title: Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice.
abstract: Exposure to di-(2-ethylhexyl) phthalate (DEHP) induces spermatogenic disturbance (SD) through oxidative stress, and affects the immune system by acting as an adjuvant. Recently, we reported that in mice, a low dose of DEHP, which did not affect spermatogenesis, was able to alter the testicular immune microenvironment. Experimental autoimmune orchitis (EAO) can be induced by repeated immunization with testicular antigens, and its pathology is characterized by production of autoantibodies and SD. In the present study, we investigated the effect of a low-dose DEHP on the susceptibility of mice to EAO. The exposure to DEHP-containing feed (0.01%) caused a modest functional damage to the blood-testis barrier (BTB) with an increase in testicular number of interferon gamma (IFN-γ)-positive cells and resulted in the production of autoantibodies targeting haploid cells, but did not affect spermatogenesis. While only single immunization with testicular antigens caused very mild EAO, the concurrent DEHP exposure induced severe EAO with significant increases in number of interferon gamma-positive cells and macrophages, as well as lymphocytic infiltration and serum autoantibody titer accompanied by severe SD. To summarize, the exposure of mice to the low-dose DEHP does not induce significant SD, but it may cause an increase in IFN-γ positive cells and modest functional damage to the BTB in the testis. These changes lead to an autoimmune response against haploid cell autoantigens, resulting in increased susceptibility to EAO.
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan. Electronic address: shinamon611@gmail.com.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Department of Anatomy, Aichi Medical University, Aichi, Japan.
authors.forename: Munekazu
authors.initials: M
authors.lastname: Naito
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kuramasu
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Anatomy, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Terayama
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
authors.forename: Ning
authors.initials: N
authors.lastname: Qu
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hatayama
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Department of Anatomy, Tokyo Medical University, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Itoh
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000139:chemically induced*; D015551:Autoimmunity / Q000187:drug effects*; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009920:Orchitis / Q000139:chemically induced*; D013737:Testis / Q000187:drug effects* / Q000276:immunology
chemical_list: D001324:Autoantigens; D004051:Diethylhexyl Phthalate
keywords: Adjuvant; Autoimmunity; Blood–testis barrier; Di-(2-ethylhexyl) phthalate; Testis