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    • br Declaration of interest br Funding

    2024-04-16


    Declaration of interest
    Funding
    Introduction The endocrine disruptor bisphenol A (BPA) is a high-production chemical used in several consumer products, including polycarbonate bottles, epoxy resins, dental sealants, and thermal paper receipts (Geens et al., 2012). Importantly, BPA monomers can leach into the foods and beverages as well as absorb across the skin. Most humans tested have detectable levels of BPA or its metabolites in their system, with highest levels found in infants and children (Calafat et al., 2008; Zhang et al., 2011). Consequently, concerns have been raised about the impact of this endocrine disruptor on human health. According to the United States Environmental Protection Agency (US EPA), BPA is considered to be safe for humans under the reference dose of 50 μg/kg/day. However, numerous studies have described negative effects on multiple hormone responsive tissues at lower doses of BPA (Castro et al., 2015a; Christiansen et al., 2014; García-Arevalo et al., 2014; Wadia et al., 2013), mainly when the exposure occurs during the developmental period. Several studies in mammals show that BPA can be transferred from mother to fetus (Ahmed, 2016; Miyakoda et al., 1999; Zalko et al., 2003). Although BPA dietary intake by pregnant women is at low-doses (Mariscal-Arcas et al., 2009), it has been demonstrated that low-doses of BPA can affect prostatic cell proliferation and architecture (Ogura et al., 2007; Ramos et al., 2001; Timms et al., 2005; Wu et al., 2015). Moreover, growing evidence indicate that early life exposure to BPA increases susceptibility to prostate cancer (PCa) (Di Donato et al., 2017; Ho et al., 2006; Prins et al., 2011). The mechanisms responsible for such alterations are only now starting to elucidate. Within the prostate, 5α-R converts circulating testosterone (T) into dihydrotestosterone (DHT), the primary androgen responsible for the development, maturation and function of the prostate gland and also implicated in the pathogenesis of prostatic diseases (Wilson, 2011). In the prostate, T can also be metabolized to estradiol (E2) by cytochrome P450 aromatase (P450arom) (Ellem et al., 2004), although the role of estrogens during prostatic development is unclear. Fetal E2 exposure on prostate development do not follow a monotonic dose-response (Timms et al., 2005; Vom Saal et al., 1997). Thus, IAA-94 may exert different effects on prostate according to the dose (Taylor et al., 2012; Vandenberg et al., 2012). We previously demonstrated for the first time that brief exposure to BPA alters the expression of aromatase and 5α-Reductase (5α-R) isozymes in the prostate and prefrontal cortex of adult rats (Castro et al., 2013a, 2013b; Sánchez et al., 2013). Much less is known, however, about the long-term effects of BPA exposure on these isozymes, especially during the perinatal period, which is thought to be the most susceptible period to endocrine disruption (Vom Saal, 2016), when the prostate gland develops in rodent (Hayashi et al., 1991).
    Materials and methods
    Results
    Discussion BPA exerts its biological effects at very low doses similar to amounts typically found in environment, which give rise to much concern on the risk of human exposure to BPA (Vom Saal and Hughes, 2005). Thus, doses considered safe for human being on daily exposure (NTP, 1982), such as the BPA doses used in this study, have been demonstrated harmful to male reproductive tract, when administered during developmental period of the rats (Akingbemi et al., 2004; Prins et al., 2011; Salian et al., 2009). BPA has traditionally been considered a weak environmental estrogen (Krishnan et al., 1993) and in vivo animal studies have demonstrated that it can interfere with endocrine signaling pathways at low doses during fetal, neonatal or perinatal periods as well as in adulthood (Alonso-Magdalena et al., 2012). However, several studies have indicated that BPA might also have antiandrogenic activity (Lee et al., 2003; Wang et al., 2017; Xu et al., 2005), but its effects on androgen metabolism and signaling remains largely unknown. This report demonstrates, to our best knowledge for the first time, that BPA is able to affect the major pathway for intraprostatic biosynthesis of DHT and E2 in juvenile rats exposed during the perinatal stage, including gestation and lactation (fetal and neonatal) periods when prostate develops occur. Specifically, BPA at administered doses produced a decrease in the intraprostatic mRNA and protein levels of 5α-R2 isozyme, as well as plasma T and DHT levels, leading to a decrease in intraprostatic DHT at the juvenile stage. In line with our results previous studies have demonstrated that rats born from mothers exposed to 2.4 μg/kg/day BPA (dose similar to the used in this study) or 12–50 mg kg/day BPA, during perinatal period (fetal and neonatal) decreased testicular testosterone levels, with a decline in the steroidogenic capacity of Leydig cells (Akingbemi et al., 2004; Xi et al., 2011). In addition, exposure to 2 μg/Kg/day BPA during perinatal period decreased plasma T levels (Bai et al., 2011). Fetal exposure to BPA also decreased steroidogenic enzymes expression and both plasma and testicular T levels (Hong et al., 2016).