Korade Zeljka, Anderson Allison C, Sharma Kanika, Tallman Keri A, Kim Hye-Young H, Porter Ned A, Gripp Karen W, Mirnics Karoly
Department of Pediatrics, Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Mol Psychiatry. 2024 Dec;29(12):3942-3949. doi: 10.1038/s41380-024-02622-5. Epub 2024 Jun 6.
A recent study discovered a novel, complex developmental disability syndrome, most likely caused by maternal fentanyl use disorder. This Fetal Fentanyl Syndrome (FFS) is biochemically characterized by elevated 7-dehydrocholesterol (7-DHC) levels in neonates, raising the question if fentanyl inhibition of the dehydrocholesterol reductase 7 (DHCR7) enzyme is causal for the emergence of the pathophysiology and phenotypic features of FFS. To test this hypothesis, we undertook a series of experiments on Neuro2a cells, primary mouse neuronal and astrocytic cultures, and human dermal fibroblasts (HDFs) with DHCR7 and DHCR7 genotype. Our results revealed that in vitro exposure to fentanyl disrupted sterol biosynthesis across all four in vitro models. The sterol biosynthesis disruption by fentanyl was complex, and encompassed the majority of post-lanosterol intermediates, including elevated 7-DHC and decreased desmosterol (DES) levels across all investigated models. The overall findings suggested that maternal fentanyl use in the context of an opioid use disorder leads to FFS in the developing fetus through a strong disruption of the whole post-lanosterol pathway that is more complex than a simple DHCR7 inhibition. In follow-up experiments we found that heterozygous DHCR7 HDFs were significantly more susceptible to the sterol biosynthesis inhibitory effects of fentanyl than wild-type DHCR7 fibroblasts. These data suggest that DHCR7 heterozygosity of mother and/or developing child (and potentially other sterol biosynthesis genes), when combined with maternal fentanyl use disorder, might be a significant contributory factor to the emergence of FFS in the exposed offspring. In a broader context, we believe that evaluation of new and existing medications for their effects on sterol biosynthesis should be an essential consideration during drug safety determinations, especially in pregnancy.
最近的一项研究发现了一种新型的、复杂的发育障碍综合征，很可能是由母亲使用芬太尼所致的物质使用障碍引起的。这种胎儿芬太尼综合征（FFS）在生物化学上的特征是新生儿体内7-脱氢胆固醇（7-DHC）水平升高，这就引发了一个问题，即芬太尼对脱氢胆固醇还原酶7（DHCR7）的抑制是否是FFS病理生理学和表型特征出现的原因。为了验证这一假设，我们对Neuro2a细胞、原代小鼠神经元和星形胶质细胞培养物以及具有DHCR7和DHCR7基因型的人皮肤成纤维细胞（HDF）进行了一系列实验。我们的结果显示，在体外将所有四种体外模型暴露于芬太尼会破坏甾醇生物合成。芬太尼对甾醇生物合成的破坏很复杂，涵盖了羊毛甾醇后大多数中间产物，包括在所有研究模型中7-DHC水平升高和去甲基胆固醇（DES）水平降低。总体研究结果表明，在阿片类物质使用障碍的背景下，母亲使用芬太尼会通过强烈破坏整个羊毛甾醇后途径导致发育中的胎儿出现FFS，这种破坏比单纯的DHCR7抑制更为复杂。在后续实验中，我们发现杂合型DHCR7 HDF比野生型DHCR7成纤维细胞对芬太尼的甾醇生物合成抑制作用更敏感。这些数据表明，母亲和/或发育中的孩子的DHCR7杂合性（以及潜在的其他甾醇生物合成基因），与母亲使用芬太尼所致的物质使用障碍相结合，可能是暴露后代出现FFS的一个重要促成因素。从更广泛的背景来看，我们认为在药物安全性评估，尤其是在孕期进行药物安全性评估时，评估新药和现有药物对甾醇生物合成的影响应是一个重要的考虑因素。
