The fathers weren't supposed to matter. But in the mid-1960s, pharmacologist Gladys Friedler was making all sorts of strange findings. She discovered that when she gave morphine to female rats, it altered the development of their future offspring — rat pups that hadn't even been conceived yet. What's more, even these rats' grandchildren seemed to have problems. In an effort to understand the unexpected result, she made a fateful decision: She would see what happened when she put male rodents on the opiate. So she shot up the rat daddies with morphine, waited a few days, and then mated them with healthy, drug-free females. Their pups, to Friedler's utter shock, were profoundly abnormal. They were underweight and chronic late bloomers, missing all their developmental landmarks. "It made no sense," she recalls today. "I didn't understand it."
For the next several decades, Friedler tried to understand this finding, ultimately assembling a strong case that morphine, alcohol and other substances could prompt male rodents to father defective offspring. There was only one problem: No one believed her. Colleagues questioned her results — her former adviser urged her to abandon the research — and she struggled to find funding and get her results published. "It didn't occur to me that you're not supposed to look at fathers' roles in birth defects," Friedler says. "I initially was not aware of the resistance. I was one of the people who was actually naïve enough to work in this field."
Over the last half-century, as scientists learned more and more about how women could safeguard their developing fetuses — skip the vodka, take your folate — few researchers even considered the possibility that men played a role in prenatal health. It would turn out to be a scientific oversight of significant proportions. A critical mass of research now demonstrates that environmental exposures — from paints to pesticides — can cause men to father children with all sorts of abnormalities. Drinking booze, smoking cigarettes, taking prescription medications and even just not eating a balanced diet can influence the health of men's future kids. In the several decades since Friedler started her work, the idea that chemicals in a man's environment can influence the health of his future children has, she says, "moved from lunatic fringe to cutting edge."
So why don't we ever hear about it?
As an andrologist, Bernard Robaire has spent his career studying the functions and dysfunctions of the male reproductive system. In the early 1980s, he was giving grand rounds at the McGill University Health Center in Montreal when an oncologist approached him with a question. The oncologist had been treating men with testicular cancer; chemotherapy and radiation were generally expected to render the patients infertile. But lo and behold, tests were showing that, even after the cancer had been licked, some of the men still had viable sperm. The patients had concerns, however: Were the sperm defective? Was it safe for them to have kids? The oncologist, surprised that reproduction was even an option for his patients, had no idea. He put the question to Robaire.
Robaire was equally stumped. He combed through the scientific literature but couldn't find a clear answer. So he decided to research the question himself. He paired up with a specialist on birth defects, and together they put together an application for a grant to study whether cancer drugs might damage sperm in ways that put men's future children at risk. They submitted their application to the Medical Research Council, Canada's equivalent of the National Institutes of Health. "And I had the absolute worst ranking on a grant I've ever had in my life," Robaire recalls today. The scientists reviewing the application rejected it outright. "This makes no sense," they had written. "How can you expect drugs given to the male to affect the progeny?"
It wasn't an unreasonable question. There was no obvious physiological mechanism that could explain the connection. It's the woman who makes her body home to a developing fetus, and damaged sperm were widely thought to be too weak to successfully fertilize an egg. The conventional wisdom, among oncologists, was that anti-cancer drugs would kill sperm, but after stopping treatment, sperm production would begin again — and the germ cells would be normal.
But that's not what Robaire found. In his early rodent studies, he discovered that chemotherapy agents could degrade the quality of sperm. These sperm were still capable of fertilizing eggs, but the embryos would often spontaneously abort themselves. Among those that actually survived to term, the rodent pups had abnormally slow development. Since then, Robaire has continued to study the effects of chemotherapy drugs on sperm in rodents and humans; some of his most recent work reveals that some men continue to manufacture damaged sperm — with abnormal numbers of chromosomes and breaks in DNA — for as long as two years after their last dose of chemo. "The chemo causes really dramatic damage," Robaire says.
While Robaire was slogging away, other scientists were quietly accumulating similar evidence. Some of the early work showed that women had more miscarriages when their male partners worked in manufacturing jobs where they were exposed to heavy metals, such as lead and mercury. Men exposed to pesticides were more likely to have children who developed leukemia. (For years, studies have linked Agent Orange, an herbicide used during the Vietnam War, to birth defects in the offspring of veterans, but a causal link has not been definitively established.) Other research suggested that men who worked with solvents, cleaning solutions, dyes and textiles, paints and other chemicals were all more likely to father kids with birth defects or childhood cancers.
Scientists also showed that it didn't require industrial-strength chemicals to wreak havoc on men's sperm. Smokers seemed to produce sperm with the wrong number of chromosomes, a DNA error that could lead to miscarriages or Down syndrome. (A stunning 2008 paper revealed that men with deficiencies in folate, that superstar maternal vitamin, had the same problem.) Paternal smoking has also been linked to childhood cancer, and even alcohol and caffeine can cause sperm abnormalities that derail child development.
We now know that what started as an inconceivable mystery — how could men's environments and lifestyles possibly affect the children they would later father? — has not just one but several answers. Certain substances interfere with the earliest phase of sperm production in the testes, prompting errors in cell division that lead to genetic mutations in immature sperm cells. Chemicals can also cause what are known as epigenetic mutations, which don't change the DNA sequence itself but alter how the body reads these genetic instructions. Essentially, an epigenetic change involves turning certain genes on or off, telling the body to pay more or less attention to the code they contain. (If genetic changes are akin to changing the lyrics of a song, epigenetic changes are like fiddling with the volume.)
Drugs can also interfere with sperm transport. A 2009 study revealed that a standard dose of paroxetine — the active drug in the antidepressant marketed as Paxil — causes a fivefold increase in the number of men who show evidence of "sperm fragmentation," which can increase the chances of miscarriage. Researchers have known that certain antidepressants can influence ejaculatory response; it turns out that they seem to slow the transportation of sperm through the male reproductive system, causing the cells to age prematurely. "Sperm are being damaged because they're not traveling properly through the body," says Peter Schlegel, who led the study and is a urologist at New York's Weill Cornell Medical College.
And these findings are just the beginning. Consider, for instance, that there are some 84,000 chemicals used in American workplaces, says Barbara Grajewski, a senior epidemiologist at the National Institute of Occupational Safety and Health. Only 4,000 of these have even been evaluated for reproductive effects in men or women, and males are particularly understudied. "There's a whole range of effects in men that really are not being given attention or are well understood," Grajewski says. "The whole area of men's reproductive health is way behind women's health."
The implications of this research deficit are huge. Some 60 percent of all birth defects today are of unknown origin; tracing even a small fraction of these back to men's environmental exposures would constitute a major public health advance.
Despite the accumulating findings, the idea that fathers can somehow contribute to birth defects has gained little traction in the public sphere. Cigarette packs have no warnings about the association between male smokers and birth defects. A woman who drinks while she's pregnant can be prosecuted, but most men have no idea that drinking in the months before conception is risky.
"Why would we not look at the paternal side of the equation? To me that's really a social and political puzzle," says Cynthia R. Daniels, a political scientist at Rutgers who studies gender and reproductive politics. "We seem to politically be in a place where we overprotect and over-warn women, but where men and fathers remain almost completely invisible. You're not likely anytime soon to see signs in bars that say, 'Men who drink should not reproduce.'"
We still assume that men are secondary partners in reproduction, that their biological contribution to a child is fleeting and ultimately less important than women's, Daniels says. What's more, both men and women can find the research threatening. After Friedler organized a scientific symposium on the paternal-fetal connection, she found herself in the elevator with two male colleagues. They turned to her and said, "Why are you picking on men?" On the other hand, when Friedler later had a fellowship at an institute for female scholars, some of the women there challenged her, demanding to know why she was spending so much time researching men. She couldn't win.
Even when the science is unambiguous, policy seems to lag. For decades, only women were banned from the lead trade, though the evidence suggested the metal could cause stillbirths and fetal problems regardless of which parent had been exposed. Today, federal occupational and health standards protect men from lead, but there are lots of regulations missing for other dangerous compounds.
Consider the well-documented hazard presented by anesthetic gases. The female partners of men who work as dentists, operating room technicians or anesthesiologists are more likely to experience miscarriages. On its website, the Occupational Safety and Health Administration has a lengthy document devoted to the hazards presented by anesthetic gases and how companies can protect their workers. But, in a prominent message at the top of the page, the agency comes straight out and says, "These guidelines are not a new standard or regulation, and they create no new legal obligations. The guidelines are advisory in nature. ..."
By law, employers are required to provide what are known as "material safety data sheets" that outline the hazards involved in any chemicals their workers might encounter. A team of researchers discovered that these sheets were 18 times more likely to mention risks to female reproduction than male reproduction. To be fair, it's harder to figure out what to do to protect men. With women, it's obvious — keep them away from these chemicals during pregnancy. But what do you do with men who are constantly making sperm and could contribute to a pregnancy at any point?
Well, we should start with a thorough review of the evidence, Daniels says, and then establish a commission to develop appropriate policy. It's also clear more research is needed — particularly research that asks the right questions. The FDA requires that new drugs be tested in rodent models for any potential effects on sperm production. But while these sorts of analyses will reveal whether a drug drastically affects sperm count, they may not show more subtle changes, says Schlegel, who conducted the study on antidepressants. Unless a chemical has "a huge and dramatic effect on sperm numbers, it often can be missed," he says.
An obvious step toward better fetal health would have obstetricians and gynecologists consider fathers' chemical exposures when trying to ensure healthy pregnancies and children. Ideally, men would be engaged even earlier, with the government issuing guidelines for young men that deal with environmental toxins and lifestyle choices that might jeopardize the health of future children. The time may be right for more engagement; many occupational health and safety guidelines, for men and women, were loosened by the Bush administration. "I think there's a great opportunity now to rebuild standards to include risks to male reproductive health," Daniels says.
There's a generational opening, too, she says. In recent years, she's noticed a change in the reaction male college students have to learning about the risks they face. "I've found, especially among young men, a sense of outrage and alarm," Daniels reports. "They say, 'How could this be? How could it be that no one has ever suggested to me that alcohol might have an impact on my ability to have healthy children?' They're angry that they don't know about this."