Eating for two. The placentas of pregnant mice fed a high-fat diet seem to do better if they're nourishing a female versus a male fetus.

Image courtesy of Paizlee T. Sieli

For Pregnant Mice, Eating Matters More for Their Sons

Moms-to-be think a lot about what they eat and how it might affect their growing fetus. Now, new research suggests that boys are more sensitive than girls to the diet their mother ingested while they were in utero.

Previous studies hinted that maternal diet affects the health of male and female fetuses differently. For example, Cheryl Rosenfeld, a reproductive biologist at the University of Missouri, Columbia, conducted a study in 2003 showing that expectant mouse moms who consume low-calorie diets tend to carry more females to term than males—indicating that male fetuses are the more sensitive sex in utero and miscarry at higher rates. That made Rosenfeld wonder if diet causes genes to behave differently in wombs with male or female fetuses.

To find out, Rosenfeld and her team studied pregnant mice that were divvied up into three dietary groups: very high fat, high carbohydrate/low fat, and moderate fat. About 12.5 days after conception—or about halfway through the gestational period and before the fetus starts to produce sex hormones that, like diet, can also alter gene expression, the scientists terminated the pregnancies and removed the animals' placentas.

The researchers scanned 40,000 genes in the placentas to determine whether their activity varied depending on a mom's diet. They found that 211 genes differed significantly between the low-fat and high-fat groups. The genes changed expression most often from the low-fat to the high-fat female placentas, suggesting that placentas nourishing females do a better job of responding to diet—and potentially protecting the fetus from harmful ingredients—than do those connected to males. So, in a classic double-edged sword, high-fat maternal diets appear to help male fetuses survive to term, but that same diet may expose male fetuses to harmful compounds.

As for the genes that seemed to be key: Rosenfeld's group was surprised to find genes that regulate smell and nutrient filtering (as in the kidney) in the placenta. "We thought we'd see genes related to metabolism, and we saw some of that, but what really came up were these genes that related to the ability of the placenta to smell or sense nutrient compounds," Rosenfeld says. "That's a very novel idea." Those genes were also expressed more strongly in female placentas than in male placentas. "There is clearly dialogue that's occurring between the mom and the fetus, and each sex responds differently to ... maternal diet," Rosenfeld says. The findings appear online today in the Proceedings of the National Academy of Sciences.

The idea that the placenta has more functions than previously thought doesn't surprise Jacob E. Friedman, a reproductive biologist at the University of Colorado School of Medicine in Denver. For the fetus, "it's your lung, it's your kidney, it's your gut. I guess if it expresses these olfactory genes, it's now your nose," he says. But Friedman, who also studies how obese mice affect their offspring's health, isn't ready to call the placenta sexist just yet. Males, he says, seem to lag behind females in all stages of development. Maybe those olfactory genes become more active in the male placenta as the pregnancy continues, he says. "Instead of 12.5 days, go to 19.5 and see if the differences are magnified or if the males catch up." Or, he says, maybe male fetuses' early exposure to harmful nutrients helps them adapt to a high-fat diet later in life.

Staci Bilbo, a developmental neuroscientist at Duke University in Durham, North Carolina, agrees that researchers don't know how these differences play out later in life or whether they apply to people. But what Bilbo finds so striking is that the placenta behaves differently with male and female fetuses right from the get-go, "at the moment of conception," she says.