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Maternal DHA supplementation influences sex-specific disruption of placental gene expression following early prenatal stress

Jašarević E, Hecht P, Fritsche K, Geary D, Rivera R, Beversdorf D (2021) Biology of Sex Differences 2021 Jan 9;12(1):10 doi: 10.1186/s13293-020-00356-x 

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Early life adversity is widely recognized as a key risk factor for early developmental perturbations and contributes to the presentation of neuropsychiatric disorders in adulthood.

Neurodevelopmental disorders exhibit a strong sex bias in susceptibility, presentation, onset, and severity, although the underlying mechanisms conferring vulnerability are not well understood.

Environmental perturbations during pregnancy, such as malnutrition or stress, have been associated with sex-specific reprogramming that contribute to increased disease risk in adulthood, whereby stress and nutritional insufficiency may be additive and further exacerbate poor offspring outcomes.

To determine whether maternal supplementation of docosahexanoic acid (DHA) exerts an effect on offspring outcome following exposure to early prenatal stress (EPS), dams were fed a purified 10:1 omega-6/omega-3 diet supplemented with either 1.0% preformed DHA/kg feed weight (DHA-enriched) or no additional DHA (denoted as the control diet, CTL). Dams were administered chronic variable stress during the first week of pregnancy (embryonic day, E0.5-7.5), and developmental milestones were assessed at E 12.5.

Exposure to early prenatal stress (EPS) decreased placenta and embryo weight in males, but not females, exposed to the CTL diet.

DHA enrichment reversed the sex-specific decrease in placenta and embryo weight following EPS.

Early prenatal exposure upregulated expression of genes associated with oxygen and nutrient transport, including hypoxia inducible factor 3α (HIF3α), peroxisome proliferator-activated receptor alpha (PPARα), and insulin-like growth binding factor 1 (IGFBP1), in the placenta of CTL diet males exposed to EPS.

DHA enrichment in EPS-exposed animals abrogated the male-specific upregulation of PPARα, HIF3α, and IGFBP1.

Taken together, these studies suggest that maternal dietary DHA enrichment may buffer against maternal stress programming of sex-specific outcomes during early development.


Sex differences in the prevalence of many neurodevelopmental disorders are well known, with ADHD, Autism and Schizophrenia Spectrum Disorders all significantly more common in males than females.

Previous research has confirmed a biological basis for some of these sex differences, in that males appear more vulnerable than females to disturbances of normal brain development in response to many environmental stressors in early life, including both maternal stress and malnutrition during pregnancy.  

Animal studies have repeatedly shown that modern, western-type diets, rich in omega-6 fats, and seriously lacking in the long-chain omega-3 (EPA and DHA), have negative effects on brain development - i.e. that the diets eaten by most humans effectively create a state of malnutrition, compared with the standard feed of laboratory animals. 

Here, researchers investigated whether supplementation during pregnancy with omega-3 DHA might protect against the negative effects of both an omega-6 rich diet and maternal stress on brain development, with a specific focus on possible sex differences.

Results confirmed that male offspring were more vulnerable than females to prenatal stress, in terms of reduced placental and embryo weight.

They also showed that maternal DHA supplementation protected against this stunting of growth in the unborn males, and also mitigated the associated changes in the expression of genes known to be important in regulating bbrain and body development.

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