Effect of cadmium chloride on transepithelial electrical resistance of Sertoli cell monolayers in two-compartment cultures--a new model for toxicological investigations of the "blood-testis" barrier in vitro.

The effect of various doses (0.75-24 microM) of cadmium chloride (CdCl2) on the development of intercellular tight junctions by immature rat Sertoli cells (Sc) was investigated in vitro using the two-compartment culture system. The status of tight junctions was monitored by repeated measurements of the transepithelial electrical resistance (TER). For defining the specificity of CdCl2 effects, the TER changes were correlated with Sc secretory activity (immunoactive inhibin), the cell number (DNA content), and viability (MTT test). The effects of CdCl2 depended on the concentration of the toxicant as well as on the onset and duration of exposure (4 and 18 hr on Day 1 or 5 of culture). The observed effects could be divided into four categories: (1) At highest doses employed, the TER values decreased significantly and irreversibly during 13 days of culture, and the decrease was accompanied by a significant and irreversible drop in inhibin secretion, cell viability, and cell number. (2) Within a narrow range of doses, the irreversible, or only partially reversible, decrease of TER was accompanied by a transient decrease, or no change, of the secretory activity and no significant changes in Sc cell number and/or viability. (3) With still lower doses, the TER values rapidly decreased and then returned to control level within 3-4 days. In this group, no changes in either inhibin secretion or cell viability were observed. (4) Exposure to the lowest doses of CdCl2 caused a delayed, but significant increase in TER. This increase was not accompanied by noticeable changes in other parameters evaluated. These data suggest that CdCl2 may selectively compromise, at least in vitro, the development and maintenance of the inter-Sc tight junctions, without affecting the secretory activity or the cell number and viability. However, increasing cumulative doses of CdCl2 (concentration multiplied by the time of exposure) led to decreased inhibition secretion and cell viability and then, finally, to irreversible cell damage and death. We believe that the experimental model and approach reported in this paper should be very useful for investigating the mechanism of action of known or potential testicular toxicants, particularly those suspected to compromise the integrity of the "blood-testis" barrier.