Abstract
Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.
Highlights
The recent decades have seen concerning increases in male reproductive disorders and diseases
Multiple studies suggest that the eicosanoid pathway is expressed throughout the testes and mechanistic studies have shown substantial PG involvement in processes of germ cell development and steroidogenesis, such that when PG synthesis is disrupted with pharmacological COX inhibitors, these processes are the ones primarily affected
Laboratory-based studies reporting adverse effects such as cryptorchidism, hypospadias, and reduced anogenital distance (AGD) were corroborated by epidemiological studies of infants exposed to non-steroidal anti-inflammatory drugs (NSAIDs) and analgesic drugs in utero
Summary
The recent decades have seen concerning increases in male reproductive disorders and diseases. The first postnatal months represent a complex period during male reproductive development in which the population of spermatogonial stem cells (SSCs) is established to support lifelong spermatogenesis. Sex determination occurs on GD12.5, driven by Sry expression in male somatic cells which differentiate into fetal Sertoli cells, whose main function is to assist germ cell development and spermatogenesis. Early male germ cell development comprises phases of quiescence, proliferation, migration and differentiation (Manku and Culty 2015). Diplotene spermatocytes undergo meiosis I to form secondary haploid spermatocytes and further undergo morphological transformations from round spermatids to spermatozoa (Chen et al, 2017) Another type of cell that plays multiple roles in testis development and adaptation to its environment are the testicular macrophages, known to exert immune functions, and to modulate Leydig and germ cell functions. A greater understanding of the etiology of TDS can lead to developing interventions to rescue the SSC population (Kanatsu-Shinohara et al, 2004; Guan et al, 2006; Izadyar et al, 2008)
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