Prenatal diet and childhood ADHD: exploring the potential role of IGF2 methylation

Written by Cecil CAM, Walton E & Barker ED

Unhealthy diet during pregnancy is a risk factor for a wide range of negative health and psychiatric outcomes [1]. For example, high-sugar and fat diets associate not only with increased risk for noncommunicable diseases [2], such as diabetes and obesity, but also for neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD) and conduct problems (CP) [3]. In the nutritional field, epigenetics is an important area of investigation, as nutrients and bioactive compounds can alter the expression of genes at the transcriptional level [4]. Because epigenetic modifications, such as DNA methylation, can be passed on during cell division and result in long-term phenotypic changes [5], they also provide a framework for understanding the biological mechanisms through which pre- and post-natal environmental exposures may influence disease vulnerability [6,7].
In a recent paper [8], we examined how exposure to unhealthy fats (e.g., vegetable oils in fast foods) and sugars (e.g., sweets) might associate with ADHD symptoms in children who follow an early onset (age ≤ 10 years; n = 83) versus low (n = 81) trajectory of CP, via DNA methylation of the IGF2 gene. We focused on IGF2 due to its relevance in metabolic function [9], placental and fetal growth [10] and the development of brain regions implicated in ADHD [11–13]. Data were drawn from the Accessible Resource for Integrated Epigenomics Studies [14], a subsample of the Avon Longitudinal Study of Parents and Children, which includes: firstly, maternal reports of diet (32-week gestation, age 3 and 7 years); secondly, peripheral measures of DNA methylation (Illumina 450 k) at birth and age 7 years (n = 671, 49% male) and thirdly, repeated assessments of psychiatric symptomatology, including CP (ages 4–13 years) and ADHD (ages 7–13 years). Below, we summarize our key findings before discussing limitations and future directions.
Firstly, we found that a maternal unhealthy diet during pregnancy prospectively associated with higher IGF2 methylation at birth across all (i.e., both CP and typically developing) children, even after adjusting for a range of inter-related risk factors (e.g., maternal smoking, psychosocial and contextual risks). This finding is consistent with previous research reporting an association between variation in offspring IGF2 methylation and prenatal dietary exposures, including periconceptional dietary supplementation (e.g., folic acid [15,16]; docosahexaenoic acid [17]), severe caloric restriction resulting from prenatal famine exposure [18], maternal obesity and BMI [17,19], as well as animal research on high-fat diet exposure [20]. The use of a prospective design additionally enabled us to examine longitudinal inter-relationships between unhealthy diet and IGF2 methylation, spanning gestation to mid-childhood. We found that, firstly, the association between diet and IGF2 methylation was specific to pregnancy (i.e., not observed postnatally) and secondly, whereas unhealthy diet showed high stability over time (i.e., what mothers ate in pregnancy related to what their children ate in childhood), IGF2 methylation did not. While these findings do not permit causal inference (see limitations), they do point to gestation as a potentially critical developmental window for diet-induced changes in IGF2 methylation, and suggest that IGF2 methylation levels may be temporally dynamic.

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