Chronic dietary administration of lower levels of diethyl phthalate induces murine testicular germ cell inflammation and sperm pathologies: Involvement of oxidative stress

Abstract

The wide occurrence of male infertility is a matter of grave concern. One of the major causes being exposure to endocrine disrupting chemicals (EDCs) many of which are known reproductive toxicants but the molecular mechanisms of action remain much unexplored. Diethyl phthalate (DEP) is ubiquitous in the environment due to its extensive use as plasticizer in myriad consumer products. In the present study, we sought to find out whether chronic DEP exposure affects reproductive function in sexually mature adult male mice. For this, 8-week old Swiss albino mice were treated with DEP (1 mg and 10 mg kg−1 body weight day−1) in diet for three months, mirroring the relevant doses of human exposure, and various analyses were carried out in the testicular germ cells and epididymal spermatozoa. We found that altered testicular histoarchitecture was accompanied with disturbed prooxidant: antioxidant balance in the germ cells. Involvement of Nrf2-HO-1 pathway was crucial in this altered cellular redox state. Besides, NFκB mediated inflammatory response was triggered in the germ cells leading to enhanced levels of proinflammatory cytokines. DEP adversely affected sperm count, motility, viability and morphology. Numerous structural anomalies were found in DEP treated mice spermatozoa reflecting decline in sperm function. Our results revealed overactivation of PARP-1 and subsequent cleavage in spermatozoa with induction of apoptosis as a key mechanism in DEP mediated sperm pathology. Given the indiscriminate use of plasticizers and long term low level human exposure, the present study highlights the undesirable male reproductive outcomes following chronic DEP exposure.