<br>小鼠尿液排泄、器官分布和小鼠 6PPD 和 6PPD-醌的胎盘转移以及通过核受体通路的潜在发育毒性,Environmental Science & Technology

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小鼠尿液排泄、器官分布和小鼠 6PPD 和 6PPD-醌的胎盘转移以及通过核受体通路的潜在发育毒性
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2023-08-29 , DOI: 10.1021/acs.est.3c05026
Haoqi Nina Zhao ₁ , Sydney P Thomas ₁ , Mark J Zylka _{2,

3,

4} , Pieter C Dorrestein _{1,

5,

6,

7} , Wenxin Hu _{2,

3}

Affiliation

橡胶防老剂 6PPD 因其剧毒的转化产物 6PPD-醌（6PPDQ）而受到广泛关注。尽管在孕妇的尿液中检测到 6PPD 和 6PPDQ，但 6PPD 和 6PPDQ 的胎盘转移和发育毒性尚不清楚。在这里，我们用 4 mg/kg 6PPD 或 6PPDQ 处理 C57Bl/6 小鼠，以研究它们的尿液排泄和胎盘转移。雌性和雄性小鼠在 6PPD 和 6PPDQ 的排泄曲线中表现出性别差异。6PPDQ 的尿液浓度比 6PPD 低一个数量级，表明 6PPDQ 的排泄量较低，生物蓄积性较高。在胚胎第 11.5 至 15.5 天用 6PPD 或 6PPDQ 治疗的怀孕小鼠中，6PPDQ 在胎盘、胚胎体和胚胎脑中的浓度比 6PPD 高 1.5-8 倍，表明 6PPDQ 的胎盘转移更高。使用体外双荧光素酶报告基因测定，我们发现 6PPDQ 在浓度低至 0.3 μM 时激活了人视黄酸受体α （RARα）和类视黄醇 X 受体α （RXRα），这比在人尿液中检测到的浓度高 ∼10 倍。6PPD 在低至 1.2 μM 的浓度下激活 RXRα。这些结果表明怀孕期间 6PPD 和 6PPDQ 的暴露风险，并强调需要进一步的毒理学和流行病学调查。

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Urine Excretion, Organ Distribution, and Placental Transfer of 6PPD and 6PPD-Quinone in Mice and Potential Developmental Toxicity through Nuclear Receptor Pathways

The rubber antioxidant 6PPD has gained significant attention due to its highly toxic transformation product, 6PPD-quinone (6PPDQ). Despite their detection in urines of pregnant women, the placental transfer and developmental toxicity of 6PPD and 6PPDQ are unknown. Here, we treated C57Bl/6 mice with 4 mg/kg 6PPD or 6PPDQ to investigate their urine excretion and placental transfer. Female and male mice exhibited sex difference in excretion profiles of 6PPD and 6PPDQ. Urine concentrations of 6PPDQ were one order of magnitude lower than those of 6PPD, suggesting lower excretion and higher bioaccumulation of 6PPDQ. In pregnant mice treated with 6PPD or 6PPDQ from embryonic day 11.5 to 15.5, 6PPDQ showed ∼1.5–8 times higher concentrations than 6PPD in placenta, embryo body, and embryo brain, suggesting higher placental transfer of 6PPDQ. Using in vitro dual-luciferase reporter assays, we revealed that 6PPDQ activated the human retinoic acid receptor α (RARα) and retinoid X receptor α (RXRα) at concentrations as low as 0.3 μM, which was ∼10-fold higher than the concentrations detected in human urines. 6PPD activated the RXRα at concentrations as low as 1.2 μM. These results demonstrate the exposure risks of 6PPD and 6PPDQ during pregnancy and emphasize the need for further toxicological and epidemiological investigations.

更新日期：2023-08-29

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