Dormans J A, Peters-Volleberg G W, Dortant P M, Speijers G J
Laboratory for Pathology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Toxicol Appl Pharmacol. 1996 Jan;136(1):179-85. doi: 10.1006/taap.1996.0022.
To study the possible age-dependent ototoxic effects of tobramycin a subacute toxicity study was performed. To young adult (3 months) and old (27-30 months) female Wag-Rij rats 0, 10, 40, and 160 mg tobramycin sulfate/kg was administered subcutaneously in two doses a day. After 14 days all animals were autopsied. The cochlea was fixed by perfusion through the opened oval window and prepared for scanning electron microscopy. The rat cochlea consists of two turns. In all animals of the young control group the row of inner hair cells (IHC) as well as the three rows of outer hair cells (OHC) of the organ of Corti were fully intact. IHC as well as OHC are provided with three rows of stereocilia, from inside to outside with increasing length. The stereocilia of OHC are arranged in a characteristic W-configuration. In the young low dose group effects were focally seen in only 1 of 10 rats, consisting of shortened, disoriented or partly disappeared stereocilia of IHC and OHC in the basal turn. In the young mid dose group 4 of 10 animals had focally shortened, disoriented, and less stereocilia in the first row of OHC in the basal turn, and once of IHC and OHC in the apical turn. Seven of 8 animals of the young high dose group showed effects consisting of focal loss or shortening of stereocilia of IHC and OHC of the apical turn (3x), of OHC in the basal turn (3x), and once of stereocilia of IHC only. In the old control group the stereocilia of IHC were fully intact. However, many OHC, independent of row or turn, had no stereocilia at all. The percentages of OHC without stereocilia in the three rows of the apical and basal turns were 44-10-50 and 40-20-50, respectively. In the old low, mid, and high dose group the percentages of OHC without stereocilia were nearly identical to those of the old control group. In the old low and high dose group a reduced number of stereocilia per IHC occurred in half of the number of animals, while in the mid dose group the IHC were fully intact. In young adult animals the number of mildly affected cochleae increased as well as the extent of the lesion increased with increasing dose of tobramycin. The lesions of IHC and OHC, consisting of a decrease in number or shortening of stereocilia, were restricted mainly to (the last part of) the basal turn. As old control rats showed already a large number of OHC without stereocilia, the possible ototoxic effects of tobramycin were not detected against this "background" of stereociliary loss, consistent with aging. The damage in old rats was certainly not greater than in young adult rats. In conclusion, old rats were not more sensitive to the possible ototoxic effects of tobramycin than young adult rats.
为研究妥布霉素可能存在的年龄依赖性耳毒性作用，进行了一项亚急性毒性研究。对年轻成年（3个月）和老年（27 - 30个月）雌性Wag - Rij大鼠，每天分两次皮下注射0、10、40和160 mg硫酸妥布霉素/千克。14天后对所有动物进行解剖。通过开放的椭圆窗灌注固定耳蜗，制备用于扫描电子显微镜检查的样本。大鼠耳蜗由两圈组成。在年轻对照组的所有动物中，柯蒂氏器的内毛细胞（IHC）排以及三排外毛细胞（OHC）均完全完整。IHC和OHC都有三排静纤毛，从内到外长度逐渐增加。OHC的静纤毛呈特征性的W形排列。在年轻低剂量组中，仅10只大鼠中的1只出现局部效应，表现为基部转弯处IHC和OHC的静纤毛缩短、方向紊乱或部分消失。在年轻中剂量组中，10只动物中有4只在基部转弯处OHC的第一排出现局部缩短、方向紊乱且静纤毛较少，在顶部转弯处有1次IHC和OHC出现这种情况。年轻高剂量组的8只动物中有7只出现效应，包括顶部转弯处IHC和OHC的静纤毛局部缺失或缩短（3次）、基部转弯处OHC的静纤毛（3次）以及仅1次IHC的静纤毛出现这种情况。在老年对照组中，IHC的静纤毛完全完整。然而，许多OHC，无论排或转弯情况如何，根本没有静纤毛。顶部和基部转弯处三排无静纤毛的OHC百分比分别为44 - 10 - 50和40 - 20 - 50。在老年低、中、高剂量组中，无静纤毛的OHC百分比与老年对照组几乎相同。在老年低剂量和高剂量组中，一半数量的动物中每个IHC的静纤毛数量减少，而在中剂量组中IHC完全完整。在年轻成年动物中，随着妥布霉素剂量增加，轻度受影响的耳蜗数量增加，病变程度也增加。IHC和OHC的病变，表现为静纤毛数量减少或缩短，主要局限于基部转弯（最后部分）。由于老年对照大鼠已经有大量无静纤毛的OHC，在这种与衰老一致的静纤毛损失“背景”下，未检测到妥布霉素可能的耳毒性作用。老年大鼠的损伤肯定不比年轻成年大鼠更严重。总之，老年大鼠对妥布霉素可能的耳毒性作用并不比年轻成年大鼠更敏感。
