Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility

Gupta, Nishi; Sudhakar, Digumarthi V S; Gangwar, Pravin Kumar; Sankhwar, Satya Narayan; Gupta, Nalini; Chakraborty, Baidyanath; Thangaraj, Kumarasamy; Gupta, Gopal; Rajender, Singh

doi:10.1038/s41598-017-10866-1

Cited by 23 publications

(16 citation statements)

References 37 publications

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“…Biological explanations that may underlie the observed association between subfertility and PCa may be PSA dynamics, 11 local (prostate) inflammation, 12 Y chromosome genetics/epigenetics, 13 shared genetic etiology such as DNA repair, 14 environmental exposures such as endocrine disrupting chemicals, 15 among other hypotheses 16,17 …”

Section: Discussionmentioning

confidence: 99%

Fatherhood status in relation to prostate cancer risks in two large U.S.‐based prospective cohort studies

et al. 2020

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Background Despite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa. Methods We examined participants of two cohorts, the NIH‐AARP Diet and Health (NIH‐AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence. Results Fatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH‐AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH‐AARP (ptrend < 0.01), despite none of the individual categorical point estimates reaching this threshold. Conclusion This study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship.

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Section: Discussionmentioning

confidence: 99%

Fatherhood status in relation to prostate cancer risks in two large U.S.‐based prospective cohort studies

et al. 2020

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“…[ 60 ] sequenced KLK3 gene in 875 infertile and 290 fertile men and identified a total of 28 substitutions in KLK3 coding region. Of 28 KLK3 substitutions, 5 SNPs (rs266881, rs174776, rs1810020, rs266875, and rs35192866) appear to be strong risk factors for male infertility, while 1 SNP (c.206 + 235 T > C) is protective [ 60 ]. Variations in other KLKs have also been correlated with male infertility.…”

Section: Factors Affecting Semen Liquefactionmentioning

confidence: 99%

Mechanism of semen liquefaction and its potential for a novel non-hormonal contraception†

Anamthathmakula

Winuthayanon

2020

Biology of Reproduction

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Semen liquefaction is a proteolytic process where a gel-like ejaculated semen becomes watery due to the enzymatic activity of prostate-derived serine proteases in the female reproductive tract. The liquefaction process is crucial for the sperm to gain their motility and successful transport to the fertilization site in Fallopian tubes (or oviducts in animals). Hyperviscous semen or failure in liquefaction is one of the causes of male infertility. Therefore, the biochemical inhibition of serine proteases in the female reproductive tract after ejaculation is a prime target for novel contraceptive development. Herein, we will discuss protein components in the ejaculates responsible for semen liquefaction and any developments of contraceptive methods in the past that involve the liquefaction process.

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“…Liquefied semen allows sperm to travel and reach the ampulla of the oviduct for fertilization [ 12 , 16 ]. Specifically, the enzyme KLK3 is primarily responsible for the liquefaction process, as mutations in KLK3 in men are directly correlated with low sperm motility and fertility defects [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Serine protease inhibitor disrupts sperm motility leading to reduced fertility in female mice†

Barton

Rock

Willie

et al. 2020

Biology of Reproduction

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Inhibition of the sperm transport process in the female reproductive tract could lead to infertility. We previously showed that a pan-serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), blocked semen liquefaction in vivo and resulted in a drastic decrease in the number of sperm in the oviduct of female mice. In this study, we used a mouse model to test the efficacy of AEBSF as a reversible contraceptive, a sperm motility inhibitor, and a spermicide. Additionally, this study evaluated the toxicity of AEBSF on mouse vaginal tissues in vivo and human endocervical cells in vitro. We found that female mice treated with AEBSF had significantly less pups born per litter as well as fertilization rates in vivo compared to the vehicle control. We then showed that AEBSF reduced sperm motility and fertilization capability in vitro in a dose-dependent manner. Furthermore, AEBSF also exhibited spermicidal effects. Lastly, AEBSF treatment in female mice for 10 min or 3 consecutive days did not alter vaginal cell viability in vivo, similar to that of the vehicle and non-treated controls. However, AEBSF decreased cell viability of human ectocervical (ECT) cell line in vitro, suggesting that cells in the lower reproductive tract in mice and humans responded differently to AEBSF. In summary, our study showed that AEBSF can be used as a prototype compound for the further development of novel non-hormonal contraceptives for women by targeting sperm transport in the female reproductive tract.

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Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility

Cited by 23 publications

References 37 publications

Fatherhood status in relation to prostate cancer risks in two large U.S.‐based prospective cohort studies

Fatherhood status in relation to prostate cancer risks in two large U.S.‐based prospective cohort studies

Mechanism of semen liquefaction and its potential for a novel non-hormonal contraception†

Serine protease inhibitor disrupts sperm motility leading to reduced fertility in female mice†

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