Looking Inside Sperm to Find the Key to Male Fertility
In the history of fertility science, the focus has largely taken a divide and conquer approach to studying human reproduction. Scientists have studied women’s anatomy and reproductive cells, and they’ve studied men’s anatomy and reproductive cells. But that only leads to an incomplete picture, since sperm are also the only type of human cell required to function and thrive in a foreign (female) environment.
“We understand almost nothing about sperm function, what sperm do,” said biologist Scott Pitnick in a recent interview with the Smithsonian.
Pitnick has been working to change that through his experiments that follow fruit fly sperm (dyed a glowing red or green for easy identification in scans) as the male cells navigate female fruit flies’ reproductive tracts. His research is part of a growing body of investigation into the whats, hows and whys of sperm — a critical study, given that sperm concentration in semen has fallen by 52% since the 70s among men in the West.
Last month, researchers at the Cincinnati Children’s Hospital Medical Center reported in the journal Genes & Development that they had identified a protein linked to infertility in male mice, a protein that suppresses fertility during childhood, until the physiological changes of maturity ‘activate’ it during puberty — except in some men, it may never activate, the team posited. Researchers still need to find out precisely how or why the protein, PRC1, changes its role from sperm suppressor to activator, raising questions about how lifestyle or other environmental factors might affect a male’s reproductive capabilities through epigenetics — that is, how environmental factors can turn genes on or off in the body, said Satoshi Namekawa, PhD, the study’s lead investigator and member of the Division of Reproductive Sciences in the Cincinnati Children’s Perinatal Institute.
Which research by environmental health scientist Richard Pilsner at the University of Massachusetts Amherst might help answer. Pilsner’s findings, released around the same time as Namekawa’s, suggest phthalate levels in expectant fathers cause epigenetic modifications to sperm DNA that affect fertility.
Phthalates are compounds found in plastics and personal care products such as shaving cream, and are estimated to be detectable in nearly 100 percent of the U.S. population. Exposure is known to disrupt some hormones and is associated in human studies with changes in such male reproductive measures as semen quality and androgen levels, Pilsner said.
To understand how and to what degree, Pilsner’s team took sperm and urine samples from 48 men (admittedly, a very small sample size) whose partners were undergoing IVF treatment. They measured phthalate levels in the urine, then analyzed the sperm DNA for associated genetic changes called methylation — that is, whether certain genes are active or inactive. They found in the sperm 131 genetic regions, many of which contained genes involved in growth and development and cellular function and maintenance, that correlated to phthalate exposure.
The authors were also interested to see if these phthalate-associated changes in sperm’s gene activation/inactivation could affect early-life development. They found that some of the affected genetic regions were also associated with poor early embryo quality, as defined by the IVF clinic’s standards for transferring viable embryos into the uterus of the female partner.
Pilsner and team stress that these early results represent a small sample; it is unclear whether the phthalate-related changes to sperm’s genetic code persist throughout prenatal and postnatal development, or are inherited. They’re now working to replicate these findings and identify a more exact phthalate dosage associated with genetic changes to sperm. But the research above, as well as research by others, all adds one more piece to the puzzle of male fertility and infertility — and levels the field of responsibility for pregnancy and what comes after. Progress on a male equivalent to The Pill has languished due to societal attitudes, of course, but the difference between male and female reproductive hormones also makes the direct translation of oral contraceptives for men untenable. And while hormonal injections have been proven effective for men, they also come with a host of side effects. Which means researchers are increasingly looking toward ways to inhibit the sperm cell itself.
“We need to really understand what makes up a sperm,” said Daniel Johnston, chief of the Contraception Research Branch at the National Institutes of Health in the US, for the same Smithsonian article as Pitnick’s interview. Johnston’s research focuses on decoding the full protein contents of sperm, which the article describes as the “first step” in developing effective male contraceptives. “When you understand that, you can potentially start understanding what we need to inhibit,” he said.