title: Fluoride-elicited developmental testicular toxicity in rats: roles of endoplasmic reticulum stress and inflammatory response.
abstract: Long-term excessive fluoride intake is known to be toxic and can damage a variety of organs and tissues in the human body. However, the molecular mechanisms underlying fluoride-induced male reproductive toxicity are not well understood. In this study, we used a rat model to simulate the situations of human exposure and aimed to evaluate the roles of endoplasmic reticulum (ER) stress and inflammatory response in fluoride-induced testicular injury. Sprague-Dawley rats were administered with sodium fluoride (NaF) at 25, 50 and 100mg/L via drinking water from pre-pregnancy to gestation, birth and finally to post-puberty. And then the testes of male offspring were studied at 8weeks of age. Our results demonstrated that fluoride treatment increased MDA accumulation, decreased SOD activity, and enhanced germ cell apoptosis. In addition, fluoride elevated mRNA and protein levels of glucose-regulated protein 78 (GRP78), inositol requiring ER-to-nucleus signal kinase 1 (IRE1), and C/EBP homologous protein (CHOP), indicating activation of ER stress signaling. Furthermore, fluoride also induced testicular inflammation, as manifested by gene up-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in a nuclear factor-κB (NF-κB)-dependent manner. These were associated with marked histopathological lesions including injury of spermatogonia, decrease of spermatocytes and absence of elongated spermatids, as well as severe ultrastructural abnormalities in testes. Taken together, our results provide compelling evidence that ER stress and inflammation would be novel and significant mechanisms responsible for fluoride-induced disturbance of spermatogenesis and germ cell loss in addition to oxidative stress.
authors.affiliation: Department of Environmental Health and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan 430030, Hubei, People's Republic of China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jiang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Guan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Lei
authors.forename: Tao
authors.initials: T
authors.lastname: Xia
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Yihu
authors.initials: Y
authors.lastname: Chen
authors.forename: Xue
authors.initials: X
authors.lastname: Wu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Yushan
authors.initials: Y
authors.lastname: Cui
authors.forename: Linyu
authors.initials: L
authors.lastname: Yu
authors.forename: Zhenglun
authors.initials: Z
authors.lastname: Wang
authors.forename: Aiguo
authors.initials: A
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005459:Fluorides / Q000633:toxicity*; D005854:Germ Cells / Q000187:drug effects; D007150:Immunohistochemistry; D007248:Infertility, Male / Q000139:chemically induced / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012969:Sodium Fluoride / Q000633:toxicity; D013482:Superoxide Dismutase / Q000378:metabolism; D013733:Testicular Diseases / Q000139:chemically induced* / Q000473:pathology; D013737:Testis / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008315:Malondialdehyde; D012969:Sodium Fluoride; D013482:Superoxide Dismutase; D005459:Fluorides
keywords: Endoplasmic reticulum stress; Fluoride; Inflammation; Oxidative stress; Testis