Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
Environmental Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts, USA.
Toxicol Sci. 2021 Jan 6;179(1):14-30. doi: 10.1093/toxsci/kfaa161.
The gut microbiome is a pivotal player in toxicological responses. We investigated the effects of maternal exposure to 3 human health-relevant toxicants (BDE-47, tetrabromobisphenol [TBBPA], and bisphenol S [BPS]) on the composition and metabolite levels (bile acids [BAs] and short-chain fatty acids [SCFAs]) of the gut microbiome in adult pups. CD-1 mouse dams were orally exposed to vehicle (corn oil, 10 ml/kg), BDE-47 (0.2 mg/kg), TBBPA (0.2 mg/kg), or BPS (0.2 mg/kg) once daily from gestational day 8 to the end of lactation (postnatal day 21). 16S rRNA sequencing and targeted metabolomics were performed in feces of 20-week-old adult male pups (n = 14 - 23/group). Host gene expression and BA levels were quantified in liver. BPS had the most prominent effect on the beta-diversity of the fecal microbiome compared with TBPPA and BDE-47 (QIIME). Seventy-three taxa were persistently altered by at least 1 chemical, and 12 taxa were commonly regulated by all chemicals (most of which were from the Clostridia class and were decreased). The most distinct microbial biomarkers were S24-7 for BDE-47, Rikenellaceae for TBBPA, and Lactobacillus for BPS (LefSe). The community-wide contributions to the shift in microbial pathways were predicted using FishTaco. Consistent with FishTaco predictions, BDE-47 persistently increased fecal and hepatic BAs within the 12α hydroxylation pathway, corresponding to an up-regulation with the hepatic BA-synthetic enzyme Cyp7a1. Fecal BAs were also persistently up-regulated by TBBPA and BPS (liquid chromatography-mass spectrometry). TBBPA increased propionic acid and succinate, whereas BPS decreased acetic acid (gas chromatography-mass spectrometry). There was a general trend in the hepatic down-regulation of proinflammatory cytokines and the oxidative stress sensor target gene (Nqo1), and a decrease in G6Pdx (the deficiency of which leads to dyslipidemia). In conclusion, maternal exposure to these toxicants persistently modified the gut-liver axis, which may produce an immune-suppressive and dyslipidemia-prone signature later in life.
肠道微生物组是毒理学反应的关键因素。我们研究了母体暴露于 3 种与人类健康相关的毒物（BDE-47、四溴双酚 A[TBBPA]和双酚 S[BPS]）对成年幼仔肠道微生物组组成和代谢物水平（胆汁酸[BAs]和短链脂肪酸[SCFAs]）的影响。CD-1 母鼠从妊娠第 8 天到哺乳期结束（产后第 21 天）每天经口给予载体（玉米油，10ml/kg）、BDE-47（0.2mg/kg）、TBBPA（0.2mg/kg）或 BPS（0.2mg/kg）。对 20 周龄成年雄性幼仔（每组 14-23 只）的粪便进行 16S rRNA 测序和靶向代谢组学分析。定量检测了肝内宿主基因表达和 BA 水平。与 TBPPA 和 BDE-47 相比，BPS 对粪便微生物组的β多样性影响最大（QIIME）。有 73 个分类群被至少 1 种化学物质持续改变，12 个分类群被所有化学物质共同调节（其中大多数来自梭菌属，且减少）。最显著的微生物生物标志物为 BDE-47 的 S24-7、TBBPA 的 Rikenellaceae 和 BPS 的 Lactobacillus（LefSe）。使用 FishTaco 预测微生物途径变化的群落贡献。与 FishTaco 预测一致，BDE-47 持续增加粪便和肝脏内 12α羟化途径中的 BA，对应于肝内 BA 合成酶 Cyp7a1 的上调。TBBPA 和 BPS 也持续上调粪便 BA（液相色谱-质谱法）。TBBPA 增加丙酸和琥珀酸，而 BPS 降低乙酸（气相色谱-质谱法）。肝脏中促炎细胞因子和氧化应激传感器靶基因（Nqo1）普遍下调，G6Pdx 减少（缺乏会导致血脂异常）。总之，母体暴露于这些毒物持续改变了肠道-肝脏轴，这可能导致生命后期产生免疫抑制和易发生血脂异常的特征。
