In 1944, a blockade in the German-occupied Netherlands cut off the food and fuel supplies for the locals, resulting in a Dutch famine that affected around 4.5 million people. It is believed that pregnant women survived on just 400-800 calories a day during this period.
Although that famine ended over 70 years ago, the health effects remain for survivors conceived during the famine. Baby’s exposure to famine during early fetal development has been linked to higher death rates, obesity, diabetes, and schizophrenia. It is also believed that the famine likely resulted in many miscarriages and early deaths.
The so-called “Dutch Hunger Winter Cohort” was studied in the years after World War II as an example of how maternal nutrition can affect the health of their children, with effects that continue to this day.
But why does an early diet have such a lasting effect on health? Previous animal studies have shown that diet during pregnancy can turn genes on or off in the offspring, leading to large changes in body weight and an increased risk of diabetes and cancer.
These studies (and many others) form the basis of the “Developmental Causes of Health and Disease” (DOHaD) hypothesis that diet and other environmental stresses in early life have important implications for lifelong health.
Over the past 10 years, researchers in The Gambia have used a “nature experiment” to investigate the mechanisms underlying the DOHaD phenomena.
In these subsistence farming communities, individuals conceived at different times of the year experience great dietary variation during early development. We and the researchers studied the potential effects and found that this affects their DNA in particular.
The researchers investigated connections between this seasonality and “DNA methylation” – a molecular marking system in DNA that can switch genes on or off.
Over the years we have identified many genes in children in which the mother’s diet in early pregnancy, around the time of conception, appears to affect DNA methylation.
The big question, however, remained: what consequences could this have for human health?
In our latest work published in Science Advances, we focused on a gene, PAX8, with DNA methylation that appears to be nutritionally sensitive at the time of conception.
PAX8 plays a key role in thyroid development, so we wanted to see if the amount that diet altered this gene could affect thyroid development and function in the offspring.
To test this, we measured PAX8 methylation in hundreds of Gambian children aged two years and then re-examined the same children aged 5 to 8 years. We showed that children with low PAX8 change, or “methylation,” had increased thyroid volume (21 percent larger) and an increased amount of free T4, an important thyroid hormone. This increased amount of free T4 has been linked to decreases in body fat and bone mineral density – which can have negative long-term effects on health.
Alternating PAX8 methylation in the children has also been linked to the maternal diet at conception, particularly to circulating vitamins B6, B12, homocysteine, and cysteine.
Taken together, these exciting results offer a compelling glimpse into a relationship between early nutrition and later health, in this case thyroid function and thyroid-related health outcomes.
What does this mean for public health?
Well, at the moment there are still many pieces of the puzzle to be put together, including confirmation that certain nutrients directly affect the PAX8 gene in the early embryo and that this continues into childhood and beyond.
If we can show that this is the case with PAX8, and perhaps other nutritionally sensitive genes as well, we can envision a world where a mother (and possibly a father) diet could be tweaked before conception to accommodate their child best start in life to enable life.
- Dr. Matt Silver and Toby Candler are researchers at the London School of Hygiene & Tropical Medicine and work in the Gambia
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