Male infertility, affecting 10% to 15% of couples worldwide, is a significant issue leading to the widespread use of in vitro fertilization for conceiving over 6.5 million babies. Approximately 50% of infertility is due to a male factor. Semen analysis is commonly used by specialists to assess male factor infertility, but around 25% of infertile men have normal semen parameters. To address this, we aim to develop a new, simple, and quick test (WHICH-A.R.T.) to evaluate sperm’s ability to capacitate and fertilize an oocyte. Our research focuses on membrane hyperpolarization (sperm membrane becoming more negative inside) , a mechanism controlling sperm function that is conserved across species. We have discovered that human sperm, like mouse sperm, undergo hyperpolarization during capacitation, and identified the sperm-specific K channel, SLO3, responsible for this change. Our investigations include studying the modulation of this channel, its relationship with calcium and pH changes during sperm capacitation, and the potential use of membrane potential measurements as a biomarker for male infertility. Furthermore, we are uncovering evidence suggesting that genetic variations in the Slo3 gene may impact male fertility. Ultimately, this research will enhance our understanding of sperm physiology, facilitate the development of new sperm function tests, and provide novel treatments for certain cases of male infertility.
In 2012, 85 million pregnancies (40% of all pregnancies) worldwide were unintended. In the United States, 45% of pregnancies are unintended, and 19% of all pregnancies end in abortion (926,200 abortions annually). This high rate of unintended pregnancy is due to inadequate access to, and incorrect or inconsistent use of, contraceptives. Although several effective contraceptive methods are available, concerns regarding side effects and convenience prevent their universal acceptance. Thus, we critically need to develop novel, non-hormonal contraceptives for women and men.
To address this need, and in collaborating with Drs. Jerod Denton and Alex Waterson labs at Vanderbilt University we started a project to develop inhibitors of the sperm specific K channel SLO3 as a new class of non-hormonal contraceptives. These drugs have the potential to be used for both male and female non-hormonal contraceptives.
Bacterial vaginosis (BV) is a common condition affecting approximately one-third of women in the US. It is caused by anaerobic microorganisms such as Escherichia coli, Gardnerella vaginalis, and Prevotella bivia. BV has been associated with increased infertility risk, likely due to inflammation, immune response against sperm antigens, presence of bacterial toxins, and higher susceptibility to sexually transmitted infections. Although previous studies have hinted at the influence of LPS on sperm motility, a comprehensive analysis of its effects on sperm function is still lacking.
Our current focus is to understand how bacterial endotoxins, produced by bacteria like Prevotella and E. coli, impact sperm function in the female tract, and fertility in patients with BV. We are pursuing these studies in collaboration with the labs of Amanda Lewis and Warren G. Lewis from the University of California San Diego. This project is now under the direction of the postdoc in the lab Shweta Bhagwat as her K99/R00 grant.
Proper timing of delivery is crucial for the health of both newborns and mothers, yet it often occurs at the wrong time, resulting in preterm or post-term deliveries. The transition from a non-contractile to a contractile state in the uterus is poorly understood, making it challenging to treat dysfunctional labor. Our research focuses on the SLO2.1 potassium channel and its role in uterine excitability. This channel is highly expressed in the uterus and regulated by oxytocin, a hormone involved in uterine contractility. Our recent studies in collaboration with Sarah England’s lab demonstrate the expression of SLO2.1 in human myometrial smooth muscle cells (MSMCs) and its modulation by oxytocin. Our future objectives include understanding the distribution of SLO2.1 channels in myometrial smooth muscle cells, their regulation by oxytocin and other factors, and assessing their contribution to uterine contractility. Ultimately, our research aims to bridge the gap between ion channel science and clinical interventions to reduce premature labor contractions.