Smialowicz R J, Riddle M M, Rogers R R, Rowe D G, Luebke R W, Fogelson L D, Copeland C B
Perinatal Toxicology Branch, U.S. Environmental Protection Agency, Research Triangel Park, North Carolina 27711.
J Toxicol Environ Health. 1988;25(4):403-22. doi: 10.1080/15287398809531220.
Studies were conducted to determine the period of immune system development that was most sensitive to perturbation by the known immunotoxicant di-n-octyltin dichloride (DOTC). Fischer 344 rats were exposed prenatally, both pre- and postnatally, or postnatally to DOTC by oral gavage of pregnant and/or lactating females. At various ages, ranging from 3 to 16 wk of age, offspring were examined for a number of immune functions. These included body and lymphoid organ weights; lymphoproliferative responses to B- and T-cell mitogens; natural killer cell activity; and primary antibody response to sheep erythrocytes. Prenatal (10-20 of gestation), pre- and postnatal (d 11-20 of gestation and 2-11 d of age), or postnatal (2-13 d of age) oral dosing of dams with 20-50 mg/kg DOTC resulted in no consistent alteration in immune function in offspring. However, direct oral dosing of rat pups to 5-15 mg/kg DOTC, beginning at 3 d of age and then 3 times per week up to 24 d of age for a total of 10 doses, resulted in significant suppression of the lymphoproliferative response of splenocytes to a T-cell mitogen in 10-wk-old rats (i.e., 7 wk after the last exposure to DOTC). Lymphoproliferative responses returned to control levels by 12 wk of age. In comparison young adult (8 wk old) rats dosed with 10 or 20 mg/kg DOTC under an identical dosing schedule (i.e., 3 times per week for a total of 10 doses) showed no suppression in the mitogen response of splenocytes 4 wk after the last exposure to DOTC. These results suggest that direct dosing of pups during early postnatal life may be the most effective means of inducing immunosuppression with DOTC during immune system development. The results also provide evidence for the greater sensitivity of the developing immune system compared with the fully developed immune system for a known immunotoxicant.
开展了多项研究，以确定免疫系统发育过程中对已知免疫毒性物质二正辛基二氯化锡（DOTC）干扰最为敏感的时期。通过对怀孕和/或哺乳期雌性大鼠经口灌胃，使Fischer 344大鼠在产前、产前和产后或产后接触DOTC。在3至16周龄的不同年龄段，对后代的多种免疫功能进行检测。这些功能包括体重和淋巴器官重量；对B细胞和T细胞有丝分裂原的淋巴细胞增殖反应；自然杀伤细胞活性；以及对绵羊红细胞的初次抗体反应。在孕期第10 - 20天、产前和产后（孕期第11 - 20天和出生后2 - 11天）或产后（出生后2 - 13天）给母鼠经口灌胃20 - 50 mg/kg DOTC，未导致后代免疫功能出现一致的改变。然而，从出生后第3天开始，对幼鼠直接经口给予5 - 15 mg/kg DOTC，然后每周3次，直至出生后第24天，共给药10次，导致10周龄大鼠（即最后一次接触DOTC后7周）脾细胞对T细胞有丝分裂原的淋巴细胞增殖反应受到显著抑制。淋巴细胞增殖反应在12周龄时恢复到对照水平。相比之下，在相同给药方案（即每周3次，共给药10次）下，给予10或20 mg/kg DOTC的年轻成年（8周龄）大鼠在最后一次接触DOTC后4周，脾细胞的有丝分裂原反应未受到抑制。这些结果表明，在出生后早期直接对幼鼠给药可能是在免疫系统发育过程中用DOTC诱导免疫抑制的最有效方法。结果还为发育中的免疫系统相比已完全发育的免疫系统对已知免疫毒性物质具有更高敏感性提供了证据。
