Background

Birthweight is an indicator of fetal growth and environmental-related alterations of birthweight have been linked with multiple disorders and conditions progressing into adulthood. Although a few studies have assessed the association between birthweight and the totality of exogenous exposures and their downstream molecular responses in maternal urine and cord blood; no prior research has considered a) the maternal serum prenatal metabolome, which is enriched for hormones, and b) non-linear and synergistic associations among exposures.

Methods

We measured the maternal serum metabolome during pregnancy using an untargeted metabolomics approach and birthweight for gestational age (BWGA) z-score in 410 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. We leveraged a Bayesian factor analysis for interaction to select the most important metabolites associated with BWGA z-score and to evaluate their linear, non-linear and non-additive associations. We also assessed the primary biological functions of the identified proteins using the MetaboAnalyst, a centralized repository of curated functional information. We compared our findings with those of a traditional metabolite-wide association study (MWAS) in which metabolites are individually associated with BWGA z-score.

Results

Among 1110 metabolites, 46 showed evidence of U-shape associations with BWGA z-score. Most of the identified metabolites (85%) were lipids primarily enriched for pathways central to energy production, immune function, and androgen and estrogen metabolism, which are essential for pregnancy and parturition processes. Metabolites within the same class, i.e. steroids and phospholipids, showed synergistic relationships with each other.

Conclusions

Our results support that the aspects of the maternal metabolome during pregnancy contribute linearly, non-linearly and synergistically to variation in newborn birthweight.

中文翻译：

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妊娠代谢组和出生体重之间的非线性和非加性关联

背景

出生体重是胎儿生长的一个指标，与环境相关的出生体重变化与进入成年期的多种疾病和病症有关。尽管一些研究评估了出生体重与外源性暴露总量及其在母体尿液和脐带血中的下游分子反应之间的关系；之前没有研究考虑过 a) 富含激素的母体血清产前代谢组，以及 b) 暴露之间的非线性和协同关联。

方法

我们使用非靶向代谢组学方法和胎龄出生体重 (BWGA) z 分数测量了怀孕期间的母体血清代谢组，该分数在 410 名参加代际压力机制规划 (PRISM) 队列的母子中进行。我们利用贝叶斯因子分析进行交互，以选择与 BWGA z 分数相关的最重要的代谢物，并评估它们的线性、非线性和非加性关联。我们还使用 MetaboAnalyst 评估了已识别蛋白质的主要生物学功能，MetaboAnalyst 是一个集中的功能信息库。我们将我们的发现与传统的全代谢物关联研究 (MWAS) 的结果进行了比较，其中代谢物与 BWGA z-score 单独相关。

结果

在 1110 种代谢物中，46 种显示出 U 型与 BWGA z 分数相关的证据。大多数已鉴定的代谢物 (85%) 是主要富含对能量产生、免疫功能以及雄激素和雌激素代谢至关重要的途径的脂质，这些途径对怀孕和分娩过程至关重要。同一类别中的代谢物，即类固醇和磷脂，显示出彼此之间的协同关系。

结论

我们的结果支持怀孕期间母体代谢组的各个方面对新生儿出生体重的变化呈线性、非线性和协同作用。