Male smokers might want to start worrying about the tiniest and "manliest" of the 46 chromosomes — the Y chromosome. A new study published today in Science indicates that men who smoke experience a higher number of cell mutations, which have been proven to lead to the loss of Y chromosomes, in their blood cells than men who don’t. This preliminary finding is alarming because the same group of researchers previously linked the loss of Y chromosomes in blood to shorter life expectancies in men and an increase in non-blood-related cancers.

Y loss linked to shorter life expectancies and cancer

"Male smokers are at greater risk for ‘loss of Y,’" says Lars Forsberg, a geneticist at Uppsala University and a co-author of the study. "It’s the most common human mutation," he says, "and it’s associated with cancer." To be clear: scientists don't know yet whether this increases cancer risk separately from known lung cancer issues. Researchers also don't know if it's directly responsible for lung cancer. The finding is still very early, but we know that men who smoke experience high frequencies of Y chromosome loss.

To understand this study and its implications, it’s important to remember that mammals typically posses a combination of two sex chromosomes, X and Y, that contain a number of important genes. Biologically speaking, almost all men have an X and a Y chromosome, while almost all women have two X chromosomes — though there are exceptions. This means that biological females aren’t at risk for losing Y chromosomes in their blood cells. And it also explains why the researchers only looked at this problem in the blood of men — over 6000 men, in fact.

effects on the Y chromosome only matter for people who are currently smoking

In the study, the researchers sampled blood from male participants belonging to three independent study groups, all of which were over 48 years of age. They analyzed the DNA contained in the blood samples, and that analysis led them to conclude that the smokers had a higher degree of loss of Y compared to non-smokers. And because some of these men had been tracked since 1974, the researchers were able to determine that the men did not start out with low Y chromosome counts in their blood. "At a younger age, specific men had normal blood cells with chromosome Y in all their cells," Forsberg says, "but then we followed them for up to 20 years, and we saw a progression where cell clones showed a loss of Y."

According to the researchers, the effect is dose-dependent, meaning that men who smoke more heavily appear to experience more "loss of Y." And it looks like effects on the Y chromosome only matter for people who are currently smoking. When the researchers looked at men who had stopped smoking, they didn’t see a difference between the ex-smokers and that of men who had never picked up a cigarette. This, Forsberg says, could indicate that the effect is reversible, meaning that smoking cessation can cause a decline in mutation rates in blood cells. There's a less happy possibility as well: perhaps some men who stopped smoking and experienced a loss of Y chromosomes died off faster than the rest of the men in the study. If that were the case, it's possible that the men who died at a young age might have been overlooked in today's study. But Forsberg doesn't think that's the case. "It’s a little far-fetched," he says. "I don’t believe it at all."

"That’s pretty scary."

Daniel Bellot, a geneticist at MIT who didn’t participate in the study, was both intrigued and surprised by the findings. The link between smoking tobacco and cancer is usually explained by the presence of chemicals in smoke, he says, which cause damage to DNA building blocks and errors in DNA replication. In addition, the loss of Y chromosomes is usually associated with the later stages of cancer. But if this association holds up, Bellot says, "it provides more evidence that smoking can cause cancer by a second mechanism," — one that directly affects the accuracy of cell division and cause gains and losses of whole chromosomes. That would mean that the function of "dozens to thousands of genes would be affected at once," depending on the chromosomes involved, he says. "That’s pretty scary."

"This is an important study," says Robert Benezra, a cell biologist at the Memorial Sloan Kettering Cancer Center who also didn’t participate in the study. But much like Bellot, Benezra thinks that more research needs to take place. Researchers should try to find out if the loss of Y chromosomes in smokers can explain smoking-related illnesses in men, he says.

"The loss of Y in blood isn't causing men to have reproductive problems."

From a diagnosis standpoint, it’ll be important to determine if losing Y chromosomes can be used as an early maker of disease. If that turns out to be the case, Benezra says, then the loss of Y chromosomes in blood cells "could allow for more stringent screening of smokers at critical early time points."

One of the questions that Forsberg and his team hope to answer soon is exactly which blood cells tend to lose their Y chromosomes, and which ones don’t. Blood contains many different types of cells, and the method the researchers used didn't isolate the blood samples' individual components. That means that the next step would be to sort the cells and try to identify specific cell types that lose Y chromosomes. Once that’s done, the researchers will be faced with the monster task of explaining why the loss Y chromosomes is linked to higher rates of cancer, as well as shorter life expectancies.

Still, Forsberg thinks that this study should be enough to make men rethink their smoking habits. "If you want to stay healthy and alive," he says, "quit smoking today." As for men who might be worried about what this finding means for their reproductive abilities, Forsberg is reassuring. "The loss of Y in blood isn't causing men to have reproductive problems," he says. "It will not cause that."