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

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: 3.72). 08/2007; 194(1):201-12. DOI: 10.1677/JOE-07-0014
Source: PubMed


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 · 3.85 Impact Factor
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    • "The documented actions of bisphenol A (BPA) include altered pubertal onset [33], [34], disruption of estrous cycles [35], [36], prostate disease [37], [38], [39], prostate neoplasia [37], [40], abnormal mammary gland development and presence of intraductal hyperplasia and preneoplastic lesions in adults [41], [42], [43], [44], alterations in the uterus (cystic endometrial hyperplasia) and ovary (cystic ovaries) abnormalities [41], [45]. BPA induced brain and behavioral changes include abnormal development of sexually dimorphic hypothalamic regions [46], [47], [48], [49], abnormal steroid receptor levels [50], [51], [52], aberrant behavior including hyperactivity [53], [54], heightened aggressiveness [55], distorted sociosexual behavior [56], changed cognitive and anxiolytic behaviors [57], and enhanced susceptibility of addiction [54], [58]. BPA alters body weight and body composition [10], [33], [35], [59], [60], [61] and abnormal glucose homeostasis [62]. "
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    ABSTRACT: Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1-F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the "plastics" or "lower dose plastics" mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.
    PLoS ONE 01/2013; 8(1):e55387. DOI:10.1371/journal.pone.0055387 · 3.23 Impact Factor
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    • "Could DNA methylation have additional roles besides just controlling gene expression? Effects of environmental endocrine disrupting chemicals on methylation of ERα in the POA indicate that in addition to altering gene expression, methylation can dictate the use of alternative promoters, which may influence the selective expression of ERα transcript variants (Monje et al., 2007). The possibility that hormonally induced changes in methylation dictate promoter usage and transcript variant expression is an understudied aspect of epigenetics but may provide a better understanding of how hormones organize the brain. "
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    ABSTRACT: Steroid hormones of gonadal origin act on the neonatal brain to produce sex differences that underlie adult reproductive physiology and behavior. Neuronal sex differences occur on a variety of levels, including differences in regional volume and/or cell number, morphology, physiology, molecular signaling, and gene expression. In the rodent, many of these sex differences are determined by steroid hormones, particularly estradiol, and are established by diverse downstream effects. One brain region that is potently organized by estradiol is the preoptic area (POA), a region critically involved in many behaviors that show sex differences, including copulatory and maternal behaviors. This review focuses on the POA as a case study exemplifying the depth and breadth of our knowledge as well as the gaps in understanding the mechanisms through which gonadal hormones produce lasting neural and behavioral sex differences. In the POA, multiple cell types, including neurons, astrocytes, and microglia are masculinized by estradiol. Multiple downstream molecular mediators are involved, including prostaglandins, various glutamate receptors, protein kinase A, and several immune signaling molecules. Moreover, emerging evidence indicates epigenetic mechanisms maintain sex differences in the POA that are organized perinatally and thereby produce permanent behavioral changes. We also review emerging strategies to better elucidate the mechanisms through which genetics and epigenetics contribute to brain and behavioral sex differences.
    Frontiers in Neuroscience 02/2012; 6:26. DOI:10.3389/fnins.2012.00026 · 3.66 Impact Factor
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