Major depressive disorder (MDD) is the leading cause of disability in the U.S. for persons ages 15-43, affecting 16.2 million adults. Furthermore, depression is comorbid with other prevalent, chronic conditions including cardiovascular disease (CVD) and obesity/metabolic syndrome (MetS). MDD alone is almost twice as prevalent in women compared to men, and women have a 62% increase in risk for comorbidities with MDD. Comorbidity of MDD with CVD is predicted to be a primary cause of disability worldwide by 2020, posing significant public health implications for women.

A Common Mechanism of Disease

MDD, CVD, and obesity/MetS have been independently linked to changes in the body’s response to stress. Stressors, including inflammation, overnutrition, and undernutrition, stimulate a route of communication that relays information from the body to the brain. The brain responds to these challenges by sending signals resulting in behavioral and physiological changes. This communication circuit is known as the hypothalamic-pituitary-adrenal (HPA) axis and a primary signal is cortisol, the most common glucocorticoid. MDD symptoms have been linked with elevated cortisol, as a result of disease (Cushing’s syndrome) or when given as glucocorticoids. MDD affects regions of the brain that are stimulated by cortisol, sex steroid hormones, and inflammatory signals. Consequently, these regions then communicate to regulate metabolism and cardiac function. Therefore, the relationship between MDD, CVD, and obesity/MetS is not surprising from a physiological perspective.

The Role of the Prenatal Environment

Studies in both humans and rats have indicated that suboptimal conditions during pregnancy, resulting in excess maternal cortisol production and inflammation, increase the risk for MDD, CVD, and obesity/MetS in offspring. Stressful prenatal conditions include a low protein diet, high salt diet, high fat diet, and malnutrition. Prenatal stressors can impact programming of the HPA axis, resulting in long-term changes into adulthood. These changes result in hyperactivity and extension of the glucocorticoid response to stress in adults.

Why are women at greater risk?

Interestingly, the same maternal stressors produce different responses in male and female offspring. This can be partly attributed to differences in the size of regions of the brain that respond to and regulate the HPA axis. These regions are implicated in regulating mood, cardiac function, and metabolism, and are abnormal in patients with MDD. Physical differences in the anatomy of the brain are a result of differences in exposure to gonadal steroid hormones, such as testosterone and estrogen, during critical periods of development. These are characterized as permanent changes. However, short-term changes can also occur with fluctuations in gonadal steroid hormones, or in response to sex-dependent differences in circulating levels of these hormones (https://doi.org/10.1113/jphysiol.2004.078212).

These findings have widespread implications in that they suggest: 1) a shared developmental origin of multiple diseases and 2) sex dependent differences in the changes underlying diseases development. Further investigation into sex differences will be critical to the treatment of MDD comorbid with CVD and obesity/MetS in both women and men.

 

 

Folic acid is a B-vitamin and is well known for its role during early neurodevelopment. It promotes the closure of the neural tube in utero. The neural tube in the developing embryo is the first step to forming the brain and spinal cord. If the neural tube does not close, it can lead to neural tube defects (NTDs), such as spina bifida. Women of child bearing age are recommended to supplement their diet with 0.4 -1 mg of folic acid daily. Additionally, to reduce the number of NTDs mandatory folic acid fortification laws were put into place in 1998 in the US and Canada, as well as other countries around the world. In response to mandatory fortification, there has been a reduction in the number of NTDs in both Canada and the US.

Recently, maternal over supplementation of folic acid has raised some concerns.  Over supplementation is defined as ingesting over 1 mg of folic acid daily. There has been an increase in over supplementation of folic acid in the US and Canada where mandatory folic acid fortification laws are in place and supplement use is high. Epidemiological studies have reported that too much folic acid has been associated with increased risk of cancer. Interestingly, too much maternal folic acid intake has been associated with autism spectrum disorder, but the data is not clear as other studies have reported protective effects. Furthermore, too much maternal folic acid has been reported to change neurodevelopment in animals.

A recent published study investigated whether too much maternal folic acid is associated with changes in the neurodevelopment of offspring. Using a mouse model of maternal over supplementation of folic acid the authors report that male offspring from mothers that were fed high levels of folic acid had impaired memory and brain development.  The amount of folic acid in the diet of mothers was 20mg/kg to model over supplementation in humans. Animals from mothers with over supplementation of folic acid did not remember seeing a familiar object as well as control animals did. Furthermore, they had reduced levels of a neurotransmitter that is important in learning and memory called acetylcholine.

These are some of the first results showing how maternal over supplementation with folic acid may affect early neurodevelopment. We recently published an up-to-date review of how maternal over supplementation of folic acid impacts offspring neurodevelopment.  Our comprehensive analysis includes studies from human populations as well as basic science studies to understand how things in the brain as well as behaviors are changing when mothers are supplementing with too much folic acid.  More studies are required to understand the full impact of how maternal over supplementation affects offspring neurological development. As someone wise once said, everything in moderation.