The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai 200030, China.
MOE-Shanghai Key Laboratory of Children's Environmental Health, Department of Child and Adolescent Healthcare, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20092, China.
Ecotoxicol Environ Saf. 2023 Apr 15;255:114798. doi: 10.1016/j.ecoenv.2023.114798. Epub 2023 Mar 20.
Prenatal single and combined exposure to lead (Pb) and stress (Ps) impairs neurodevelopment. Prenatal single exposure to Pb or Ps affects the composition of intestinal microbiota, and bidirectional communication between gut microbiota and central nervous system has been well recognized. However, whether gut microbiota mediated the effects of prenatal Pb+Ps co-exposure on neurodevelopmental deficits remains unclear. This study established rat models with prenatal single and combined exposure to Ps and Pb. We investigated the effects of such prenatal single and combined exposure on hippocampal structures using morphological analyses, on learning/memory using the Morris-water-maze test, and on fecal microbiota using 16S rRNA sequencing. The mediating roles of gut microbiota were analyzed using the bootstrap method. The study found both single and combined exposure affected hippocampal ultra-structures and spatial learning/memory, and the most significant impairments were observed in the Pb+Ps group. Prenatal Pb+Ps co-exposure decreased fecal microbial alpha/beta-diversity. Significantly lower levels of B/F-ratio, class-Bacteroidia, order-Bacteroidales, and family-S24-7, and significantly higher levels of class-Bacilli, order-Lactobacillales, family-Lactobacillaceae, and genus-Lactobacillus were observed in the co-exposure group, compared with the controls. Increased relative abundances of genus-Helicobacter mediated the detrimental effect of prenatal Ps+Pb co-exposure on learning/memory [β (95%CI) for the total and indirect effects: - 10.70 (-19.19, -2.21) and - 4.65(-11.07, -1.85)], accounting for 43.47% of the total effect. As a result, increased relative abundances of genus-Lactobacillus alleviated the adverse effects of the co-exposure on learning/memory, and the alleviation effect accounted for 44.55% of the direct effect [β (95%CI) for the direct and indirect effects: - 0.28(-0.48, -0.08) and 0.13(0.01, 0.41)]. This study suggested that prenatal combined exposure to Pb and Ps induced more impairments in offspring gut microbiota and neurodevelopment than single exposure, and alterations in fecal microbiome may mediate the developmental neurotoxicity induced by such prenatal co-exposure.
产前铅（Pb）和应激（Ps）单一和联合暴露会损害神经发育。产前单一暴露于 Pb 或 Ps 会影响肠道微生物群落的组成，肠道微生物群落与中枢神经系统之间的双向通讯已得到充分认识。然而，肠道微生物群是否介导了产前 Pb+Ps 共同暴露对神经发育缺陷的影响尚不清楚。本研究建立了产前单一和联合暴露于 Ps 和 Pb 的大鼠模型。我们使用形态分析研究了这种产前单一和联合暴露对海马结构的影响，使用 Morris 水迷宫测试研究了对学习/记忆的影响，并使用 16S rRNA 测序研究了粪便微生物群。使用自举法分析了肠道微生物群的中介作用。研究发现，单一和联合暴露都会影响海马的超微结构和空间学习/记忆，而 Pb+Ps 组的损伤最明显。产前 Pb+Ps 共同暴露降低了粪便微生物多样性。与对照组相比，共同暴露组的 B/F 比、Bacteroidia 类、Bacteroidales 目和 S24-7 科的水平显著降低，而 Bacilli 类、Lactobacillales 目、Lactobacillaceae 科和 Lactobacillus 属的水平显著升高。相对丰度增加的 Helicobacter 属介导了产前 Ps+Pb 共同暴露对学习/记忆的不利影响[总效应和间接效应的β（95%CI）：-10.70（-19.19，-2.21）和-4.65（-11.07，-1.85）]，占总效应的 43.47%。因此，相对丰度增加的 Lactobacillus 属缓解了共同暴露对学习/记忆的不良影响，缓解效应占直接效应的 44.55%[直接和间接效应的β（95%CI）：-0.28（-0.48，-0.08）和 0.13（0.01，0.41）]。本研究表明，产前 Pb 和 Ps 的联合暴露比单一暴露对后代肠道微生物群和神经发育的损伤更大，粪便微生物组的改变可能介导了这种产前共同暴露引起的发育神经毒性。
