Since the birth of the first “test tube baby” in 1978, more than three million children have been born with the help of reproductive technology. Most of them are healthy. But as a group they’re at a higher risk for low birth weight, which is associated with obesity, hypertension and type 2 diabetes later in life.

Carmen Sapienza, a geneticist at Temple University School of Medicine in Philadelphia, is studying two groups of children—one comprising those conceived naturally, the other made up of children conceived via assisted reproductive technology—to identify epigenetic (changes in gene expression caused by molecular mechanisms other than mutations in the DNA sequence itself) differences among them. He is particularly interested in a chromosomal modification called “DNA methylation,” research he presented February 22 at the annual meeting of the American Association for the Advancement of Science. “We found that 5 to 10 percent of these chromosome modifications were different in children born through assisted reproduction, and this altered the expression of nearby genes,” Sapienza says. Several of the genes whose expression differed between the two groups have been implicated in chronic metabolic disorders, such as obesity and type 2 diabetes.

Because we have identical DNA in each of our cells, our bodies have mechanisms, such as DNA methylation, to control which genes are expressed in certain cell types—a process called genomic imprinting. When a methyl group (a carbon atom with three hydrogen atoms attached) binds to a cytosine molecule (one of the four nucleotides that make up DNA), it tells the cell’s transcription machinery not to transcribe that gene. “It’s important, because all the same genes can’t be expressed in every cell,” Sapienza explains. “DNA methylation in the kidney is different from DNA methylation in the liver,” he says. That’s what makes each organ unique.

But the mechanism isn’t perfect: “If you look at tumors, they tend to have hypomethylation overall, but hypermethylation in some genes,” Sapienza says. “If you look in the normal population and ask what fraction of people have [a defect in methylation in the gene encoding insulin-like growth factor 2] it’s about 5 percent. But if you go to the [gastrointestinal] clinic and pick out all the people with colon cancer, well now it’s like a third.”

The first clues that assisted reproduction was causing changes in methylation and gene expression came from animal cloning studies back in 2001, Sapienza says. “They realized that in vitro fertilization resulted in large offspring syndrome [distinguished by a large, dysfunctional placenta] and heart defects,” he says. “When you use animal models and do the things that are commonly done in assisted reproduction, the answer is yes—it affects DNA methylation.”

Defects in methylation also cause the rare chromosomal disorders Angelman syndrome and Beckwith–Wiedemann syndrome—both of these complex congenital afflictions are characterized by abnormal birth weight. Their risk increases as much as fivefold with assisted reproduction—jumping from one in 15,000–20,000 to one in 4,000, Sapienza says.

Whether it’s the reproductive technology or some by-product of infertility causing the methylation defects is still unknown, but Sapienza plans to tease out the answer in future studies. “A fraction of people who have children using assisted reproductive technology were fertile prior to tubal ligation. You could compare their children to those born to infertile parents to determine whether fertility was in question. That’s the way were going try to do it,” he says. He didn’t speculate as to which is the more likely culprit, but said that many things, such as gene mutations, could cause defects in methylation that might result in infertility. “Assisted reproduction technology subverts those [defects],” he says.

Sapienza says the next step is to repeat the study looking at more genes. The present study examined nearly 800, but he would like to look at all 54,000. He also hopes to monitor these children long-term to determine whether they have higher rates of obesity or diabetes down the road. He says the goal is not to make parents worry, but rather to make people aware of their genetic predispositions and encourage them to stay on top of their health.

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