Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation, and mitochondrial dysfunction in the testis

TY - JOUR

T1 - Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation, and mitochondrial dysfunction in the testis

AU - Li, Xiaolin

AU - Fang, Evandro Fei

AU - Scheibye-Knudsen, Morten

AU - Cui, Honghua

AU - Qiu, Lu

AU - Li, Jian

AU - He, Yuping

AU - Huang, Jing

AU - Bohr, Vilhelm A.

AU - Ng, Tzi Bun

AU - Guo, Hongwei

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923304409&partnerID=8YFLogxK

U2 - 10.1038/srep06434

DO - 10.1038/srep06434

M3 - Journal article

C2 - 25242624

AN - SCOPUS:84923304409

SN - 2045-2322

VL - 4

JO - Scientific Reports

JF - Scientific Reports

M1 - 6434

ER -