Effects of rosiglitazone on ovarian function and fertility in animals with reduced fertility following fetal and neonatal exposure to nicotine

Abstract

We have previously shown that in utero nicotine exposure causes impaired fertility, follicle immaturity, and ovarian dysfunction in adult female rat offspring. These characteristics overtly resemble the clinical profile of polycystic ovarian syndrome (PCOS) and recent studies have shown that thiazolidinediones such as rosiglitazone improve fertility in women with PCOS but the mechanism is not well defined. Our goal was to examine whether rosiglitazone would (1) ameliorate the altered ovarian physiology that occurs following fetal and neonatal exposure to nicotine and (2) to examine whether this could be due to normalization of ovarian vascularization. At weaning, offspring of nicotine-exposed dams were given either vehicle (NV) or rosiglitazone (3 mg kg(-1) day(-1); NR). Offspring of saline-exposed dams received vehicle (SV). Tissues were collected when the female offspring reached 26 weeks of age. NV animals had reduced granulosa cell proliferation and increased ovarian cell apoptosis. Treatment with rosiglitazone increased proliferation, and decreased apoptosis, compared NV animals. NV animals had decreased ovarian vascularity relative to controls, whereas NR animals had an intermediate level of ovarian vessel density. Moreover, ovaries from NV animals had decreased levels of the pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF both of which were increased with rosiglitazone treatment. Rosiglitazone reversed some of the nicotine effects in the ovary and increased ovarian vascularization, follicle maturation and improved oocyte competence. Rosiglitazone may be an important treatment option for PCOS and the present study provides a potential mechanism by which rosiglitazone may have beneficial effects on fertility in these patients.

PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development

“…Interestingly, it has been reported that PPAR␥ activation by rosiglitazone reversed adverse nicotine effects on the ovary vascularization by increasing EG-VEGF expression (37).…”

Adverse effects of perinatal nicotine exposure on reproductive outcomes

“…To date, there are no human studies examining the reproductive outcomes in children exposed to NRTs in utero. Studies in animal models have identified that prenatal exposure to nicotine alone can result in increased germ cell depletion and altered steroidogenesis in male offspring (Lagunov et al 2011, Paccola et al 2014) and increased ovarian cell apoptosis, altered steroidogenesis, and impaired fertility in female offspring (Holloway et al 2006, Petrik et al 2009.…”

“…The relationship between nicotine, oxidative stress, and ovarian physiology has been less well studied, although nicotine has been shown to cause oxidative stress in Chinese Hamster Ovary cells (Yildiz et al 1998, Yildiz 2004. Importantly, oxidative stress is associated with increased ovarian cell apoptosis and follicle loss -outcomes that have been similarly observed in rats exposed to nicotine in adulthood (Camargo et al 2014) and fetal life (Petrik et al 2009). Collectively, these findings suggest that nicotine-induced oxidative stress may be an important, and potentially modifiable, pathway leading to impaired reproductive health in the offspring.…”

“…Importantly, these cytokines play key roles in germ cell survival and gonadal steroidogenesis (Bornstein et al 2004, Perez et al 2013, Field et al 2014. As fetal exposure to nicotine in rodents has been demonstrated to cause germ cell loss and altered steroidogenesis (Holloway et al 2006, Petrik et al 2009, Lagunov et al 2011, Paccola et al 2014, it is biologically plausible that these effects may be mediated by an altered inflammatory response, although this has yet to be experimentally determined.…”

“…Firstly, ER stress has been shown to play a key role in ovarian cell apoptosis and follicular atresia (Yang et al 2015), a phenotype similarly observed in nicotine-exposed offspring (Petrik et al 2009). Secondly, nicotine exposure causes morphological changes in the ER of adult mouse oocytes (Rajikin et al 2009); ultrastructural changes in the ER have also been documented in response to ER stress (Schonthal 2012).…”