孕早期金属暴露对胎膜早破风险的贡献可能通过干扰孕妇阴道微生物群和Collinsella的定植

The relationships of metals exposure and disturbance of the vaginal microbiota with the risk of PROM: Results from a birth cohort study

金属暴露和阴道微生物群紊乱与胎膜早破风险的关系：来自一项出生队列研究的结果

Authors: Dongyang Zhang,  Rui Dong,  Tingting Jiang,  Shiwei Ren,  Xinyu Yue,  Muxin Zhai,  Siyu Jiang,  Bingxia He,  Ran Tang,  Yujie Deng,  Wenjie Lyu,  Baojing Zhao,  Fangbiao Tao,  Yuanyuan Yang,  Zongzhi Yin,  Zhen Yu,  Dongmei Ji,  Chunmei Liang.

Source: Ecotoxicol Environ Saf.

Doi: 10.1016/j.ecoenv.2024.117420.

Abstract

The vaginal microbiota is proposed to be associated with reproductive health. Exposure to metals during pregnancy is a risk factor for premature rupture of membranes (PROM). PROM can lead to serious maternal complications, thus, identifying the cause and therapeutic targets for it is crucial. However, the role of vaginal microbiota in the association between metals exposure and the risk of PROM are not clear. Based on a prospective birth cohort study including 668 pregnant women, maternal blood levels of 15 metals in the first trimester (n=668) and microbiota of vaginal secretions in the third trimester (n=244) were assessed. The metals that significantly associated with the risk of PROM were screened out via four statistical models, the top three were barium (Ba), chromium (Cr) and thallium (Tl) according to their weight indices. The results from the BKMR model showed a positive association of the mixture (Ba, Cr and Tl) with the risk of PROM. PROM and non-PROM were characterised by different beta diversities, moreover, the relative abundances of Bifidobacterium, Corynebacterium and Collinsella were statistically and negatively related to the risk of PROM [the adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were 0.06 (0.00, 0.82), 0.32 (0.14, 0.74) and 0.50 (0.30, 0.84), respectively]. On the other hand, women with different levels of Ba exposure were also characterised by different beta diversities (p value = 0.047); and blood Ba levels were also negatively associated with the relative abundances of Collinsella; additionally, Cr levels were positively associated with alpha diversity indices [Shannon index: β (95 % CI) = 0.25 (0.01, 0.50); Simpson index: β (95 % CI) = 0.08 (0.00, 0.17), respectively]. The results from mediation analysis showed the proportion of the relationship between Ba exposure and PROM risk mediated by the relative abundance of Collinsella was 26.4 %. Further verification analysis exploring the potential cause of the above phenomenon indicated that the neutrophil count, one of blood inflammation indicators for PROM, was higher in women with the absence of Collinsella (p value = 0.039), moreover, the cumulative hazard of PROM for women with the presence of Collinsella was also significantly lower than that of those without Collinsella (p value = 0.007). Collectively, the changes in the diversity and composition of the bacterial community, especially the reduction in Collinsella abundance caused by metal exposure, may be related to the occurrence of PROM, which provides a new microbiota-based perspective for intervention in metal exposure-related PROM. Confirming these relationships and determining the possible processes at play will require more investigation.

Keywords: Mediation analysis; Metal exposure; Premature rupture of fetal membranes; Vaginal microbiota.

摘要

阴道微生物群被认为与生殖健康有关。孕期接触金属暴露是胎膜早破（premature rupture of membranes，PROM）的危险因素。PROM 可导致严重的孕产妇并发症，因此，确定其原因和治疗靶点至关重要。然而，阴道微生物群在金属暴露与 PROM发生风险之间的关联中的作用尚不清楚。基于一项包括 668 名孕妇的前瞻性出生队列研究，评估了孕早期（n=668）和孕晚期阴道分泌物微生物群（n=244）的母体血液中 15 种金属的水平。通过 4 个统计模型筛选出与 PROM 风险显著相关的金属，根据其权重指标排名前 3 位的是钡（Ba）、铬（Cr）和铊（Tl）。BKMR 模型的结果显示混合物（Ba、Cr 和 Tl）与 PROM 风险呈正相关。PROM 和非 PROM 的特征在于β多样性不同，此外，双歧杆菌属（Bifidobacterium）、棒状杆菌属（Corynebacterium）和柯林斯菌属（Collinsella）的相对丰度与 PROM 风险呈统计学负相关 [校正比值比（ORs）和 95 % 置信区间（CIs）分别为 0.06 （0.00， 0.82）、 0.32 （0.14， 0.74）和 0.50 （0.30， 0.84） ]。另一方面，具有不同 Ba 暴露水平的女性也具有不同的 β 多样性（P = 0.047）;血液 Ba 水平也与Collinsella的相对丰度呈负相关;此外，Cr 水平与 α 多样性指数呈正相关 [Shannon 指数：β （95 % CI） = 0.25 （0.01， 0.50）;Simpson指数：β （95 % CI） = 0.08 （0.00， 0.17）。中介分析结果显示，柯林斯菌属（Collinsella）相对丰度介导的 Ba 暴露与 PROM 风险之间的关系比例为 26.4 %。探索上述现象潜在原因的进一步验证分析表明，阴道微生物群中不存在Collinsella的女性中性粒细胞计数（PROM 血液炎症指标之一）较高（P = 0.039），此外，阴道微生物群中存在Collinsella的女性发生 PROM 的累积风险也显著低于不存在Collinsella的女性（P = 0.007）。总的来说，细菌群落多样性和组成的变化，尤其是金属暴露引起的Collinsella相对丰度的减少，可能与 PROM 的发生有关，这为干预金属暴露相关的 PROM 提供了新的基于微生物群的视角。确认这些关系并确定可能的过程将需要更多的调查。

关键词：中介分析；金属暴露；胎膜早破；阴道微生物群