Edelmann A, Galli B, Hennes U, Kistler A, Kuhn H, Mettler F
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Arch Toxicol. 1994;68(6):385-93. doi: 10.1007/s002040050086.
The arotinoid Ro 14-9706, though devoid of any teratogenic potential, was found to reduce dose dependently the survival of pups when their mothers were treated with toxic doses during days 6-15 of gestation. The increased mortality was primarily seen during early lactation. When pups derived from treated mothers were nursed by control foster mothers unexposed to the drug, their survival was significantly improved indicating that the increased mortality was not solely due to fetal drug exposure. When pups derived from untreated mothers were fostered by dams that were exposed to the arotinoid during pregnancy, a significant pup mortality (p < 0.01) was observed, suggesting that the nursing behaviour of lactating dams was seriously affected. This impairment could be linked to a prolactin-suppressive activity of the arotinoid during lactation which was also seen during pregnancy. Other pituitary hormones, however, were not affected by the compound. Although the drug induced pronounced structural alterations in mitochondria of adrenocortical cells, visualized by light microscopy as extended vacuolization in the zona fasciculata and reticularis, this pathological finding did not translate into functional impairment of steroidogenesis. Thus, the arotinoid Ro 14-9706 exhibits in rats a prolactin-suppressive activity which affects lactation and subsequently pup survival. This particular endocrinological interference is a new phenomenon and uncommon for retinoids.
芳香维甲酸Ro 14 - 9706虽然没有任何致畸潜力，但研究发现，当孕鼠在妊娠第6至15天接受毒性剂量药物治疗时，其幼崽的存活率会呈剂量依赖性降低。死亡率增加主要出现在哺乳期早期。当来自经治疗的母鼠的幼崽由未接触该药物的对照代孕母鼠哺育时，它们的存活率显著提高，这表明死亡率增加并非仅仅由于胎儿接触药物所致。当来自未经治疗的母鼠的幼崽由孕期接触过芳香维甲酸的母鼠代孕时，观察到显著的幼崽死亡率（p < 0.01），这表明哺乳期母鼠的哺育行为受到严重影响。这种损害可能与芳香维甲酸在哺乳期的催乳素抑制活性有关，在孕期也观察到了这种活性。然而，其他垂体激素不受该化合物影响。尽管该药物在肾上腺皮质细胞线粒体中引起了明显的结构改变，在光学显微镜下表现为束状带和网状带的空泡化扩展，但这一病理发现并未转化为类固醇生成的功能损害。因此，芳香维甲酸Ro 14 - 9706在大鼠中表现出催乳素抑制活性，影响哺乳并随后影响幼崽存活。这种特殊的内分泌干扰是一种新现象，对视黄酸类物质来说并不常见。
