You are what your mother eats…or doesn’t eat

Increasing evidence suggests that maternal nutrition has significant and long-lasting effects on fetal well-being. Now, a study led by the Research Center for Advanced Science and Technology (RCAST) at the University of Tokyo has shown that reduced caloric intake during pregnancy can result in offspring developing hypertension, or high blood pressure, later in life.

According to the study published in JCI Insight, maternal malnutrition causes prenatal exposure to high levels of glucocorticoids, a type of steroid hormone. As well as being responsible for reduced birth weight, excessive glucocorticoid exposure appears to “program” offspring for life-long struggles with metabolic conditions such as hypertension and hyperglycemia, which have potentially fatal consequences.

But how does prenatal overexposure to glucocorticoids result in permanent hypertension?

The team responsible for the study predicted that changes in gene expression caused by exposure to glucocorticoids might be behind this prenatally programmed hypertension. Changes that affect gene expression but do not cause alterations in the DNA sequence are called epigenetic factors. One of these factors, called DNA methylation, involves the binding of methyl groups to the DNA, causing permanent changes in gene expression.

“We examined whether prenatal exposure to increased glucocorticoid levels induced by a low-protein diet or glucocorticoid administration might alter DNA methylation,” says corresponding author Toshiro Fujita, Emeritus Professor at the University of Tokyo and RCAST Fellow. “We then assessed whether the subsequent permanent changes in the expression of specific genes could lead to adverse metabolic programming, resulting in postnatal salt-sensitive hypertension.”

Using a rat model, the researchers showed that the adult offspring of mothers fed a low-protein diet or administered glucocorticoid were significantly more likely to develop hypertension when fed a high-salt diet compared with offspring of mothers fed a normal diet. When they looked more closely at changes in gene expression in the different groups of rats, the research team noted that stress during pregnancy, including low-level malnutrition, resulted in decreased expression of a protein responsible for DNA methylation in the offspring. Importantly, this resulted in demethylation of a gene involved in angiotensin signaling, the hormone pathway controlling changes in blood pressure.

“Normally, methylation prevents excessive angiotensin signaling. However, glucocorticoid overexposure in utero results in permanent changes in methylation, leading to increased angiotensin signaling in the brain and the ensuing salt-induced hypertension in adult offspring,” explains Professor Fujita.

Understanding the role of epigenetic modifications in prenatal programmed hypertension sheds light on how the system could be targeted to prevent and treat this condition in the future.

Journal Article

Fumiko Kawakami-Mori, Mitsuhiro Nishimoto, Latapati Reheman, Wakako Kawarazaki, Nobuhiro Ayuzawa, Kohei Ueda, Daigoro Hirohama, Daisuke Kohno, Shigeyoshi Oba, Tatsuo Shimosawa, Takeshi Marumo, Toshiro Fujita*
Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension, JCI Insight. DOI: 10.1172/jci.insight.95625