Understanding the Villain: DMBA-Induced Preantral Ovotoxicity Involves Selective Follicular Destruction and Primordial Follicle Activation through PI3K/Akt and mTOR Signaling

Abstract

7,12-Dimethylbenz-[a]anthracene (DMBA) is an environmental carcinogen which has a potent ovotoxic affect on rat and mouse ovaries, causing complete follicular depletion resulting in premature ovarian failure. Although the overall effects of DMBA on ovarian folliculogenesis are well known, little is known about the exact molecular mechanisms behind its ovotoxicity. In this study, we characterized the mechanisms behind DMBA-induced ovotoxicity in immature follicles. Microarray analysis of neonatal mouse ovaries exposed to DMBA in vitro revealed a multilayered mechanism of DMBA-induced neonatal ovotoxicity involving a distinct cohort of genes and ovarian signaling pathways primarily associated with follicular atresia, tumorigenesis, and follicular growth. Histomorphological and immunohistological analysis supported the microarray data, showing evidence of primordial follicle activation and preantral follicle atresia both in vitro and in vivo. Further immunohistological analysis identified increased Akt1 phosphorylation, mTOR activation, and decreased FOXO3a expression in DMBA-treated primordial oocytes. Our results reveal a novel mechanism of DMBA-induced preantral ovotoxicity involving selective immature follicle destruction and primordial follicle activation involving downstream members of the PI3K/Akt and mTOR signaling pathways.

All Your Eggs in One Basket: Mechanisms of Xenobiotic Induced Female Reproductive Senescence

“…There is now an increasing volume of studies which link primordial follicle depletion with xenobiotic exposure, suggesting that these irreplaceable follicles are highly sensitive to www.intechopen.com cytotoxic insult (Hoyer and Devine, 2001;Mattison et al, 1983aMattison et al, , 1983bSobinoff et al, 2010Sobinoff et al, , 2011. It is thought that this sensitivity may stem from the primordial follicles quiescent nature.…”

“…In addition to direct primordial follicle injury, certain xenobiotics which target developing follicles have been shown to cause excessive primordial follicle activation Sobinoff et al, 2010Sobinoff et al, , 2011. This may be due to a homeostatic mechanism of follicular replacement, in which destroyed developing follicles result in primordial follicle activation to replace the developing pool.…”

“…An example of this localised bioactivation is the reported metabolism of the polycyclic aromatic hydrocarbon DMBA (Fig.3). Ovarian exposure to DMBA disrupts folliculogenesis, resulting in the destruction of all follicle populations leading to POF in rodents, although recent evidence suggests an alternate mechanism of ovotoxicity resulting in primordial follicle depletion in the mouse (Mattison and Schulman, 1980;Sobinoff et al, 2011). This toxicity has been attributed to the bioactivation of DMBA into its ultimate DNA-adduct forming intermediate DMBA-3,4-diol-1,2-epoxide (Shiromizu and Mattison, 1985).…”

“…However, there is now a growing body of evidence which suggests that xenobiotics cause primordial follicle depletion through accelerated primordial follicle activation Sobinoff et al, 2010Sobinoff et al, , 2011. A study of VCD and MXC induced primordial follicle depletion has revealed a selective mechanism of pre-antral ovotoxicity involving small developing follicle atresia and primordial follicle activation both in vitro and in vivo (Sobinoff et al, 2010).…”

“…There is now a growing body of evidence which suggests that foreign synthetic chemicals, also known as xenobiotics, are capable of causing POF by inducing premature follicular depletion. Indeed, exposure to pesticides, workplace chemicals, chemotherapeutic agents and cigarette smoke have all been associated with primordial follicle reduction resulting in premature ovarian senescence (Hoyer and Devine, 2001;Mattison et al, 1983aMattison et al, , 1983bSobinoff et al, 2010Sobinoff et al, , 2011.…”