For a lucky few, ‘dioxins’ might be heart healthy

SALT LAKE CITY Dioxins and their kin are notorious poisons. They work by turning on what many biologists had long assumed was a vestigial receptor with no natural beneficial role. But it now appears that in a small proportion of people, this receptor may confer heart benefits.

The trick: You need to have the right parents. Ones from whom you’ve inherited a rare, mutant version of the receptor. Or so Lars Lind of Uppsala University in Sweden reports here, at the Society of Toxicology annual meeting.

Every cell of the body contains the aryl hydrocarbon receptor, better known as the dioxin receptor. It’s a weird evolutionary artifact, a biochemical lock whose only known keys are dioxin and a host of other drugs and chemicals that came into existence long after the lock was first fashioned. It’s an old lock, present in fish and other species that evolved long before humans. And keys for this lock usually elicit biological havoc, such as perturbed development, impaired fertility – even disease, possibly including cancer.

Lind’s interest in the Ah receptor dates back to a study that his wife, a toxicologist, was planning to conduct in female rats. “I’m a clinician and cardiologist,” Lars points out. “So I asked: ‘Why shouldn’t we look at the heart and blood pressure in these animals,’” which were going to be exposed for three months to a dioxinlike chemical, PCB-126.

It was just a whim. But it paid off. As their team reported in 2004, rats exposed to the pollutant developed a 10 millimeter mercury (mmHg) increase in blood pressure and an enlargement of their hearts. Not good changes, by any stretch. But it did indicate that the dioxin receptor might play a role in heart disease.

A few years later, an international team of researchers correlated body burdens of PCBs and dioxins with heart disease in a representative cross section of the U.S. population. And people with the highest blood concentrations of these pollutants were four to five times more likely to have cardiovascular disease than those with the lowest levels of these toxic chemicals.

Which got Lind thinking about the high blood pressure that had quickly developed in the rats that his wife had studied. Blood vessels should relax when volume builds. It’s a natural mechanism to prevent unhealthy pressure increases. So did the PCBs do something to mess with the vessels’ ability to stave off hypertension by dilating as needed?

Lars Lind and his colleagues decided to explore this question in a randomly selected group of 1,000 Swedish 70-year-olds. First, they sampled the senior citizens’ blood, looking for genetic variations in their dioxin receptor.

And the researchers turned up 20 SNPs, or single nucleotide polymorphisms, in the gene for this receptor. Each SNP represents a slightly different variant of the gene, where one of the four building blocks of DNA has been substituted by another at some particular point. (A Science News story about SNPs points out that there are an estimated 10 million locations for SNPs in the approximately 3 billion letters that make up the human genome.) Lind says the SNPs in the Swedish seniors “covered more than 90 percent of the variation in that particular gene.”

Next, his team correlated rates of hypertension among the participants with each SNP for the dioxin receptor. And six of those SNPs showed a strong link to risk of hypertension. The incidence of high blood pressure among people who inherited one especially rare SNP (known as rs17137566) was amazingly low.

The overall rate of high blood pressure within this group of Swedish seniors was 75 percent. Among those with the rare SNP for the dioxin receptor, however, the rate was just two-thirds that: 50 percent.

Then Lind’s team administered a chemical into a forearm artery in each participant. The chemical could provoke an initial clenching, and pressure increase, in the vessel. But among people who had inherited the special SNP, this challenged artery responded by quickly – and healthily – dilating. Meanwhile, a group of people with a SNP associated with the highest rate of hypertension also had the worst dilation response to the chemical challenge.

SNPs can occur many places within an individual’s DNA. Not all of those places are active, however; some don’t code for the production of a protein. And that was true here, Lind says. The SNP associated with the best vasodilation and lowest risk of hypertension occurs in an inactive stretch of DNA. As such, he says, it’s just a biomarker of some advantageous mutation in an as-yet-unidentified portion of the dioxin receptor’s gene.

What’s next? Lind plans to see how people with this and other subtly altered genetic recipes for the dioxin receptor respond to dioxinlike compounds. Not by administering these poisons, but by correlating hypertension risk with levels of the pollutants already in their blood.