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Di(2-ethylhexyl)-phthalate (DEHP) is the most abundantly used phthalate derivative, inevitable environmental exposure of which is suspected to contribute to the increasing incidence of testicular dysgenesis syndrome in humans. Oxidative stress and mitochondrial dysfunction in germ cells are suggested to contribute to phthalate-induced disruption of spermatogenesis in rodents, and Leydig cells are one of the main targets of phthalates' testicular toxicity. Selenium is known to be involved in the modulation of intracellular redox equilibrium, and plays a critical role in testis, sperm, and reproduction. This study was aimed to investigate the oxidative stress potential of DEHP and its consequences in testicular cells, and examine the possible protective effects of selenium using the MA-10 mouse Leydig tumor cell line as a model. In the presence and absence of selenium compounds [30 nM sodium selenite (SS), and 10 μM selenomethionine (SM)], the effects of exposure to DEHP and its main metabolite mono(2-ethylhexyl)-phthalate (MEHP) on the cell viability, enzymatic and non-enzymatic antioxidant status, ROS production, p53 expression, and DNA damage by alkaline Comet assay were investigated. The overall results of this study demonstrated the cytotoxicity and genotoxicity potential of DEHP, where MEHP was found to be more potent than the parent compound. SS and SM produced almost the same level of protection against antioxidant status modifying effects, ROS and p53 inducing potentials, and DNA damaging effects of the two phthalate derivatives. It was thus shown that DEHP produced oxidative stress in MA-10 cells, and selenium supplementation appeared to be an effective redox regulator in the experimental conditions used in this study, emphasizing the critical importance of the appropriate selenium status.

WHAT'S KNOWN ON THIS SUBJECT:Being an androgen antagonist and a possible estrogen agonist, several endocrinologic effects of DEHP have been demonstrated mostly in vitro and in animals. A limited number of studies have linked the endocrinologic effects of DEHP and its metabolite, MEHP, in humans. WHAT THIS STUDY ADDS:To our knowledge, this is the first study to define a possible effect of DEHP and MEHP in pubertal gynecomastia. The etiology of pubertal gynecomastia is attributed either to excessive estrogen, deficient androgen, increased aromatase enzyme activity, or a combination. abstract OBJECTIVE: Several untoward health effects of phthalates, which are a group of industrial chemicals with many commercial uses including personal-care products and plastic materials, have been defined. The most commonly used, di-(2-ethylhexyl)-phthalate (DEHP), is known to have antiandrogenic or estrogenic effects or both. Mono-(2-ethylhexyl)-phthalate (MEHP) is the main metabolite of DEHP. In this study, we aimed to determine the plasma DEHP and MEHP levels in pubertal gynecomastia cases. PATIENTS AND METHODS:The study group comprised 40 newly diagnosed pubertal gynecomastia cases who were admitted to Hacettepe University Ihsan Dog ramacı Children's Hospital. The control group comprised 21 age-matched children without gynecomastia or other endocrinologic disorder. Plasma DEHP and MEHP levels were measured by using high-performance liquid chromatography. Serum hormone levels were determined in some pubertal gynecomastia cases according to the physician's evaluation. RESULTS:Plasma DEHP and MEHP levels were found to be statistically significantly higher in the pubertal gynecomastia group compared with the control group (P Ͻ .001) (DEHP, 4.66 Ϯ 1.58 and 3.09 Ϯ 0.90 g/mL, respectively [odds ratio: 2.77 (95% confidence interval: 1.48 -5.21)]; MEHP, 3.19 Ϯ 1.41 and 1.37 Ϯ 0.36 g/mL [odds ratio: 24.76 (95% confidence interval: 3.5-172.6)]). There was a statistically significant correlation between plasma DEHP and MEHP levels (r: 0.58; P Ͻ .001). In the pubertal gynecomastia group, no correlation could be determined between plasma DEHP and MEHP levels and any of the hormone levels.CONCLUSIONS: DEHP, which has antiandrogenic or estrogenic effects, may be an etiologic factor in pubertal gynecomastia. These results may pioneer larger-scale studies on the etiologic role of DEHP in pubertal gynecomastia. Pediatrics 2010;125:e122-e129

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