Researchers are identifying molecules that affect Leydig cell development to better understand hormone-based therapies for men and infertility related to environmental toxicant exposure.
Leydig cells produce steroids, notably the androgens testosterone and dihydrotestosterone (DHT), important hormones involved in male fertility. Low levels of testosterone can result in male infertility. Throughout a man’s life, testosterone levels may decline as a result of aging. Low testosterone can also be seen in adolescent boys experiencing interrupted puberty (hypogonadism). Characterizing these cells may provide new insights into physiological methods to help restore testosterone production, promote healthy sexual development, provide reversible contraception, and protect a man’s fertility.
Environmental contaminants and xenoestrogens such as the phthalate diethylhexylphthalate (DEHP) and bisphenol A (BPA) are ubiquitous chemical substances that are added to plastics for increased flexibility, transparency, durability, and longevity in a wide variety of medical devices, dental sealants, food packaging, toys, and many everyday household applications. Preclinical studies in rodents indicate that DEHP may suppress the biosynthesis of testosterone in fetuses, resulting in de-masculinization. BPA is believed to disrupt the function of the endocrine system in animals and humans. Council researchers are investigating the effect of these compounds on the function of Leydig cells, the production of androgens, and ultimately on spermatogenesis (sperm production).
Earlier Council research established a basic understanding of the physiological development of Leydig cells in rats, and confirmed how the cells synthesize androgens. The effects of DEHP and BPA on the function of these cells were studied to determine whether:
- The effects of these chemicals depend on the stage of Leydig cell development at exposure;
- DEHP- and BPA-related effects that occur early in development persist into adulthood; and
- Exposure to DEHP induces Leydig cell hyperplasia (increased cell size and potentially change in steroid production)
Understanding the basic processes of reproduction—even in early stages of pre-clinical research—may provide important contributions that influence future drug development.
Researchers developed experimental methods for isolating Leydig stem cells in the testes of young rats. The goal is to isolate and treat Leydig cells in a way that increases steroid levels (steroidogenic capacity), which helps regulate sperm production. After this process is finished, the cells are transplanted back into experimentally manipulated rodent testes that are devoid of endogenous Leydig cells.
Additional research has indicated that the effects of DEHP are influenced by the stage of development at exposure, inducing changes in androgen activity and hormone levels. An analysis on the effect of BPA showed that this agent may affect reproductive activity at very low levels of exposure by suppressing pituitary and/or Leydig cell function. Consistent exposure to DEHP chemicals also:
- Increased gonadotropin stimulation, which decreased the steroid function of Leydig cells; and
- Caused abnormalities in the cell division process that supported increased cell division (mitosis) and an abnormal increase in the number of cells
Understanding the basic biology and physiology of Leydig cells provides a deeper understanding of the essential androgen support for male fertility and may reveal causes of Leydig cell dysfunction resulting in hormone-based infertility. New basic biological and physiological information will be forthcoming on stem, progenitor, and mature Leydig cells and will better inform the development of hormone-based male contraceptives and suggest new therapies for hypogonadal abnormalities. And if successful, the process of isolating and enhancing Leydig stem cells could offer a physiological method of androgen replacement as a therapeutic intervention for low testosterone. Studies are ongoing.
Understanding the effects of toxic chemicals on fertility may also identify new testicular regulators that could be investigated further for contraceptive development.