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.

Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder

“…[37][38][39] Phthalates cause mitochondrial dysfunction in mouse Leydig cells, and in the testis. 40,41 A recent meta-analysis found that the prevalence of mitochondrial disease in children with autism spectrum disorder was 5%. 42 Clinical evaluation and laboratory analyses (blood lactate, pyruvate, alanine, total carnitine, creatine kinase, ammonia, aspartate aminotransferase, and alanine aminotransferase) did not indicate mitochondrial disease in this study.…”

Toxic Effects of Di-2-ethylhexyl Phthalate: An Overview

“…Activation of DNA damage leads to SIRT1 (regulator of mitochondrial function) attenuation and thereby suppresses testicular ATP levels. The DEHP-induced attenuation of ATP levels may be a crucial problem to male fertility since the motility of spermatozoa depends on sperm ATP [ 37 ].…”

Endocrine Disruptors and Reproductive Health in Males

“…Kasahara et al [96] indicate associations between DEHP administration and increased production of ROS and selectively decreased GSH and ascorbic acid in the testis with a consequent induction of rat sperm cell apoptosis leading to testicular atrophy after in vivo DEHP exposition. More specifically, the results provided by Li et al [108] when male rats were fed DEHP for 2 weeks. The result was that the spermatogenesis became disrupted with decreased spermatocytes and spermatids counts and in addition, DEHP (20, 100, 500, to 1000 mg/kg) appeared to inhibit DNA replication.…”