University of Oregon biologists have used the model organism Caenorhabditis elegans to identify molecular mechanisms that produce DNA damage in sperm and contribute to male infertility following exposure to heat.
In humans, the optimal temperature for sperm production is just below body temperature, in a range of about 90-95 degrees F. Human studies have found that exposure to temperatures as little as 1 degree C (1.8 F) above this normal range adversely affects male fertility, said Diana Libuda, a professor in the Department of Biology and Institute of Molecular Biology.
The phenomenon of heat-induced male infertility is well known, and the effects of modern exposures to heat such as hot tubs, tight clothing and excessive drive times have been extensively studied. The underlying mechanisms that damage sperm and impair fertilization are not completely understood.
“In both humans and C. elegans, relatively small increases in temperature are sufficient to reduce male fertility,” said Libuda.
An increase of 2 C (3.6 F) above normal in C. elegans, a type of roundworm, led to a 25-fold increase in DNA damage in developing sperm compared to unexposed sperm. Eggs fertilized by these damaged sperm failed to produce offspring.
This basic research discovery is detailed in a paper published online Oct. 15 in the journal Current Biology by researchers in Libuda’s UO lab. Postdoctoral researcher Nicole A. Kurhanewicz is the study’s lead author.
The study provides a roadmap for scientists to pursue studies in mammals and humans to confirm if the same mechanisms contribute to male infertility, said R. Scott Hawley, a meiosis research expert who was not involved in the research.
Hawley, a member of the National Academy of Sciences and dean emeritus of the graduate school of the Stowers Institute for Medical Research in Kansas City, Missouri, had heard about preliminary findings at an academic conference.
“I think this is a hallmark paper because it shows an environmental effect that alters specific DNA sequences and the presumably the proteins that control their activity,” Hawley said. “What Diana and Nicole’s work has done is to clearly say what goes wrong, at the level of molecules, when sperm-making is altered by heat, at least in worms.”
The paper also helps to understand how meiosis, the process that produces sex cells, differs between sperm and eggs.
Sperm, the smallest cell in a person’s body, form by the billions at temperatures below body temperature and are produced throughout the entire adult lifespan. Eggs, the largest cells in a person’s body, are formed internally, where a consistent temperature is maintained, and are produced only for a limited time during fetal development.
“We know that sperm development is very sensitive to increased temperature, while egg development is not affected,” Kurhanewicz said. “The data presented in this paper suggest that another way egg and sperm develop differently is in how tightly they control the ability of mobile DNA elements, which are also known as ‘jumping genes’ or transposons, to move in the genome, and how sensitive to heat stress those mechanisms are in preventing that movement.”
Transposons are DNA segments that move around and alter genetic information by inserting themselves in new positions. They also leave DNA damage in their wake. Movement of these “jumping genes” is normally repressed in developing sperm and eggs. However, this study found that with exposure to heat transposons are moving specifically in developing sperm.
The research team used microscopy to observe developing sperm and eggs under both normal and heat-stressed conditions. In the latter, the researchers saw higher amounts of DNA damage in sperm, but not eggs. Using next-generation genome sequencing, they also identified the locations of transposons across the whole genome with and without exposure to heat.
“We found that after heat shock, certain transposons are found in new and more variable locations in the male genome,” Kurhanewicz said.
The study, Hawley said, not only shows that a small rise in temperature affects meiotic divisions but she also identifies a mechanism — not only where the error occurs but what the error is.
“This is where it gets exciting,” he said. “If we can determine how much of a change is bad, and if you are really concerned about the environmental matters such as hot tubs or ‘boxers versus briefs’, this type molecular understanding may allow us to reframe the debate on solid scientific grounds.”
The biological ‘record’ of extremely preterm birth differs in men and women
Researchers at McMaster University have found distinct effects of adversity early in life in the genomes of men compared to women who were born extremely preterm.
The study, published online in the journal Development and Psychopathology, followed infants who weighed between 580 and 1000 grams at birth. The cohort was initiated by Saroj Saigal in the Department of Pediatrics in the late 1970’s and has been prospectively followed over four decades.
Birth size is a rough indicator of the quality of the perinatal environment, explain researchers. The fetus adapts to cope with the adverse conditions leading to small birth size, which in turn may result in long-lasting changes in the epigenome. The epigenome is the dimension of genomic control that influences gene expression and, ultimately, physiology.
The scientists studied what are known as epigenetic adaptations to early environmental stress.
Being born small and extremely preterm exposes infants to early loss of the protective environment of the womb, postnatal separation from the mother, and life-saving but invasive medical procedures in the hospital. Infant boys are especially vulnerable to these stresses, and respond differently to them than infant girls.
“Premature birth is profoundly traumatic for infants,” says Karen Mathewson, a research associate and lead author of the study, who conducted the work with Louis Schmidt, a professor in the Department of Psychology, Neuroscience & Behaviour at McMaster, and Patrick McGowan, an associate professor in the Department of Biological Sciences at the University of Toronto.
“They are simply not ready to lose the safety and protection of the womb or to be separated from the mother. Later in life, problems affecting cognition, emotion, and physical health may develop for some of them,” Mathewson says.
For the study, researchers analyzed DNA samples from cheek swabs taken from 45 adults born at extremely low birth weight (ELBW) in the early days of neonatal intensive care, and a comparison group of adults born at normal birth weight, when both groups were in their early thirties.
Mathewson and her team examined DNA methylation (DNAm) levels at 850,000 sites across the genome of each adult in the study. They found multiple sex differences in DNAm in both groups (outside the sex chromosomes), but the number was hugely exaggerated in the ELBW group at nearly 78,000 sites, versus 3,400 sites in the normal birth weight adults. There were also more than 1,350 differences between ELBW men and control men, but women showed almost no differences.
Extreme perinatal adversity appeared to elicite wide-ranging epigenetic changes in men that remained detectable years later. Not only did males born extremely preterm differ greatly from females, they differed significantly from other males.
“The changes in the DNAm profile are a biological record of the past that stretches back to development in the womb. Yet they were still evident in men decades after their exposure to extreme adversity so early in life,” says Mathewson.
The DNAm differences between ELBW men and control men were located on genes related to cellular and metabolic processes, neuron development, and interneuron communication, suggesting the possibility of altered long-term physical and mental health in males born extremely preterm.
Precisely how altered DNAm patterns may influence future health is an important follow-up question. The research team recently received additional funding to study how DNAm patterns change over time in adults born at ELBW, and whether they are linked to long-term health or age-related decline.
Exercise and nutrition regimen benefits physical, cognitive health
Researchers studied the effects of a 12-week exercise regimen on 148 active-duty Air Force airmen, half of whom also received a twice-daily nutrient beverage that included protein; the omega-3 fatty acid, DHA; lutein; phospholipids; vitamin D; B vitamins and other micronutrients; along with a muscle-promoting compound known as HMB. Both groups improved in physical and cognitive function, with added gains among those who regularly consumed the nutritional beverage, the team reports.
The findings appear in the journal Scientific Reports.