Generational Epigenetics: How Nutrition and Environment Shape Lifelong Brain Development

Figure 1. Overview of epigenetic mechanisms. ‘Epigenetics’ literally means ‘above DNA.’ It refers to processes that modify gene expression without altering the underlying DNA sequence. These changes can be passed on during cell division (mitotically inheritable). Key epigenetic mechanisms: (1) DNA methylation – Involves the addition of methyl groups to cytosine nucleotides near gene start sites. Often leads to the repression of gene transcription. (2) Histone modification – Histones (H2A, H2B, H3, H4) are proteins around which DNA is wound. Modifications like acetylation, methylation, and phosphorylation affect how tightly DNA is wound around histones, influencing gene accessibility and expression. (3) RNA-based mechanisms – Involve non-coding RNA molecules, such as microRNAs and long non-coding RNAs. These RNAs can regulate gene expression post-transcriptionally by degrading mRNA or inhibiting its translation. These epigenetic modifications are essential for regulating gene expression and maintaining cellular identity, allowing organisms to adapt to changing environments without altering their genetic code.

Our genes, the blueprint of our biological makeup, are not fixed in their function. Instead, they can be influenced by external factors like diet and environment through a process known as epigenetics. This means that what we eat, and our surroundings can cause chemical changes in our DNA, affecting how our genes work without altering the underlying sequence.

Nutrition plays a crucial role in this process. Essential nutrients like folate and choline provide the necessary components for DNA methylation, a key mechanism in gene regulation (see Figure 1). A diet lacking these nutrients, especially during pregnancy, can lead to significant and lasting changes in gene expression, impacting a child’s development and health.

Environmental influences, such as maternal care and prenatal exposure to substances like alcohol, can also cause epigenetic changes. These changes can affect brain development and behavior and can be passed down to future generations. For instance, the amount of care a mother rat provides to her pups can alter their stress response and caregiving behaviors through epigenetic modifications.

Understanding the connection between diet, environment, and epigenetics highlights the importance of a healthy lifestyle and supportive environment, especially during critical developmental periods. These factors together shape our health and well-being, not just for ourselves but for generations to come. (Cf. previous blogs entitled as: “Developmental Origins of Health and Disease: Epigenetics, Nutrition, and Infant Health.” and “Brain Plasticity – III: Fueling Brain Growth – The Vital Role of Nutrition During Sensitive Periods of Learning.”)

The epigenetics of nutrition – Our diets influence our epigenetic states because the methyl groups that methylate our DNA come from food. The key molecule in DNA methylation, s-adenosylmethionine (SAM), gets most of its methyl groups from vitamins B2, B6, B9 (folic acid and folate), B12, and choline. Therefore, a diet lacking or abundant in these nutrients can alter the supply of methyl groups (see Figure 1 and 2; Box-1) [1].

Box-1. S-Adenosylmethionine (SAM) and its significance in epigenetics and nutrition.

These nutrients provide the raw materials necessary for various biological processes, which is why cereals are often fortified with them. For instance, folic acid is vital for fetal development, and doctors advise women who might become pregnant to take folic acid supplements and consume folate-rich foods like eggs, asparagus, liver, and dark leafy greens. A lack of folic acid around conception increases the risk of major congenital abnormalities. Similarly, choline, found in eggs, meats, wheat germ, cauliflower, and milk, is crucial for fetal development and SAM production. Insufficient choline or folate results in low SAM levels, leading to reduced methylation of DNA and histones.

An early study on the effects of maternal diet on offspring’s epigenetics involved feeding pregnant rats a normal diet, a protein-restricted diet, or a protein-restricted diet supplemented with folic acid. The offspring of mothers on the protein-restricted diet had less DNA methylation compared to those of normally fed mothers. Supplementing the diet with folic acid prevented this effect, maintaining normal DNA methylation levels.

Subtle dietary changes during pregnancy can significantly impact offspring. UK scientists fed sheep a methyl-deficient diet for eight weeks before conception and the first week of pregnancy. The offspring, after being transferred to surrogate mothers with complete diets, were fatter, insulin-resistant, and hypertensive as adults [2]. Examination of their fetal DNA revealed altered methylation patterns due to the methyl-deficient diet.

This research suggests that our body compositions may partly result from our mothers’ diets before and during pregnancy. Early nutritional experiences have epigenetic effects seen in humans, rats, and sheep. For instance, a study found that the methylation status of specific DNA segments accounted for about half of the variation in body compositions among nine-year-old children.

Altering choline intake during pregnancy also has long-term effects on offspring’s behavior and neurological traits. Pregnant rats on choline-supplemented diets have offspring with better spatial memory, while choline-deficient diets impair memory performance. These dietary manipulations affect prenatal hippocampus development, influencing learning and memory [3].

Given that a choline-deficient diet reduces access to SAM and alters DNA methylation globally and specifically, it is possible that long-term effects of prenatal nutrition on learning, memory, and body mass result from changes in DNA methylation [5].

Epigenetic mechanisms and sensitive periods – Recent discoveries in developmental genetics reveal that environmental factors can influence gene function across lifespans and even generations, a phenomenon known as epigenetic changes. These changes, or ‘marks,’ are chemical modifications to chromosomes that do not alter the DNA sequence but can significantly impact development and function.

One type of epigenetic mark involves the methylation of cytosine nucleotides near gene start sites, which represses transcription. Other marks include modifications to histone proteins, which can make nearby genes more or less likely to be transcribed (see Figure 1).

A notable example is the role of folate (vitamin B9) in metabolism (see Figure 2). Folate deficiency during pregnancy increases the risk of neural tube defects like spina bifida. The enzyme methionine synthase reductase (MTRR) is essential for folate metabolism. Embryos in the wombs of MTRR mutant mothers exhibit epigenetic defects in DNA methylation, leading to a high incidence of spina bifida. Wild-type embryos transferred to these mutant mothers show epigenetic effects that persist through generations, creating less favorable uterine environments [4].

Figure 2. DNA methylation and demethylation cycle. DNA methylation involves the addition of a methyl group (CH₃) from the universal donor S-adenosylmethionine (SAM) to the fifth carbon of cytosine (C), facilitated by DNA methyltransferase (DNMT), resulting in 5-methylcytosine (5-mC). This process produces S-adenosylhomocysteine (SAH) as a byproduct. DNA demethylation occurs through passive or active processes: (1) Passive demethylation – Happens over successive cell divisions without the addition of new methyl groups. (2) Active demethylation – Involves the sequential conversion of 5-mC to 5-hydroxymethylcytosine (5-hmC), then to derivatives like 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), ultimately returning to cytosine (C). This process is regulated by the ten-eleven translocation (TET) family of proteins. The combined actions of these mechanisms ensure that DNA methylation and demethylation are dynamic processes, crucial for regulating gene expression and maintaining cellular function.

In humans, high alcohol exposure during pregnancy can cause ‘fetal alcohol syndrome,’ impairing many aspects of brain development. Recent studies link prenatal alcohol exposure to differential methylation of neurodevelopmental genes [6].

Social experiences, such as maternal care, can also lead to epigenetic changes affecting neural development and behavior in subsequent generations. In rodents, maternal behaviors like licking and grooming influence offspring’s stress responses and grooming behaviors through epigenetic modifications. High-grooming mothers produce offspring with lower stress levels and higher grooming tendencies, while low-grooming mothers produce the opposite traits. Cross-fostering experiments confirm that these behaviors are epigenetically inherited.

These epigenetic modifications start when maternal grooming stimulates serotonin release in the hypothalamus, increasing histone acetylase activity in neurons that respond to stress hormones. This leads to demethylation of the glucocorticoid receptor (GR) gene promoter, enhancing its expression and making pups less sensitive to stress. These traits can be reversed by early postnatal experiences, showing the impact of epigenetic marks across generations.