A new paper captures the growing evidence that paternal preconception exposures can matter a lot to the health of offspring

Historically, the ways that a child’s health could be impacted by their parent was thought to be limited to early life exposures in utero. This is why pregnant women are encouraged to take prenatal vitamins, eat well and avoid substances like alcohol or tobacco that could harm fetal development.

In more recent years, however, scientists have learned that preconception exposures – those that occur before a pregnancy – can impact the epigenome of offspring.

Now, researchers from the University of Georgia has captured what we know about paternal preconception exposures, which until recently had largely been ignored.

“For a long time, maternal-fetal exposures really drove the field. The thought was that sperm gets reprogrammed at conception, so what does the guy matter? Male preconception exposures should have no bearing on offspring health,” said corresponding author Charles Easley, an associate professor of environmental health science in UGA’s College of Public Health.

“We’re starting to realize that that’s not true. In fact, a lot of alterations that can happen to the sperm epigenome can get transferred to the offspring.”

In a paper, which published in Nature Reviews Urology on January 18, Easley and his co-authors captured the growing body of evidence exploring how chemical and lifestyle exposures on sperm affect the health of offspring.

Exposures of the Father

Environmental exposures can disrupt what scientists call the sperm epigenome, which is in charge of regulating gene activity. Chemicals can alter the way that genes express in sperm, causing some genes to turn on when they should be turned off and vice versa. When this happens in a non-reproductive cell, says Easley, it can cause defects or “improper function that could then cause a disease state.”

In eggs or sperm, numerous studies have now shown that alterations to the epigenome can be passed on, making children more susceptible to certain diseases, including neurological delays.

In the paper, the researchers pointed to studies that found measurable changes in sperm DNA when exposed to DDT, Agent orange and various flame retardants. Notably, lifestyle factors such as drinking alcohol, smoking tobacco or cannabis, and dietary habits have also been linked to changes in sperm gene expression.

Collectively, these studies have given rise to a new paradigm: the paternal origins of health.

Modeling Possible Outcomes

Paternal origins of health and disease is an emerging field, says Easley, with many questions about how exposures act upon sperm in ways that alter the genome.

“There’s a lot of deliberate studies that need to be done that aren’t correlative, and that’s hard to do with human populations,” he said.

This is a direction where Easley’s own research team has made some promising headway. They have developed an in vitro spermatogenesis model, which simulates the impact of various exposures on sperm cells and allows the team to follow its impact on new sperm creation and across multiple generations.

In a 2020 study, the lab used the model to recreate the effect of a heavy exposure to a now-banned flame retardant PBB-153 on sperm and to identify mechanism that may have caused health problems for children of the men who were exposed. And in 2021, they showed that they could fertilize and make healthy embryos with the model, which provides a platform to test exposures over multiple generations in a species whose biological systems closely resemble our own.

“I would say we’ve set the stage to do those causal studies with the in vitro model,” said Easley.

The Road Ahead

The next big question is what exposures should scientists focus on? PFAS, the group of man-made chemicals that have been linked to cancer and neurodevelopment delays, are receiving a lot of attention. As are flame retardants and other forms of chemicals that leak into our waters and soil.

Beyond environmental exposures, Easley and colleagues at Oregon Health & Science University have been looking into the preconception risks of marijuana on sperm, and alcohol use could be another area of concern.

The authors note that researchers need to continue work to understand how paternal exposures translate to health outcomes in human populations when exposure to chemicals is ever-increasing.

“The transmission of the effects of widespread environmental exposures and lifestyle factors to future generations has the potential to have resounding and possibly devastating effects,” they wrote.

Katherine Greeson, who conducted her doctoral research under Easley’s mentorship is the paper’s first author. Co-authors include Krista Crowe and Clayton Edenfield, graduate students in UGA’s College of Public Health.

The paper, “Inheritance of paternal lifestyles and exposures through sperm DNA methylation,” is available online: https://www.nature.com/articles/s41585-022-00708-9.

– Lauren Baggett

Posted on February 27, 2023.