The current world population of 7.3 billion is expected to rise to 8.5 billion by 2030, 9.7 billion by 2050 and 11.2 billion by 2100. Thirty seven percent of world’s population resides in China and India. According to the United Nations, by 2028 India is estimated to have 1.454 billion people against 1.453 billion in China. Though India’s fertility rates have dropped from 3.6 in 1991 to 2.3 in 2013, China’s fertility rates have dropped to much lower levels. On the other hand, India is much more densely populated (382 people per sq km) than China (141 people per sq km), which puts a lot of pressure on our natural resources. Even after achieving replacement level fertility rate of 2.1, the population growth in India would be driven by the “population momentum”, which is due to increased life span of people resulting in several generations living together. On the other hand, curable sexually transmitted infections, which increase the risk of contracting viral STDs and HIV, are a major health problem in developing countries like India. Hence reversible contraceptive methods aimed at spacing childbirth and protecting against some common STDs become very important.
The search of novel targets for contraception and reproductive health by studying:
Molecular mechanisms associated with motility initiation of the sperm during ejaculation
Sperm are the most divergent cell type in the universe, which are produced in testis by spermatogenesis and possess the capability of navigating through the female reproductive tract to reach and fertilize the oocyte for production of new progeny. Spermatozoa leaving the testis and entering the epididymis areneither motile nor competent of fertilization, and they gainpotential motility and fertilizing ability while passing from the proximal to thedistal endof the epididymis through its three distinguished segments. In most mammals, includingrat and human, fully mature sperm with absolute potential to exhibit vigorous motility are held quiescent in the cauda epididymis to conserve energy. This unique arrangement holds the sperm viable for long periods of time (up to 30 days) during their stay (storage) in the epididymis and ensures a ready supply of millions of potentially motile sperm during coitus. Ejaculation marks the initiation of sperm motilityand takes place in the female reproductive tract. The mechanisms governing the crucial processes of quiescence and motility initiation remain an enigma. We have made an attempt to study some of the molecular changes associated with motility initiation of rat sperm with a view to identify novel targets for contraception.For the first time we haveevolved a simple technique to isolate viable quiescent sperm from rat cauda epididymis and have studied the various molecular, physiological and metabolic events associated with motility initiation. Our validated proof-of-concept studies have indicated the vulnerability of sperm energy metabolism, thiolnumber and ORP to designed chemical interference for contraception.
Thermal regulation of testicular spermatogenesis in mammals
Mammalian spermatogenesisoccurs at a temperature3-6°C lower than the body temperature outside the abdomen in a scrotal sac, and fails rapidly at body temperature. The molecular factors involved in the thermal regulation of sperm production are largely unknown. Limited clinical studies indicate that the thermal effects are reversible in adults and could be used for contraception. In testis, the meiotic/post-meiotic germ cell types (spermatocytes and spermatids) are most vulnerable to temperature variations. We are attempting to decipher the molecular factors controlling this phenomenon, to identify new targets/methods for contraception
Identification of common targets on sperm and some common STD pathogens like Trichomonasvaginalis that are vulnerable to designed chemical interference for prophylactic contraception
Sexually transmitted infections (STIs) and unintended pregnancies are the leading causes of morbidity and mortality among women of childbearing age. An estimated 340 million cases of curable STIs occur annually worldwide, with trichomoniasis having the highest incidence. On the other hand, of 208 million pregnancies that occurred globally in 2008, ~41% were unintended. It has been seen that the primary responsibility of pregnancy and sexually transmitted disease (STD) protection lies with the female partner during most of the heterosexual contacts. Consequently, woman-controlled, dually protective contraceptives that are safe, effective, andvirtually imperceptible are highly desirable to curb the STD/HIV epidemic. Trichomoniasis, the most-prevalent nonviral STD, predisposes women to viral STDs, including HIV. Moreover, trichomoniasis in women is also associatedwith vaginitis, endometritis, adnexitis, pyosalpinx, infertility,preterm delivery, low birth weight, bacterial vaginosis,and increased risk of cervical cancer. Antitrichomonasagents offering simultaneous pregnancy protection would havethe advantage of providing the required impetus for use compliancesince women would prefer dual-protection contraceptivesover pure microbicides. Some duallyactive molecules such as nonoxynol-9 (N-9) and cellulose sulfatefailed to provide twin protection in clinical situations plausibly due to their general, nonspecific toxicity againstsperm and cervicovaginal cells. Hence, there is a need fordesigned synthesis of potent, more specifically acting spermicidalmicrobicides for prophylactic contraception. Free thiol groups play an important role in the survival of predominantly anaerobic cells such as spermatozoa and T. vaginalis. The strongly nucleophilic character of the sulfur atom and the unique redox properties of the thiol group make it a key residue for enzyme catalysis, protein folding, and redox signaling and regulation, which are important for the cellular energy metabolism, motility, and subsistence of sperm and Trichomonas. We hypothesized that a topical agent capable of targeting free thiols would arrest both sperm and Trichomonas in semen quite specifically since free thiols are unlikely to be available elsewhere in normal vaginal environment due to the low pH.Our medicinal chemist collaborator is utilizing this target for the design and synthesis of novel anti-trichomonal spermicides.
Association of Trichomoniasis with pathogenesis of prostate cancer
Sexually Transmitted Infection/Disease (STI/STD) driven chronic inflammation has been implicated in the initiation and progression of cancer. Recent studies suggest that among the STD’s, Trichomonosis (caused by the parasite Trichomonasvaginalis)is associated with increased risk of prostate cancer, which is the most commonly diagnosed cancer and the second leading cause of cancer death among men. Elucidation of the role of T. vaginalis infection in the pathogenesis of prostate cancer is crucial sinceTrichomoniasis is globally the most-prevalent, non-viral STD. Trichomoniasis in men is not as well studied as it is in women.Furtherthe development of drug resistance in Trichomonasvaginalis against FDA-approved metronidazole is a cause of serious concern. Hence novel, preferably non-nitro imidazole anti-Trichomonalmolecules need to be discovered that can act by a distinct mechanism to counter the drug-resistance in Trichomonas. A basic-cum-applied studyon the pathogenesisand progression ofprostate cancerinduced by T. vaginalisinfection is in progress.
The epigenetic regulation of hormonal sensitivity of prostate cancer
• Design, synthesis and evaluation of novel chemical entities with sperm immobilizing (spermicidal/spermiostatic) and anti-Trichomonas (Trichomonasvaginalis causing Trichomoniasis, which is globally the most prevalent STD that increases susceptibility to HIV) agents
• Some 1-Alkyl-3,4-dibrobo-1H-pyrrole-2,5-diones are being designed for synthesis as novel dually-active spermicidal agents with trichomonicidal activity in collaboration with our Medicinal chemist collaborator Dr. VL Sharma. Two promising compounds identified earlier are under detailed evaluation for further development as vaginal, spermicidal microbicides.
• Mimicking the natural safe period of menstrual cycle for designing a novel and safe method of contraception
• The study of sperm energetics
• In a unique basic study we are trying to measure the power of sperm (joules/s or watts) required for motility and its basic energy consumption (ATP/min). By using different laws of motion in fluids an attempt is being made to derive these useful basic information for rat and human sperm.