Neonatal exposure to bisphenol A modifies the abundance of estrogen receptor alpha transcripts with alternative 5 '-untranslated regions in the female rat preoptic

Laboratorio de Endocrinología y Tumores Hormonodependientes, School of Biochemistry and Biological Sciences, Universidad Nacional del Litoral, Casilla de Correo 242, 3000 Santa Fe, Argentina.
Journal of Endocrinology (Impact Factor: 3.59). 08/2007; 194(1):201-12. DOI: 10.1677/JOE-07-0014
Source: PubMed

ABSTRACT The xenoestrogen bisphenol A (BPA) is commonly ingested by humans. We examined the effects of neonatal exposure to low versus high doses of BPA over the control of estrogen receptor alpha (ERalpha) expression in the preoptic area (POA) of prepubertal female rats. Pups received s.c. injections every 48 h of BPA (high dose, 20 mg/kg and low dose, 0.05 mg/kg) or diethylstilbestrol (DES, 0.02 mg/kg) from postnatal day (PND) 1 to PND7 and were killed at PND8 or PND21. Relative expression of ERalpha transcripts containing alternative 5'-untranslated regions OS, ON, O, OT, and E1 in POA were evaluated by RT-PCR. Methylation status of ERalpha promoters was determined by bisulfited DNA restriction analysis and ERalpha protein by immunohistochemistry. In PND8, the high dose of BPA and DES diminished total ERalpha mRNA levels, mediated by the decreased expression of ERalpha-O and ERalpha-OT variants. In contrast, the low dose of BPA augmented total ERalpha mRNA by increasing the expression of the ERalpha-E1 variant. In PND21, both BPA doses increased total ERalpha mRNA by means of the augmented expression of ERalpha-O and ERalpha-OT variants. In PND21, the methylation status of the ERalpha promoters and the circulating levels of estradiol were similar in all experimental groups. At PND8 and PND21, DES and the high dose of BPA decreased, while the low dose of BPA increased ERalpha protein in the POA. These findings show that neonatal BPA exposure alters the abundance of hypothalamic ERalpha transcript variants and protein in a dose-dependent manner.

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Available from: Enrique H Luque, Oct 27, 2014
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    • "Because BPA-related effects on ESR expression differed with age, this appears to be unlikely, but compensation for cell loss via increased expression in existing cells cannot be ruled out (De Vries, 2004). Presumably, decreased ESR expression is indicative of reduced ESR protein levels; a relationship established in prior studies (Monje et al., 2007). "
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    ABSTRACT: Concerns have been raised regarding the long term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of pre-pubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 μg BPA/kg bw/day, or 0.5 or 5.0 μg ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in-situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work.
    Toxicological Sciences 04/2014; 140(1). DOI:10.1093/toxsci/kfu074 · 4.48 Impact Factor
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    • "Many studies have clearly shown that BPA has estrogenic properties. In previous works, using rodent and reptile models, we have shown that early BPA exposure impairs the normal development of different endocrine-related tissues [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]. "
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    ABSTRACT: We hypothesized that neonatal xenoestrogen exposure affects the ovarian follicular dynamics in lambs. Female lambs were exposed from postnatal day (PND) 1-14 to low doses of diethylstilbestrol (DES) or bisphenol A (BPA). At PND 30, the follicular dynamics and ovarian biomarkers (ERα, ERβ, AR, Ki67, p27) were evaluated. Lambs exposed to DES or BPA showed a decline in the stock of primordial follicles with stimulation of follicular development. BPA reduced ovarian weight and increased the number of multioocyte follicles. BPA promoted proliferation of granulosa/theca cells in antral follicles, and increased both the number of antral atretic follicles and p27 expression. Neonatal exposure to BPA or DES reduced the primordial follicle pool by stimulating their initial recruitment and subsequent follicle development until antral stage. In prepubertal lambs, the accelerated folliculogenesis resulted in increased incidence of atretic follicles. These alterations may affect the ovarian function in the adult.
    Reproductive Toxicology 06/2011; 32(3):304-12. DOI:10.1016/j.reprotox.2011.06.118 · 2.77 Impact Factor
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    • "Estrogens either increase or decrease the use of individual ERα promoters depending on the cell line (Donaghue et al., 1999), and this effect may be the result of estrogen-induced differences in promoter methylation. Furthermore, estrogenic compounds can influence differential expression of ERα isoforms in the developing POA (Monje et al., 2007). Although the function of individual ER and PR isoforms in sexual differentiation of the brain is unknown, estradiolinduced differences in methylation at specific promoters may influence the expression of receptor subtypes and potentially result in differential estrogen-mediated responses. "
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    ABSTRACT: The establishment of sex-specific neural morphology, which underlies sex-specific behaviors, occurs during a perinatal sensitive window in which brief exposure to gonadal steroid hormones produces permanent masculinization of the brain. In the rodent, estradiol derived from testicular androgens is a principal organizational hormone. The mechanism by which transient estradiol exposure induces permanent differences in neuronal anatomy has been widely investigated, but remains elusive. Epigenetic changes, such as DNA methylation, allow environmental influences to alter long-term gene expression patterns and therefore may be a potential mediator of estradiol-induced organization of the neonatal brain. Here we review data that demonstrate sex and estradiol-induced differences in DNA methylation on the estrogen receptor α (ERα), estrogen receptor β (ERβ), and progesterone receptor (PR) promoters in sexually dimorphic brain regions across development. Contrary to the overarching view of DNA methylation as a permanent modification directly tied to gene expression, these data demonstrate that methylation patterns on steroid hormone receptors change across the life span and do not necessarily predict expression. Although further exploration into the mechanism and significance of estradiol-induced alterations in DNA methylation patterns in the neonatal brain is necessary, these results provide preliminary evidence that epigenetic alterations can occur in response to early hormone exposure and may mediate estradiol-induced organization of sex differences in the neonatal brain.
    Hormones and Behavior 03/2011; 59(3):338-44. DOI:10.1016/j.yhbeh.2010.08.009 · 4.51 Impact Factor
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