Department of Biological Sciences, NC State University, Raleigh, North Carolina, USA.
Department of Chemistry, NC State University, Raleigh, North Carolina, USA.
Neuroendocrinology. 2023;113(12):1262-1282. doi: 10.1159/000526959. Epub 2022 Sep 8.
Flame retardants (FRs) are common bodily and environmental pollutants, creating concern about their potential toxicity. We and others have found that the commercial mixture FireMaster® 550 (FM 550) or its individual brominated (BFR) and organophosphate ester (OPFR) components are potential developmental neurotoxicants. Using Wistar rats, we previously reported that developmental exposure to FM 550 or its component classes produced sex- and compound-specific effects on adult socioemotional behaviors. The underlying mechanisms driving the behavioral phenotypes are unknown.
To further mechanistic understanding, here we conducted transcriptomics in parallel with a novel lipidomics approach using cortical tissues from newborn siblings of the rats in the published behavioral study. Inclusion of lipid composition is significant because it is rarely examined in developmental neurotoxicity studies. Pups were gestationally exposed via oral dosing to the dam to FM 550 or the BFR or OPFR components at environmentally relevant doses.
The neonatal cortex was highly sexually dimorphic in lipid and transcriptome composition, and males were more significantly impacted by FR exposure. Multiple adverse modes of action for the BFRs and OPFRs on neurodevelopment were identified, with the OPFRs being more disruptive than the BFRs via multiple mechanisms including dysregulation of mitochondrial function and disruption of cholinergic and glutamatergic systems. Disrupted mitochondrial function by environmental factors has been linked to a higher risk of autism spectrum disorders and neurodegenerative disorders. Impacted lipid classes included ceramides, sphingomyelins, and triacylglycerides. Robust ceramide upregulation in the OPFR females could suggest a heightened risk of brain metabolic disease.
This study reveals multiple mechanisms by which the components of a common FR mixture are developmentally neurotoxic and that the OPFRs may be the compounds of greatest concern.
阻燃剂（FRs）是常见的体内和环境污染物，引起了人们对其潜在毒性的关注。我们和其他人已经发现，商用混合物 FireMaster® 550（FM 550）或其单独的溴化（BFR）和有机磷酸酯（OPFR）成分是潜在的发育神经毒物。使用 Wistar 大鼠，我们之前报道过，发育暴露于 FM 550 或其成分类别会对成年社交情绪行为产生性别和化合物特异性影响。驱动这些行为表型的潜在机制尚不清楚。
为了进一步深入了解机制，我们使用从发表的行为研究中大鼠新生同胞的皮质组织，并行进行了转录组学和新型脂质组学方法。纳入脂质组成非常重要，因为在发育神经毒性研究中很少进行检查。通过口服给药将母体妊娠期暴露于 FM 550 或 BFR 或 OPFR 成分，剂量与环境相关。
新生皮质的脂质和转录组组成具有高度性别二态性，雄性受 FR 暴露的影响更大。BFR 和 OPFR 对神经发育的多种不良作用模式已被确定，OPFR 通过多种机制比 BFR 更具破坏性，包括线粒体功能失调和胆碱能和谷氨酸能系统的破坏。环境因素引起的线粒体功能障碍与自闭症谱系障碍和神经退行性疾病的风险增加有关。受影响的脂质类包括神经酰胺、鞘磷脂和三酰基甘油。OPFR 雌性中丰富的神经酰胺上调可能表明大脑代谢疾病的风险增加。
本研究揭示了常见 FR 混合物成分在发育过程中具有神经毒性的多种机制，并且 OPFR 可能是最值得关注的化合物。
