Varicocele-associated human male infertility (VAI) represents greater then 20 percent of male infertility in the US. Surgical repair of varicocele restores fertility only 1/3 of time. Identification of VAI likely to benefit from surgical correction offers health cost savings. In preliminary studies, VAI patients' seminal plasma and testes biopsies contain significantly higher cadmium (Cd2+) than other infertile males, though blood levels were indistinguishable. VAI sperm lose normal sperm surface proteins binding actin, including mannose and progesterone receptors, and normal sperm head cytoskeletal structures. In vitro incubation of fertile human sperm in Cd2+ containing media replicate VAI cytoskeletal defects. Autometallographic imaging of biopsies confirmed high Cd2+ in VAI testes. Probing serial testes sections revealed decreased actin expression with differentiation stage, and increased frequency of apoptotic nuclei in VAI tubules. Sperm voltage-dependent calcium channels (VDCC) are an apparent entry point for Cd2+ VDCC isoform expression variability correlates with mannose receptor function. VAI patient partners became pregnant within three years only if surgical correction restored normal mannose receptor function. Therefore Cd2+ may be a cofactor with heat in producing VAI. In an expanded prospective study we will determine if seminal Cd2+ correlates with testicular Cd2+, and if seminal Cd2+, testicular Cd2+ and scrotal temperature are biomarkers for VAI reversal assessed by pregnancy and birth, taking one testicular biopsy and duplicate semen samples before and 3 months after correction. Intermediate endpoints for characterizing VAI will include: seminal plasma and testicular Zn2+, testicular Cd2+ and Zn2+ distributions by autometallography, sperm response to capacitating incubation (mannose receptor assay) and to acrosome-reaction induction by polvalent mannose, assessment of actin distributions, levels of apoptosis and VDCC expression. Controls will include men from couples undergoing IVF/ICSI for non-obstructive azoospermia and males with primary VAI who refuse correction. To further characterize VAI, abnormalities in intermediate endpoints among individuals (e.g. apoptosis and actin loss) will be correlated with changes in VDCC primary structure in regions afecting metal ion sensitivity, channel gating potential and Ca2+ channel blocker binding as assesed from VDCC mRNA present in mature sperm, and with changes in a region of VDCC channel precursor sensitive to mannose-induced proteolysis, assessed by Western blot of sperm membrane proteins. Controls will include fertile donors and fertile men with varicocele.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
6R01ES010496-04
Application #
6635513
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Heindel, Jerrold
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
4
Fiscal Year
2003
Total Cost
$303,360
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Benoff, Susan; Hauser, Russ; Marmar, Joel L et al. (2009) Cadmium concentrations in blood and seminal plasma: correlations with sperm number and motility in three male populations (infertility patients, artificial insemination donors, and unselected volunteers). Mol Med 15:248-62
Benoff, Susan; Marmar, Joel L; Hurley, Ian R (2009) Molecular and other predictors for infertility in patients with varicoceles. Front Biosci (Landmark Ed) 14:3641-72
Benoff, Susan; Auborn, Karen; Marmar, Joel L et al. (2008) Link between low-dose environmentally relevant cadmium exposures and asthenozoospermia in a rat model. Fertil Steril 89:e73-9
Marmar, Joel L; Agarwal, Ashok; Prabakaran, Sushil et al. (2007) Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril 88:639-48
Benoff, Susan; Chu, Charles C; Marmar, Joel L et al. (2007) Voltage-dependent calcium channels in mammalian spermatozoa revisited. Front Biosci 12:1420-49
Marmar, Joel L; Benoff, Susan (2005) The safety of ultrasonically guided testis aspiration biopsies and efficacy of use to predict varicocelectomy outcome. Hum Reprod 20:2279-88
Benoff, Susan; Goodwin, Leslie O; Millan, Colleen et al. (2005) Deletions in L-type calcium channel alpha1 subunit testicular transcripts correlate with testicular cadmium and apoptosis in infertile men with varicoceles. Fertil Steril 83:622-34
Benoff, Susan H; Millan, Colleen; Hurley, Ian R et al. (2004) Bilateral increased apoptosis and bilateral accumulation of cadmium in infertile men with left varicocele. Hum Reprod 19:616-27
Benoff, S; Gilbert, B R (2001) Varicocele and male infertility: part I. Preface. Hum Reprod Update 7:47-54