Differential Effects of Phthalates on the Testis and the Liver1

Abstract

Phthalates have been shown to elicit contrasting effects on the testis and the liver, causing testicular degeneration and promoting abnormal hepatocyte proliferation and carcinogenesis. In the present study, we compared the effects of phthalates on testicular and liver cells to better understand the mechanisms by which phthalates cause testicular degeneration. In vivo treatment of rats with di-(2-ethylhexyl) phthalate (DEHP) caused a threefold increase of germ cell apoptosis in the testis, whereas apoptosis was not changed significantly in livers from the same animals. Western blot analyses revealed that peroxisome proliferator-activated receptor (PPAR) alpha is equally abundant in the liver and the testis, whereas PPAR gamma and retinoic acid receptor (RAR) alpha are expressed more in the testis. To determine whether the principal metabolite of DEHP, mono-(2-ethylhexyl) phthalate (MEHP), or a strong peroxisome proliferator, 4-chloro-6(2,3-xylindino)-2-pyrimidinylthioacetic acid (Wy-14,643), have a differential effect in Sertoli and liver cells by altering the function of RAR alpha and PPARs, their nuclear trafficking patterns were compared in Sertoli and liver cells after treatment. Both MEHP and Wy-14,643 increased the nuclear localization of PPAR alpha and PPAR gamma in Sertoli cells, but they decreased the nuclear localization of RAR alpha, as previously shown. Both PPAR alpha and PPAR gamma were in the nucleus and cytoplasm of liver cells, but RAR alpha was predominant in the cytoplasm, regardless of the treatment. At the molecular level, MEHP and Wy-14,643 reduced the amount of phosphorylated mitogen-activated protein kinase (activated MAPK) in Sertoli cells. In comparison, both MEHP and Wy-14,643 increased phosphorylated MAPK in liver cells. These results suggest that phthalates may cause contrasting effects on the testis and the liver by differential activation of the MAPK pathway, RAR alpha, PPAR alpha, and PPAR gamma in these organs.

Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition

“…In the testis, the three PPAR isoforms are expressed in both somatic and germ cells (Braissant et al 1996, Elbrecht et al 1996, Bhattacharya et al 2005. PPAR and PPAR / are widely expressed in interstitial Leydig cells and seminiferous tubule cells (Sertoli and germ cells) (Braissant et al 1996, Schultz et al 1999.…”

“…Indeed, PPAR -and PPAR / -null mice are viable and fertile (Lee et al 1995, Peters et al 2000. Xenobiotic ligands of PPAR and PPAR induce the translocation of these receptors to the nucleus of Sertoli cells (Bhattacharya et al 2005). PPAR is also more strongly expressed in human testicular cancer cells than in normal testicular tissues.…”

Contribution of environmental pollutants to male infertily: A working model of germ cell apoptosis induced by plasticizers

“…In this regard, it has been shown that stress signals are related to an increase in ROS production, along with an activation of the p38MAPK pathway (Liu and Chang, 2009) that in turn upregulates the Fas/FasL system. However, EDs promote inactivation of p38MAPK and ERK1/2 in isolated Sertoli cells and TM4 cells (Aravindakshan and Cyr, 2005;Bhattacharya et al, 2005), which has been related to the downregulation of TJ, AJ and GJ proteins and in this way induces sloughing and apoptosis of germ cells, showing that the mechanisms of ED affects spermatogenesis are still a subject of controversy.…”

Biochemical and Histopathological Effects of in Utero Di-N-Hexyl Phthalate and Di-Cyclohexyl Phthalate Exposure on the Thyroid Axes and T3, T4, TSH Hormone Levels of Male and Female Rats: at Adulthood

“…Phthalates are a class of widely used industrial compounds known technically as di-alkyl or alkyl aryl esters of 1,2-benzenedicarboxylic acid and are used mainly as a specialty plasticizer for nitrocellulose, polyvinyl acetate, and polyvinyl chloride, a lubricant for aerosol valves, an antifoaming agent, a skin emollient, and plasticizer in nail polish, fingernail elongates, and hair spray (1,2). There are many phthalates with many uses, and just as many toxicological properties.…”