During adulthood, in healthy conditions, the ovarian reserve constitutes several stages of follicles in the process of development (Ford et al., 2020; Pan and Li, 2019), while the aging process naturally diminishes the follicle population in ovaries (Shifren and Schiff, 2000). These follicles are recruited throughout the woman's reproductive life through hormonal control, to assure reproductive function (Ford et al., 2020; Ouni et al., 2019a). In this regard, local estrogens and progesterone act in balance to progress each oocyte by the development of follicle features, under the regulation of the hypothalamic-pituitary axis (Brodowska et al., 2007; Emmen et al., 2005). In addition the main synthesis of female steroid hormones occurs in the ovarian follicles, as well as in the adrenal gland (Azziz, 2018). The enhancement of serum levels of these hormones is an outcome of follicle growth during the menstrual cycle and determines ovulation and the development of secondary characteristics, such as mammary and uterine development (Cunha et al., 2004; Dinny Graham and Clarke, 1997). Therefore, imbalances in follicular development and ovarian steroidogenesis directly affect female fertility and homeostasis (De Vos et al., 2010; Ouni et al., 2019b; Zhang and Liu, 2015).

Ovarian function may be impaired due to exposure to endocrine disruptors (Patel et al., 2015, 2017). These exogenous agents act directly in the ovarian tissue, diminishing ovarian reserve and, thus, depleting steroidogenic potential (Cho et al., 2020; Costa et al., 2014). Polycystic ovarian syndrome and ovarian cancer have been described as outcomes related to exposure to these compounds (Palioura and Diamanti-Kandarakis, 2015). Bisphenol A (BPA), an exogenous endocrine disruptor, disrupts estrogenic pathways associated with both the main steroid receptors, estrogen receptor alpha (ERα) and beta (ERβ), inducing different cellular effects (Dumitrascu et al., 2020; Nadal et al., 2018). In contrast, recent studies demonstrated the potential of BPA to activate different receptors in cells (Shafei et al., 2018), triggering important impacts in different levels of biological systems (Ruiz et al., 2021c).

Major effects of perinatal and neonatal exposure to BPA in ovaries have been widely described. Ovarian reserve is drastically decreased after BPA exposure (Cao et al., 2018), leading to infertile characteristics in adult females (Ehrlich et al., 2012). Atresia and apoptosis are frequently associated with BPA exposure in neonates and adults, decreasing the healthy follicular population in the ovaries (Bilgi et al., 2019; Cao et al., 2018). In addition, BPA exposure during the perinatal period impairs follicular activation by disrupting the transcription of STAR and CYP genes (Bloom et al., 2016; Mansur et al., 2016). These features implicate disrupted ovarian steroidogenesis (Bloom et al., 2016), since pre-formation of several steroidogenic enzymes that convert cholesterol by-products are damaged (Nakamura et al., 2010; Peretz et al., 2011). However, although these characteristics are well recognized in exposure during the perinatal window of susceptibility, the outcomes in the mother's microenvironment remain undiscovered and the effects in the aged gonad are not well documented.

Our study focused on females exposed to BPA during two main windows of ovarian tissue remodeling, pregnancy, and lactation, and examined ovarian status in aged individuals. During pregnancy, ovaries are responsible to secrete endocrine hormones to develop and mature secondary structures, remodeling itself to house a large corpus luteum, which produces progesterone, estrogens, and androgens (Ruiz et al., 2021c; Sitruk-Ware and El-Etr, 2013). In lactation, the process was coordinated by hypothalamus-pituitary axis, whereas ovaries were under remodeling and their hormonal secretion were decreased (McNeilly, 1997; Yu et al., 2010). Previous studies demonstrated that mothers exposed to BPA during both periods developed mammary carcinoma features through modulation of hormone receptors (Ruiz et al., 2021a; 2021b), as well as affects glucose metabolism in long-term (Alonso-Magdalena et al., 2015) contributing to the development of diabetes (Blesson and Yallampalli, 2015). Considering that aging is a factor in the development of ovarian dysfunction (Donnez and Dolmans, 2017; Liu and Li, 2010) and, consequently, infertility and systemic symptoms of lower hormonal production, understanding the impacts of endocrine disruptors during these phases is of particular relevance (Kling et al., 2019; Meldrum, 1993). Since perimenopause causes an imbalance in hormonal release and regulation of endocrine-dependent organs, as well as the viability of follicles for reproduction (Batrinos, 2013; Butler and Santoro, 2011), we aimed to describe the histopathological repercussions of BPA exposure in pregnancy and lactation in aged ovaries using a rodent model.