Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
Department of Biology, East Carolina University, Greenville, NC, United States; Department of Chemistry, East Carolina University, Greenville, NC, United States.
Neurotoxicology. 2012 Dec;33(6):1491-1498. doi: 10.1016/j.neuro.2012.10.016. Epub 2012 Nov 5.
Immune comorbidities often are reported in subsets of patients with neurodevelopmental disorders, including autism spectrum disorders and attention-deficit hyperactivity disorder. A common immunopathology is an increase in serum autoantibodies against myelin basic protein (MBP) relative to control patients. Increases in autoantibodies suggest possible deficits in self-tolerance that may contribute to the formation of brain-specific autoantibodies and subsequent effects on the central nervous system (CNS). Oppositely, the formation of neuronal autoantibodies may be a reaction to neuronal injury or damage. Perfluorooctanoic acid (PFOA) is an environmental pollutant that induces multisystem toxicity in rodent models, including immunotoxicity and neurotoxicity. We hypothesized that developmental exposure to PFOA may induce immunotoxicity similar to that observed in subsets of patients with neurodevelopmental disorders. To test this hypothesis, we evaluated subsets of T cells from spleens, serum markers of autoreactivity, and levels of MBP and T cell infiltration in the cerebella of adult offspring exposed to 0.02, 0.2, or 2mg/kg of PFOA given to dams from gestation through lactation. Litter weights of offspring from dams exposed to 2mg/kg of PFOA were reduced by 32.6%, on average, from postnatal day one (PND1) through weaning (PND21). The percentage of splenic CD4+CD25+Foxp3+ T cells in male and female offspring from dams exposed to 2mg/kg of PFOA was reduced by 22% relative to the control percentage. Ex vivo co-cultures of splenic CD4+CD25+ T cells and CD4+CD25- T cells from dosed male offspring produced less IL-10 relative to control cells. Anti-ssDNA, a serum marker of autoreactivity, was decreased by 26%, on average, in female offspring from dams exposed to 0.02 and 2mg/kg PFOA. No other endpoints were statistically different by dose. These data suggest that developmental PFOA exposure may impact T cell responses and may be a possible route to downstream effects on other systems.
免疫合并症经常在神经发育障碍患者的亚组中报道，包括自闭症谱系障碍和注意缺陷多动障碍。一种常见的免疫病理学是血清髓鞘碱性蛋白（MBP）自身抗体相对于对照患者的增加。自身抗体的增加表明可能存在自我耐受缺陷，这可能导致脑特异性自身抗体的形成，并随后对中枢神经系统（CNS）产生影响。相反，神经元自身抗体的形成可能是神经元损伤或损伤的反应。全氟辛酸（PFOA）是一种环境污染物，可在啮齿动物模型中引起多系统毒性，包括免疫毒性和神经毒性。我们假设，在神经发育障碍患者亚组中观察到的发展性接触 PFOA 可能会引起类似的免疫毒性。为了验证这一假设，我们评估了来自暴露于 0.02、0.2 或 2mg/kg PFOA 的母体的后代脾脏中的 T 细胞亚群、自身反应的血清标志物以及小脑髓鞘碱性蛋白（MBP）和 T 细胞浸润的水平。暴露于 2mg/kg PFOA 的母体的后代的产仔体重从出生后第一天（PND1）到断奶（PND21）平均减少了 32.6%。暴露于 2mg/kg PFOA 的母体的后代的脾脏中 CD4+CD25+Foxp3+T 细胞的百分比相对于对照百分比减少了 22%。与对照细胞相比，来自暴露于 2mg/kg PFOA 的雄性后代的脾脏 CD4+CD25+T 细胞和 CD4+CD25-T 细胞的体外共培养物产生的 IL-10 减少。血清自身反应性标志物抗 ssDNA 在暴露于 0.02 和 2mg/kg PFOA 的母体的雌性后代中平均减少了 26%。其他终点没有按剂量统计差异。这些数据表明，发育性 PFOA 暴露可能会影响 T 细胞反应，并且可能是对其他系统产生下游影响的一种可能途径。
