title: Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation, and mitochondrial dysfunction in the testis.
abstract: Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitously used endocrine disruptor.There is widespread exposure to DEHP in the general population which has raised substantial public concern due to its potential detrimental health effects. It is particularly pertinent to investigate the molecular mechanisms of its testicular toxicity which are largely unknown. By feeding male rats DEHP for 2 weeks, rat spermatogenesis became disrupted, resulting in a decreased number of spermatocytes and spermatids. Since rapidly dividing tissues appeared to be particularly vulnerable to DEHP toxicity we investigated the effect of DEHP on DNA replication. Intriguingly, DEHP appeared to inhibit DNA replication as evidenced by results of fiber tract analysis. This led to induction of the mitochondrial apoptotic pathways and increased ROS production. Furthermore, the toxicity of DEHP led to respiratory chain defects and attenuation of ATP level probably brought about by hyperPARylation and undermined SIRT1 activity. Our findings reveal a previously unknown mitochondrial dysfunction in DEHP-induced testicular toxicity and highlight the importance of SIRT1 in male reproduction.
authors.affiliation: 1] School of Public Health, Fudan University, Shanghai, 200032, China [2] Shanghai Entry-Exit Inspection and Quarantine Bureau, Shanghai, 200135, China [3].
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.affiliation: 1] Laboratory of Molecular Gerontology, National Institute on Ageing, National Institutes of Health, Baltimore, MD USA [2] School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, New Territories, Hong Kong [3].
authors.forename: Evandro Fei
authors.initials: EF
authors.lastname: Fang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Ageing, National Institutes of Health, Baltimore, MD USA.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.affiliation: Shanghai Stomatological Disease Centre. Shanghai, 200001, PR China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Cui
authors.affiliation: Shanghai Entry-Exit Inspection and Quarantine Bureau, Shanghai, 200135, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Shanghai Entry-Exit Inspection and Quarantine Bureau, Shanghai, 200135, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Entry-Exit Inspection and Quarantine Bureau, Shanghai, 200135, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: He
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Ageing, National Institutes of Health, Baltimore, MD USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Ageing, National Institutes of Health, Baltimore, MD USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Tzi Bun
authors.initials: TB
authors.lastname: Ng
authors.affiliation: School of Public Health, Fudan University, Shanghai, 200032, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Guo
mesh_terms: D000818:Animals; D004261:DNA Replication / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D012098:Reproduction / Q000187:drug effects / Q000235:genetics; D056564:Sirtuin 1 / Q000096:biosynthesis*; D013091:Spermatogenesis / Q000187:drug effects* / Q000235:genetics; D013737:Testis / Q000187:drug effects
chemical_list: C488368:Sirt1 protein, rat; D056564:Sirtuin 1