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We also verified whether the changes are reversible following treatment interruption.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      Adult rats received paroxetine (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and malondialdehyde concentrations were measured. To confirm serotonergic and estrogenic effects,\n                      <jats:italic>Htr1b<\/jats:italic>\n                      and\n                      <jats:italic>Esr1<\/jats:italic>\n                      expressions were analyzed. The daily sperm production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL\n                      <jats:sup>+<\/jats:sup>\n                      germ cells, M1 (CD68\n                      <jats:sup>+<\/jats:sup>\n                      ), and M2 (Perls\n                      <jats:sup>+<\/jats:sup>\n                      ) macrophages were quantified. 17\u03b2\u2010HSD7, CYP19A1, NDRG2, oxytocin, TNF\u2010\u03b1, and iNOS were evaluated by immunoreactions. Oxytocin and NDRG2 protein levels as well as\n                      <jats:italic>Tnfa<\/jats:italic>\n                      mRNA expression were also analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>Htr1b<\/jats:italic>\n                      downregulation in testes confirmed the paroxetine serotonergic effect. The testicular sections showed abnormal ST frequency, ST atrophy and reduction of DSP, LCnu, SC number and Perls\n                      <jats:sup>+<\/jats:sup>\n                      macrophages. TUNEL\n                      <jats:sup>+<\/jats:sup>\n                      germ cells and LC were associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 17\u03b2\u2010HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF\u2010\u03b1 and iNOS.\n                      <jats:italic>Esr1<\/jats:italic>\n                      and\n                      <jats:italic>Tnfa<\/jats:italic>\n                      overexpression and increased number of CD68\n                      <jats:sup>+<\/jats:sup>\n                      macrophages were also observed together with high nitrite and malondialdehyde levels. Most parameters were not recovered in PG65.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Paroxetine serotonergic effect impairs LC steroidogenesis, via aromatization, increasing estrogen\/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, and impairing sperm production. Serotonin\u2013estrogen pathways may be responsible for M2\/M1 polarization,\n                      <jats:italic>Tnfa<\/jats:italic>\n                      upregulation, and induction of oxidative stress. The unrecovered testicular changes after treatment discontinuation are due to persistent paroxetine serotonin\/estrogen effects.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/andr.13513","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T07:48:51Z","timestamp":1694072931000},"page":"655-673","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of serotonin, estrogen, and TNF\u2010\u03b1 in the paroxetine\u2010impaired steroidogenesis and testicular macrophages polarization"],"prefix":"10.1111","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1833-1150","authenticated-orcid":false,"given":"Fl\u00e1via Luciana","family":"Beltrame","sequence":"first","affiliation":[{"name":"Department of Morphology and Genetics Federal University of S\u00e3o Paulo  S\u00e3o Paulo Brazil"},{"name":"Institute of Health Sciences, Paulista University 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