Molecular Effects of Developmental FM 550 Exposure in Wistar Rat Fetal Forebrain

Firemaster® 550 (FM 550) is a flame retardant (FR) mixture that has become one of the most commonly used FRs in foam-based furniture and baby products. Human exposure to this commercial mixture, comprised of brominated and organophosphate components, is widespread. We have repeatedly shown that developmental exposure can lead to sex-specific behavioral effects in rats. Accruing evidence of endocrine disruption and potential neurotoxicity have raised concerns regarding the neurodevelopmental effects of FM 550 exposure, but the specific mechanisms of action remains unclear. Additionally, we observed significant, and in some cases sex-specific, accumulation of FM 550 in placental tissue following gestational exposure. Because the placenta is an important source of hormones and neurotransmitters for the developing brain, it may be a critical target of toxicity to consider in the context of developmental neurotoxicity. Using a mixture of targeted and exploratory approaches, the goal of the present study was to identify possible mechanisms of action in the developing forebrain and placenta. Wistar rat dams were orally exposed to FM 550 (0, 300, or 1,000 µg/day;) for 10 days during gestation and placenta and fetal forebrain tissue collected for analysis. In placenta, evidence of endocrine, inflammatory, and neurotransmitter signaling pathway disruption was identified. Notably, 5-HT turnover was reduced in placental tissue and fetal forebrains indicating that 5-HT signaling between the placenta and the embryonic brain may be disrupted. These findings demonstrate that environmental contaminants, like FM 550, have the potential to impact the developing brain by disrupting normal placental functions.Firemaster® 550 (FM 550) 是一种阻燃剂（flame retardant, FR）混合物，目前已成为泡沫基家具与婴儿产品中应用最为广泛的阻燃剂之一。人类广泛暴露于这种由溴化组分与有机磷酸酯组分构成的商用混合物。我们此前多次证实，发育期暴露可诱导大鼠出现性别特异性的行为效应。越来越多关于其引发内分泌干扰与潜在神经毒性的研究证据，引发了学界对FM 550暴露所致神经发育风险的担忧，但其具体作用机制仍未明确。此外，我们观察到，妊娠期暴露后，FM 550会在胎盘组织中出现显著积累，且部分积累特征呈现性别特异性。由于胎盘是发育中大脑的激素与神经递质重要来源，其或为发育性神经毒性研究中需重点关注的毒性作用靶点。本研究采用靶向研究与探索性研究相结合的策略，旨在明确发育性前脑与胎盘中的潜在作用机制。实验中，妊娠Wistar大鼠经口暴露于FM 550（剂量分别为0、300或1000 μg/天），于妊娠期连续暴露10天，随后收集胎盘与胎儿前脑组织以开展分析。在胎盘中，研究人员发现了内分泌、炎症及神经递质信号通路受干扰的证据。值得注意的是，胎盘组织与胎儿前脑中的5-羟色胺（5-hydroxytryptamine, 5-HT）更新速率均出现下降，这表明胎盘与胚胎大脑之间的5-羟色胺信号传导可能遭到破坏。上述研究结果表明，诸如FM 550这类环境污染物，有可能通过干扰胎盘的正常生理功能，对发育中的大脑造成不良影响。