Genistein attenuates di‑(2‑ethylhexyl) phthalate-induced testicular injuries via activation of Nrf2/HO‑1 following prepubertal exposure

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) and genistein (GEN) are of the most common endocrine disrupting chemicals (EDCs) present in the environment or the diet. However, investigation of the effects of acute exposure to these two EDCs during prepuberty has been lacking. In this study, DEHP and GEN were administrated to prepubertal male Sprague-Dawley rats by gavage from PND22 to PND35 with vehicle control, GEN 50 mg/kg body weight (bw)/day, DEHP50, 150 and 450 mg/kg bw/day, and combined treatment. Reproductive parameters including testis weight, anogenital distance and organ coefficient were evaluated on PND36. Enzyme activity involved in the regulation of testicular redox state as well as expression of genes and proteins related to anti-oxidative ability and apoptosis were also investigated. The results revealed that by PND36, DEHP treatment had significantly decreased the testis weight, organ coefficient, testicular anti-oxidative enzyme activities and caused tubular vacuolation; however, co-administration of GEN partially alleviated DEHP-induced testicular injuries and enhanced testicular anti-oxidative enzyme activities and upregulated the expression of NF-E2 related factor 2 and heme oxygenase-1, which indicated that GEN partially attenuated DEHP-induced male reproductive system damage through anti-oxidative action following acute prepubertal exposure to DEHP. Thus, GEN may have use in attenuating the damaging effects of other EDCs that lead to reproductive disorders.

Epigenetic repression of miR-17 contributed to di(2-ethylhexyl) phthalate-triggered insulin resistance by targeting Keap1-Nrf2/miR-200a axis in skeletal muscle

“…Keap1-Nrf2 signaling is a key antioxidant system that can detoxify exogenous toxicants to maintain cellular homoeostasis 17 , 40 , 41 . Decreased Nrf2 rendered cells susceptible to oxidative stress.…”

“…The role of oxidative stress in DEHP-induced IR was also emphasized in a cross-sectional pilot study in which exposure to DEHP at the community level promoted IR in 10-13-year-old children by inducing systemic oxidant stress, characterized by the increased urinary level of F2-isoprostane 15 . Nrf2 is a master regulator of the cytoprotective program against oxidative stress and, more importantly, has the capability to detoxify DEHP 16 , 17 . Our previous study indicated a critical role for the Nrf2-mediated antioxidant response in DEHP-induced rat insulinoma INS-1 cells dysfunction 8 .…”

Low Dose of Genistein Alleviates Mono-(2-Ethylhexyl) Phthalate-Induced Fetal Testis Disorder Based on Organ Culture Model

“…Culty et al [12] reported that fetal testosterone biosynthesis was suppressed via activation of peroxisome proliferatoractivated receptors (PPARs) after phthalate exposure; in this process, imbalance in prooxidant/antioxidant ratio was induced and reactive oxygen species (ROS) production was elevated [12]. Our previous studies revealed that exposure to MEHP at doses higher than human exposure level induced the impairment of testicular antioxidative enzyme activities, and oxidative stress aggravated testicular injuries as the doses increased [6,7]. Other studies also observed an increased apoptosis rate of spermatocytes, atrophy of testis, and high sperm DNA fragmentation index together with elevated ROS level [46,47].…”

“…However, the combined effects after exposure to at least two kinds of EDCs have rarely been investigated [5]. Genistein (GEN), a kind of soy isoflavones commonly present in the Asian diet [6], and mono-(2-ethylhexyl) phthalate (MEHP), the metabolite of the widely used plasticizer di(2-ethylhexyl) phthalate (DEHP), are two kinds of the most prevalent EDCs which act via different mechanisms [7]. In previous studies, genistein was categorized as a weak estrogenic phytoestrogen, but more recently, it was found to be a potential antioxidant [8].…”

“…It is notable that genistein could exert biphasic effects on male fertility by promoting acrosome reaction at lower doses while suppressing acrosome reaction at higher doses [9]. Soy isoflavones including genistein were confirmed to enhance cellular antioxidative system and alleviate the oxidative injury induced by EDCs like cadmium, TPA [6,10,11]. DEHP and MEHP were reported to suppress fetal testosterone biosynthesis by activating peroxisome proliferator-activated receptors (PPARs) [12].…”