Nazzari Sarah, Cagliero Lucia, Grumi Serena, Pisoni Enrico, Mallucci Giulia, Bergamaschi Roberto, Maccarini Julia, Giorda Roberto, Provenzi Livio
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Developmental Psychobiology Lab, IRCCS Mondino Foundation, Pavia, Italy.
Mol Psychiatry. 2023 Aug;28(8):3503-3511. doi: 10.1038/s41380-023-02206-9. Epub 2023 Aug 4.
Antenatal exposures to maternal stress and to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM) have been independently associated with developmental outcomes in early infancy and beyond. Knowledge about their joint impact, biological mechanisms of their effects and timing-effects, is still limited. Both PM and maternal stress exposure during pregnancy might result in altered patterns of DNA methylation in specific stress-related genes, such as the serotonin transporter gene (SLC6A4 DNAm), that might, in turn, influence infant development across several domains, including bio-behavioral, cognitive and socio-emotional domains. Here, we investigated the independent and interactive influence of variations in antenatal exposures to maternal pandemic-related stress (PRS) and PM on SLC6A4 DNAm levels in newborns. Mother-infant dyads (N = 307) were enrolled at delivery during the COVID-19 pandemic. Infants' methylation status was assessed in 13 CpG sites within the SLC6A4 gene's region (chr17:28562750-28562958) in buccal cells at birth and women retrospectively report on PRS. PM exposure throughout the entire gestation and at each gestational trimester was estimated using a spatiotemporal model based on residential address. Among several potentially confounding socio-demographic and health-related factors, infant's sex was significantly associated with infants' SLC6A4 DNAm levels, thus hierarchical regression models were adjusted for infant's sex. Higher levels of SLC6A4 DNAm at 6 CpG sites were found in newborns born to mothers reporting higher levels of antenatal PRS and greater PM exposure across gestation, while adjusting for infant's sex. These effects were especially evident when exposure to elevated PM occurred during the second trimester of pregnancy. Several important brain processes (e.g., synaptogenesis and myelination) occur during mid-pregnancy, potentially making the second trimester a sensitive time window for the effects of stress-related exposures. Understanding the interplay between environmental and individual-level stressors has important implications for the improvement of mother-infant health during and after the pandemic.
产前暴露于母亲压力以及空气动力学直径小于2.5微米的颗粒物（PM），已分别与婴儿早期及以后的发育结果相关。关于它们的联合影响、作用的生物学机制以及时间效应的知识仍然有限。孕期暴露于PM和母亲压力都可能导致特定应激相关基因（如血清素转运蛋白基因，SLC6A4 DNA甲基化）的DNA甲基化模式改变，进而可能影响婴儿多个领域的发育，包括生物行为、认知和社会情感领域。在此，我们研究了产前暴露于母亲大流行相关压力（PRS）和PM的变化对新生儿SLC6A4 DNA甲基化水平的独立和交互影响。母婴二元组（N = 307）在COVID - 19大流行期间分娩时入组。在出生时对婴儿颊细胞中SLC6A4基因区域（chr17:28562750 - 28562958）内的13个CpG位点进行婴儿甲基化状态评估，母亲则回顾性报告PRS情况。使用基于居住地址的时空模型估算整个孕期及每个孕期的PM暴露情况。在几个潜在的混杂社会人口统计学和健康相关因素中，婴儿性别与婴儿SLC6A4 DNA甲基化水平显著相关，因此在分层回归模型中对婴儿性别进行了调整。在调整婴儿性别后，发现报告产前PRS水平较高且整个孕期PM暴露量较大的母亲所生新生儿中，6个CpG位点的SLC6A4 DNA甲基化水平较高。当孕期第二个月暴露于高浓度PM时，这些影响尤为明显。孕期中期会发生几个重要的脑过程（如突触形成和髓鞘形成），这可能使第二个月成为应激相关暴露影响的敏感时间窗口。了解环境和个体水平应激源之间的相互作用对于改善大流行期间及之后的母婴健康具有重要意义。
