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.

中文翻译：

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母体 DHA 补充剂影响早期产前应激后胎盘基因表达的性别特异性破坏

早期生活逆境被广泛认为是早期发育障碍的关键风险因素，并导致成年后出现神经精神疾病。神经发育障碍在易感性、表现、发病和严重程度方面表现出强烈的性别偏见，尽管赋予易感性的潜在机制尚不清楚。怀孕期间的环境干扰，例如营养不良或压力，与导致成年期疾病风险增加的性别特异性重编程有关，因此压力和营养不足可能是累加的，并进一步加剧后代的不良结局。为了确定母体补充二十二碳六烯酸 (DHA) 是否对暴露于早期产前压力 (EPS) 后的后代结果产生影响，给大坝喂食纯化的 10:1 omega-6/omega-3 日粮，辅以 1.0% 预制 DHA/kg 饲料重量（富含 DHA）或不添加额外 DHA（表示为对照日粮，CTL）。在怀孕的第一周（胚胎日，E0.5-7.5）对大坝进行慢性可变压力，并在 E 12.5 评估发育里程碑。暴露于早期产前压力 (EPS) 会降低暴露于 CTL 饮食的男性的胎盘和胚胎重量，但不会降低女性。DHA 富集逆转了 EPS 后胎盘和胚胎重量的性别特异性下降。早期产前暴露上调了与氧气和营养转运相关的基因的表达，包括缺氧诱导因子 3α (HIF3α)、过氧化物酶体增殖物激活受体 α (PPARα) 和胰岛素样生长结合因子 1 (IGFBP1)，在暴露于 EPS 的 CTL 饮食男性的胎盘中。EPS 暴露动物中的 DHA 富集消除了 PPARα、HIF3α 和 IGFBP1 的雄性特异性上调。综上所述，这些研究表明，母体膳食 DHA 的富集可能会缓冲母体在早期发育过程中对性别特异性结果的压力编程。