Tiwary Richa, Fang Xin, Nguyen Vivian, Richburg John H
The Center for Molecular Carcinogenesis and Toxicology, Division of Pharmacology and Toxicology, College of Pharmacy, 2409 University Avenue, The University of Texas at Austin, Austin, TX, 78712, United States.
College of Natural Sciences, 120 Inner Campus Drive, Austin, TX 78712, The University of Texas at Austin, Austin, TX, 78712, United States.
Toxicol Res (Camb). 2025 Jul 24;14(4):tfaf097. doi: 10.1093/toxres/tfaf097. eCollection 2025 Aug.
We have previously reported that acute MEHP exposure resulted in a significant increase in peritubular macrophages along with differentiating spermatogonia. Here, we hypothesize that the recruitment of peritubular macrophages is MEHP dose-dependent and that the peritubular macrophages stimulate spermatogonial differentiation in response to MEHP-induced testicular injury. Peripubertal rats were exposed to a single dose of either 250 mg/kg or 500 mg/kg MEHP or 250 mg/kg MEHP for 3 consecutive days or 100 mg/kg for 7 consecutive days to study chronic exposure. Here, we report that an acute exposure to 500 mg/kg and a repeated 250 mg/kg exposure to MEHP resulted in significant loss of spermatocytes as well as increased numbers of peritubular macrophages and that this increase in peritubular macrophages corresponded closely with an observed increase in the numbers of differentiating (PLZF+) spermatogonia. Interestingly, a disruption of the blood-testis barrier (BTB) also corresponded closely with increased peritubular macrophage numbers after MEHP exposure. To delineate if the peritubular macrophages play a role in the repair and recovery of spermatogenesis after MEHP exposure, depletion of MEHP-induced increase in the numbers of peritubular macrophages via pre-treatment with clodronate resulted in a consequent decrease in number of PLZF-positive differentiating spermatogonia. Our findings are significant as it is the first demonstration of the infiltration of peritubular macrophages by a toxicant and is dose-dependent. Additionally, this recruitment of PTMO depends on the disruption of BTB and not germ cell loss. Furthermore, depletion of peritubular macrophages resulted in a decrease in the number of differentiating spermatogonia.
我们之前曾报道，急性暴露于邻苯二甲酸单（2-乙基己基）酯（MEHP）会导致睾丸间质巨噬细胞以及分化中的精原细胞显著增加。在此，我们假设睾丸间质巨噬细胞的募集是MEHP剂量依赖性的，并且睾丸间质巨噬细胞会响应MEHP诱导的睾丸损伤而刺激精原细胞分化。将青春期前大鼠单次暴露于250 mg/kg或500 mg/kg的MEHP，或连续3天暴露于250 mg/kg的MEHP，或连续7天暴露于100 mg/kg的MEHP，以研究慢性暴露情况。在此，我们报告，急性暴露于500 mg/kg以及重复暴露于250 mg/kg的MEHP会导致精母细胞显著减少，同时睾丸间质巨噬细胞数量增加，并且这种睾丸间质巨噬细胞数量的增加与观察到的分化中的（PLZF+）精原细胞数量增加密切相关。有趣的是，血睾屏障（BTB）的破坏也与MEHP暴露后睾丸间质巨噬细胞数量的增加密切相关。为了确定睾丸间质巨噬细胞在MEHP暴露后精子发生的修复和恢复中是否起作用，通过用氯膦酸盐预处理来减少MEHP诱导的睾丸间质巨噬细胞数量增加，结果导致PLZF阳性的分化中的精原细胞数量随之减少。我们的发现具有重要意义，因为这是首次证明有毒物质对睾丸间质巨噬细胞的浸润且呈剂量依赖性。此外，这种睾丸间质巨噬细胞的募集取决于血睾屏障的破坏，而非生殖细胞的损失。此外，睾丸间质巨噬细胞的减少导致分化中的精原细胞数量减少。
