cadmium and apoptosis in infertile men with varicoceles.

OBJECTIVE: To identify and understand predictors of successful varicocelectomy. DESIGN: Examination of testicular L-type voltage-dependent calcium channel (L-VDCC) mRNAs and proteins in testis biopsies and comparison of presence and absence of various mRNAs with testicular cadmium levels, with apoptosis, and with sperm count change after varicocelectomy. SETTING: University clinical urology practice and research laboratories. PATIENT(S): Infertile men with varicocele (left varicocele only, n = 18; bilateral varicoceles, n = 26) and controls (men with obstructive azoospermia undergoing testicular sperm extraction before intracytoplasmic sperm injection; n = 7). INTERVENTION(S): Left testis biopsies by percutaneous needle aspiration biopsy. Varicocele repair by subinguinal approach. MAIN OUTCOME MEASURE(S): Calcium channel mRNA sequence by reverse transcription-polymerase chain reaction and amplicon analysis; calcium channel protein distribution by immunocytochemistry; cadmium levels by atomic absorption and apoptosis by deoxynucleotidyl transferase labeling; and sperm counts in the ejaculate before and after varicocelectomy. RESULT(S): Calcium channel mRNAs are polymorphic in human testis biopsies from different men. Proteins from sequence-deleted exons 7 and/or 8 localize to germ cell membranes. Expression of undeleted L-type calcium channel mRNAs correlates with normal testes cadmium and increased sperm count after varicocelectomy. Apoptosis is lower in such cases. CONCLUSION(S): Expression of normal testicular L-VDCC sequence in exons 7-8 predicts postvaricocelectomy sperm count increase. Deletions may alter calcium channel function and affect testicular cadmium and apoptosis.

Adult↗
PubMed2003

Seminal lead concentrations negatively affect outcomes of artificial insemination.

OBJECTIVE: To determine the relationships among seminal lead levels, acrosome status, and artificial insemination cycle fecundity (AI f) in semen donors. DESIGN: Longitudinal analysis of seminal lead levels, sperm function testing, and fecundity. SETTING: University medical center andrology and research laboratories. PATIENT(S): Semen donors (n = 15) participating in a therapeutic donor insemination program. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Seminal plasma lead levels, acrosome sensitivity to progesterone (P) and voltage-gated potassium channel inhibitors (e.g., charybdotoxin [CBTx]), and AI f. RESULT(S): Seminal plasma lead levels and AI f were strongly negatively correlated. Semen donors were divided into three groups by acrosome response to P: normal (CBTx sensitive [Rs] or CBTx resistant [Rr]: responders) and reduced (nonresponders [NR]) (Rs > Rr >> NR). Seminal lead differed among the three groups (NR > Rr > Rs). Comparison of 330 artificial insemination cycles from four Rs, four Rr, and two NR demonstrated that cycle AI f also differed significantly between groups (Rs >Rr >>NR). CONCLUSION(S): Measurements of seminal plasma lead, P-stimulated acrosome loss, and sensitivity to CBTx may provide prognostic information on the fertility status of potential donors as well as male infertility patients. Such evaluations may assist in donor acceptance, or in the case of patients, in selection of the appropriate treatment regimen.

Acrosome Reaction↗
PubMed2003

Increased seminal plasma lead levels adversely affect the fertility potential of sperm in IVF.

BACKGROUND: Lead remains in high levels in the environment and is known to reduce fertility in animal models, but a direct link between lead exposures and human infertility has not yet been established. METHODS: In a prospective, double-blind study of the metal ion levels and sperm function, semen was obtained from partners of 140 consecutive women undergoing their first IVF cycle. Lead in seminal plasma was determined by atomic absorption spectroscopy. Motile sperm populations were assessed for surface receptors for mannose binding, and the ability to undergo premature ('spontaneous'), and free mannose-induced acrosome reactions. Fertile donor (n = 9) sperm were exposed to exogenous lead during capacitating incubations and then assessed for mannose receptor expression and acrosome loss. RESULTS: Lead levels were negatively correlated with IVF rates. Lead levels were negatively correlated to two of the three sperm function biomarkers (mannose receptors, mannose-induced acrosome reactions). Lead levels positively correlated with the spontaneous acrosome reaction. These findings were mimicked by in-vitro exposure of fertile donor sperm to lead. CONCLUSIONS: Multiple sperm parameters are affected as lead levels rise. Increased lead levels may contribute to the production of unexplained male infertility.

Biomarkers↗
PubMed1999

Receptors and channels regulating acrosome reactions.

Prospective clinical studies informed by cloning and sequencing of sperm surface receptors and metal ion channels have elucidated critical early steps in the acrosome reaction that explain aspects of metal ion-related male infertility. Induction of the acrosome reaction is proposed to include non-nuclear progesterone receptor activation of Shaker-related sperm head voltage-gated potassium ion channels (VGKC). Men express VGKC isoforms with differing sensitivities to lead (Pb(2+)) inhibition, thus explaining interindividual variabilities in Pb(2+)-related male infertility. VGKC opening induces calcium (Ca(2+)) transients, and a signalling cascade induced by zona receptor aggregation requires an actin cytoskeleton created by the VGKC-induced Ca(2+) transients. Actin polymerization and stabilization, favoured by zinc (Zn(2+)) and depolymerized by cadmium (Cd(2+)), may mediate low Zn(2+) and high Cd(2+) infertile states. Zona receptor aggregation induces phosphotyrosine signals at sites, including sperm voltage-dependent Ca(2+) channels (VDCC), intermediate in electrophysiology between T- and L-type channels. Sperm surface VDCC localize at the sperm equatorial segment, the terminus of zona receptor translocation. Opening of VDCC admits a second Ca(2+) wave that activates phospholipase C phosphorylated in the zona receptor cascade. Phospholipase C induces fusogenic lipids and activates actin-severing proteins, depolymerizing the actin cytoskeleton and permitting apposition and fusion of acrosomal and plasma membranes.

Journal Article↗