Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States.
Toxicol Sci. 2024 Sep 1;201(1):48-60. doi: 10.1093/toxsci/kfae073.
Emerging epidemiological evidence indicates perfluorooctane sulfonic acid (PFOS) is increasingly associated with asthma and respiratory viral infections. Animal studies suggest PFOS disrupts lung development and immuno-inflammatory responses, but little is known about the potential consequences on respiratory health and disease risk. Importantly, PFOS exposure during the critical stages of lung development may increase disease risk later in life. Thus, we hypothesized that developmental PFOS exposure will affect lung inflammation and alveolar/airway development in a sex-dependent manner. To address this knowledge gap, timed pregnant Balb/cJ dams were orally dosed with a PFOS (1.0 or 2.0 mg/kg/d) injected mealworm or a vehicle control daily from gestational day (GD) 0.5 to postnatal day (PND) 21, and offspring were sacrificed at PND 22-23. PFOS-exposed male offspring displayed increased alveolar septa thickness. Occludin was also downregulated in the lungs after PFOS exposure in mice, indicative of barrier dysfunction. BALF macrophages were significantly elevated at 2.0 mg/kg/d PFOS in both sexes compared with vehicles, whereas BALF cytokines (TNF-α, IL-6, KC, MIP-1α, MIP-1β, and MCP-1) were suppressed in PFOS-exposed male offspring compared with vehicle controls. Multiplex nucleic acid hybridization assay showed male-specific downregulation of cytokine gene expression in PFOS-exposed mice compared with vehicle mice. Overall, these results demonstrate PFOS exposure exhibits male-specific adverse effects on lung development and inflammation in juvenile offspring, possibly predisposing them to later-in-life respiratory disease. Further research is required to elucidate the mechanisms underlying the sex-differentiated pulmonary toxicity of PFOS.
新兴的流行病学证据表明，全氟辛烷磺酸 (PFOS) 与哮喘和呼吸道病毒感染的关联性日益增加。动物研究表明，PFOS 会破坏肺部发育和免疫炎症反应，但对于其对呼吸道健康和疾病风险的潜在影响知之甚少。重要的是，PFOS 在肺部发育的关键阶段暴露可能会增加日后的疾病风险。因此，我们假设 PFOS 发育暴露将以性别依赖的方式影响肺部炎症和肺泡/气道发育。为了解决这一知识空白，我们对定时怀孕的 Balb/cJ 孕鼠进行了研究，它们从妊娠第 0.5 天到产后第 21 天每天口服给予 1.0 或 2.0mg/kg/d 的 PFOS 或载体对照物，然后在产后第 22-23 天处死幼鼠。PFOS 暴露的雄性后代肺泡间隔厚度增加。PFOS 暴露后，小鼠肺部的紧密连接蛋白 occludin 也下调，表明屏障功能障碍。与载体相比，2.0mg/kg/d PFOS 暴露的雄性和雌性 BALF 巨噬细胞均显著升高，而 PFOS 暴露的雄性后代的 BALF 细胞因子（TNF-α、IL-6、KC、MIP-1α、MIP-1β 和 MCP-1）则受到抑制。多重核酸杂交分析显示，与载体对照相比，PFOS 暴露的雄性小鼠的细胞因子基因表达呈性别特异性下调。总的来说，这些结果表明，PFOS 暴露对幼年后代的肺部发育和炎症表现出雄性特异性的不良影响，可能使他们易患日后的呼吸道疾病。需要进一步的研究来阐明 PFOS 肺部毒性的性别差异的机制。
