{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:32:30Z","timestamp":1763389950777,"version":"3.41.2"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":19,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH\/NIEHS","award":["R01ES016591"],"award-info":[{"award-number":["R01ES016591"]}]},{"name":"Center for Molecular Carcinogenesis and Toxicology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u00a0mg\/kg or 500\u00a0mg\/kg MEHP or 250\u00a0mg\/kg MEHP for 3 consecutive days or 100\u00a0mg\/kg for 7 consecutive days to study chronic exposure. Here, we report that an acute exposure to 500\u00a0mg\/kg and a repeated 250\u00a0mg\/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.<\/jats:p>","DOI":"10.1093\/toxres\/tfaf097","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:03:02Z","timestamp":1752501782000},"source":"Crossref","is-referenced-by-count":1,"title":["Dose-dependent testis infiltration of peritubular macrophages after MEHP exposure of Peri-pubertal rats and their role in the recovery of spermatogenesis"],"prefix":"10.1093","volume":"14","author":[{"given":"Richa","family":"Tiwary","sequence":"first","affiliation":[{"name":"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 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Fang","sequence":"additional","affiliation":[{"name":"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 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"Nguyen","sequence":"additional","affiliation":[{"name":"College of Natural Sciences, 120 Inner Campus Drive, Austin, TX 78712, The University of Texas at Austin , Austin, TX, 78712 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6334-9777","authenticated-orcid":false,"given":"John H","family":"Richburg","sequence":"additional","affiliation":[{"name":"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 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"2025072400285393800_ref1","doi-asserted-by":"publisher","first-page":"152","DOI":"10.3389\/fimmu.2012.00152","article-title":"Structural, cellular and molecular aspects of immune privilege in the testis","volume":"3","author":"Li","year":"2012","journal-title":"Front Immunol"},{"key":"2025072400285393800_ref2","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1007\/BF00251049","article-title":"Macrophages in the interstitial tissue of the rat testis","volume":"243","author":"Niemi","year":"1986","journal-title":"Cell Tissue Res"},{"key":"2025072400285393800_ref3","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/0165-0378(95)91391-Q","article-title":"Indomethacin blocks the immunosuppressive activity of rat testicular macrophages cultured in vitro","volume":"28","author":"Kern","year":"1995","journal-title":"J Reprod Immunol"},{"key":"2025072400285393800_ref4","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1002\/j.1939-4640.1996.tb00585.x","article-title":"Secretion of bioactive interleukin 1 by rat testicular macrophages in vitro","volume":"17","author":"Hayes","year":"1996","journal-title":"J Androl"},{"key":"2025072400285393800_ref5","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1095\/biolreprod.113.115527","article-title":"Age- and species-dependent infiltration of macrophages into the testis of rats and mice exposed to mono-(2-ethylhexyl) phthalate (MEHP)1","volume":"91","author":"Murphy","year":"2014","journal-title":"Biol Reprod"},{"key":"2025072400285393800_ref6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1530\/REP-18-0093","article-title":"MEHP-induced rat testicular inflammation does not exacerbate germ cell apoptosis","volume":"156","author":"Voss","year":"2018","journal-title":"Reproduction"},{"key":"2025072400285393800_ref7","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1016\/j.celrep.2015.07.015","article-title":"Macrophages contribute to the Spermatogonial niche in the adult testis","volume":"12","author":"DeFalco","year":"2015","journal-title":"Cell Rep"},{"key":"2025072400285393800_ref8","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/toxsci\/kfab059","article-title":"Peritubular macrophages are recruited to the testis of Peripubertal rats after mono-(2-Ethylhexyl) phthalate exposure and is associated with increases in the numbers of Spermatogonia","volume":"182","author":"Gillette","year":"2021","journal-title":"Toxicol Sci"},{"key":"2025072400285393800_ref9","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1093\/toxsci\/kfad128","article-title":"Responses of peritubular macrophages and the testis transcriptome profiles of peripubertal and adult rodents exposed to an acute dose of MEHP","volume":"198","author":"Fang","year":"2024","journal-title":"Toxicol Sci"},{"key":"2025072400285393800_ref10","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1093\/toxsci\/kfae043","article-title":"The blood-testis barrier disruption is a prerequisite for toxicant-induced peritubular macrophage increases in the testis of peripubertal rats","volume":"200","author":"Fang","year":"2024","journal-title":"Toxicol Sci"},{"key":"2025072400285393800_ref11","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1093\/toxsci\/kfad116","article-title":"Mono-(2-ethylhexyl) phthalate (MEHP) reversibly disrupts the blood-testis barrier (BTB) in pubertal rats","volume":"197","author":"Tiwary","year":"2023","journal-title":"Toxicol Sci Off J Soc Toxicol"},{"key":"2025072400285393800_ref12","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/BF00302755","article-title":"Distribution and elimination of di-2-ethylhexyl phthalate (DEHP) and mono-2-ethylhexyl phthalate (MEHP) after a single oral administration of DEHP in rats","volume":"51","author":"Oishi","year":"1982","journal-title":"Arch Toxicol"},{"key":"2025072400285393800_ref13","doi-asserted-by":"publisher","first-page":"3456","DOI":"10.1172\/JCI57984","article-title":"Foxo1 is required in mouse spermatogonial stem cells for their maintenance and the initiation of spermatogenesis","volume":"121","author":"Goertz","year":"2011","journal-title":"J Clin Invest"},{"key":"2025072400285393800_ref14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1248\/bpb.27.13","article-title":"Phagocytic removal of apoptotic spermatogenic cells by Sertoli cells: mechanisms and consequences","volume":"27","author":"Nakanishi","year":"2004","journal-title":"Biol Pharm Bull"},{"key":"2025072400285393800_ref15","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1002\/(SICI)1521-1878(200005)22:5&lt;423::AID-BIES4&gt;3.0.CO;2-0","article-title":"Germ cell suicide: new insights into apoptosis during spermatogenesis","volume":"22","author":"Print","year":"2000","journal-title":"Bioessays."},{"key":"2025072400285393800_ref16","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1095\/biolreprod.109.080374","article-title":"Mono-(2-ethylhexyl) phthalate-induced disruption of junctional complexes in the seminiferous epithelium of the rodent testis is mediated by MMP2","volume":"82","author":"Yao","year":"2010","journal-title":"Biol Reprod"},{"key":"2025072400285393800_ref17","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.semcdb.2014.02.011","article-title":"Sertoli cells \u2013 immunological sentinels of spermatogenesis","volume":"30","author":"Kaur","year":"2014","journal-title":"Semin Cell Dev Biol"},{"key":"2025072400285393800_ref18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/153537020623100101","article-title":"Physiologic interactions between macrophages and Leydig cells","volume":"231","author":"Hutson","year":"2006","journal-title":"Exp Biol Med"}],"container-title":["Toxicology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/14\/4\/tfaf097\/63836241\/tfaf097.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxres\/article-pdf\/14\/4\/tfaf097\/63836241\/tfaf097.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T04:28:58Z","timestamp":1753331338000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxres\/article\/doi\/10.1093\/toxres\/tfaf097\/8211418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,5]]},"references-count":18,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7,5]]}},"URL":"https:\/\/doi.org\/10.1093\/toxres\/tfaf097","relation":{},"ISSN":["2045-4538"],"issn-type":[{"type":"electronic","value":"2045-4538"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,7,5]]},"article-number":"tfaf097"}}