Dixon Aaron, Rowan Evelyn G, Yackley Allison N, Hines Erin P
Reproductive and Developmental Toxicology Branch, Public Health Integrated Toxicology Division, Center for Public Health and Environmental Assessment, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Oak Ridge Institute for Science and Education, U.S. Department of Energy, Oak Ridge, TN 37831, USA.
Toxics. 2024 Feb 23;12(3):170. doi: 10.3390/toxics12030170.
Various PFAS have been identified as potential endocrine-disrupting chemicals due to estrogen receptor activation, impacts on puberty timing, or impacts on hormonally sensitive endpoints in fish. This study screened multiple PFAS in the rat uterotrophic assay to determine potential estrogenic effects on the uterus with PFAS exposure. This study also explored PFAS-dependent uterine signaling with an osmotic stress mRNA gene expression array. Briefly, Sprague-Dawley rats (26-39 days old) were ovariectomized, and uterine tissue was allowed to regress for a 3-week period of recovery. Animals were then exposed daily via oral gavage to PFAS for 4 days, and then uterine weight was determined. In contrast to the positive control estrogens, the PFAS tested (4:2, 6:2, and 8:2FTOH; perfluorooctanesulfonamide (PFOSA), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), nafion byproduct 2 (NBP2), 1H,1H,8H,8H-perfluorooctane-1,8-diol (FC8-diol) and 1H,1H,10H,10H-perfluorodecane-1,10-diol (FC10-diol)) caused no significant changes in the uterine weight. Hormonally active compounds can act as carcinogens, and because earlier rodent work has demonstrated that chronic PFOA exposure is associated with increased risk of uterine cancer, uterine mRNA gene expression was explored with an osmotic stress RT-qPCR array. PFAS exposure significantly upregulated multiple genes across the array, with PFOSA being the compound most similar to the reference estrogens (estradiol benzoate and ethinyl estradiol) in its expression pattern. Also, across all PFAS, pathway analysis revealed that the paxillin pathway, a pathway important in tumor suppressor gene SHP-2 signaling, was significantly upregulated with PFAS exposure. These results demonstrate that in vitro estrogen screens or impacts in fish may show different responses from direct impacts on mammalian uterine weight as assessed with the uterotrophic assay. This study also builds out new mechanisms that may contribute to understanding of carcinogenic changes seen in the uterus after PFAS exposure.
由于激活雌激素受体、影响青春期时间或影响鱼类中激素敏感的终点指标，多种全氟和多氟烷基物质（PFAS）已被确定为潜在的内分泌干扰化学物质。本研究在大鼠子宫增重试验中筛选了多种PFAS，以确定PFAS暴露对子宫的潜在雌激素效应。本研究还利用渗透压应激mRNA基因表达阵列探索了PFAS依赖的子宫信号传导。简要地说，将26至39日龄的斯普拉格-道利大鼠进行卵巢切除，让子宫组织在3周的恢复期内退化。然后，动物每天通过灌胃暴露于PFAS 4天，之后测定子宫重量。与阳性对照雌激素不同，所测试的PFAS（4:2、6:2和8:2氟调聚物醇；全氟辛烷磺酰胺（PFOSA）、全氟壬酸（PFNA）、全氟己烷磺酸盐（PFHxS）、全氟辛烷磺酸盐（PFOS）、全氟磺酸离子交换膜副产物2（NBP2）、1H,1H,8H,8H-全氟辛烷-1,8-二醇（FC8-二醇）和1H,1H,10H,10H-全氟癸烷-1,10-二醇（FC10-二醇））未引起子宫重量的显著变化。具有激素活性的化合物可作为致癌物，并且由于早期的啮齿动物研究表明，长期暴露于全氟辛酸（PFOA）与子宫癌风险增加有关，因此利用渗透压应激逆转录定量聚合酶链反应（RT-qPCR）阵列探索了子宫mRNA基因表达。PFAS暴露显著上调了阵列中的多个基因，其中PFOSA在其表达模式上与参考雌激素（苯甲酸雌二醇和乙炔雌二醇）最为相似。此外，在所有PFAS中，通路分析显示，桩蛋白通路（在肿瘤抑制基因SHP-2信号传导中起重要作用的通路）在PFAS暴露后显著上调。这些结果表明，体外雌激素筛选或对鱼类的影响可能与子宫增重试验评估的对哺乳动物子宫重量的直接影响表现出不同的反应。本研究还建立了新的机制，这可能有助于理解PFAS暴露后子宫中出现的致癌变化。
