Effects of In Utero Exposure to Bisphenol A on Expression of RAR.ALPHA. and RXR.ALPHA. mRNAs in Murine Embryos

Abstract

Abstract. Retinoic acid receptor (RAR) α and retinoid X receptor (RXR) α are key factors in a nuclear receptor-dependent signal. To evaluate the effects of bisphenol A (BPA), a candidate endocrine disruptor (ED), on embryonic development, we examined the mRNA levels of RARα and RXRα in murine embryos, exposed in utero to BPA (2 µg/kg/day) at 6.5-17.5 days post-coitum (dpc), by the realtime reverse transcription-polymerase chain reaction (RT-PCR) method. Higher levels of RARα mRNA in cerebra of male and female embryos of control groups were detected at 14.5 dpc. In utero BPA reduced the RARα mRNA expression. Higher levels of RXRα mRNA in cerebra of male and female embryos were seen at 12.5 dpc. The exposure decreased RXRα mRNA expression in male but not female embryos. No remarkable change in the RAR α mRNA expression level was noted in cerebella of male or female embryos of the control group during embryonic development. Exposure to BPA increased expression levels of RARα mRNA in cerebella of male and female embryos at 12.5 dpc. Higher levels of RXRα mRNA in cerebella of male and female embryos were seen, but no remarkable changes were noted during embryonic development. BPA significantly decreased the expression levels of RXRα mRNA in cerebella of female embryos at 12.5, 14.5 and 18.5 dpc. RARα and RXRα mRNAs were expressed in gonads (testes and ovaries) of murine embryos from 12.5 to 18.5 dpc.In utero exposure to BPA decreased levels of RARα mRNA in testes of 14.5-and 18.5-dpc-embryos, levels of RXRα mRNA in testes of 14.5-dpc-embryos, and levels of RXRα mRNA in ovaries of 14.5-dpc-embryos. The present findings indicate that RARα and RXRα play crucial roles in organogenesis, and the growth and development of murine embryos, and will contribute to the assessment of the toxic effects of BPA on retinoid signals in embryogenesis. Key words: Bisphenol A, Embryo, Mouse, Retinoic acid receptor α, Retinoid X receptor α (J. Reprod. Dev. 49: [539][540][541][542][543][544][545] 2003) isphenol A [BPA; 2,2-bis (4-hydroxyphenyl) propane], a plasticizer and a cand idate endocrine disruptor (ED), has physiological effects on the reproductive, immunological and nervous systems in mammals [1][2][3]. BPA binds to estrogen receptor α (ERα; NR3A1) and ERβ (NR3A2) and induces estrogenic activity [1][2][3]. BPA affects the levels of ER and nuclear receptor mRNA in rat uterus [4], but no detailed information on the mechanism of its actions has been reported.Retinoic acid receptor α (RARα; NR1B1) and retinoid X receptor α (RXRα ; NR2B1) specifically bind with 9-cis-retinoic acid (RA), a bioactive metabolite of vitamin A (retinol), and all-trans-RA, r e s p e c t i v e l y . R A h a s m a r k e d e f f e c t s o n embryogenesis, and cell proliferation, growth, differentiation and death [5,6]. In mouse embryos, RA is endogenously synthesized from 7 days postcoitum (dpc) [7], and the expression of RARα and

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

“…Nishizawa et al (2003), supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology, examined the effects of prenatal bisphenol A exposure on expression of retinoic acid receptor a and retinoid X receptor a in mouse embryos. ICR mice were fed standard feed (CM; Oriental Yeast).…”

“…Variable changes in retinoic acid retinoid X receptors á mRNA expression in brain, ovary, and testis, depending on brain region and day of exposure Nishizawa et al (2003) Other Prepubertal Poll Dorset female lambs (i.m. injection) 3.5 biweekly, at 4-11 weeks of age (ovariectomy at 9 weeks of age)…”

“…Neural and Behavioral Endpoints Following Oral Administration: Several studies addressing effects on neural and behavioral endpoints have been conducted following gestational and lactational exposure [rats: (Funabashi et al, 2004a;Negishi et al, 2004a;Della Seta et al, 2005)]; mice: [(Palanza et al, 2002;Nishizawa et al, 2003Nishizawa et al, , 2005bLaviola et al, 2005;Ryan and Vandenbergh, 2006)], pubertal exposure [rat: (Akingbemi et al, 2004;Della Seta et al, 2006;Ceccarelli et al, 2007)], and exposure during adulthood [gerbils: (Razzoli et al, 2005)]. …”

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

“…We observed that Cln2 gene promoter lacked the PPAR-binding site but contained an RXR-binding site instead. Because of the facts that RXR␣ is abundant in the brain and astrocytes (32,33) and that PPAR␣ and RXR␣ form a heterodimer, we thought the mechanism of up-regulation of TPP1 may involve cooperative action of both PPAR␣ and RXR␣ and not PPAR␣ alone. To verify our hypothesis, we performed an array of experiments.…”

Effects of endocrine disruptors on imprinted gene expression in the mouse embryo

“…51 Hormones are known regulators of transcription through their effect on DNA methylation and chromatin composition. 52,53 Since EDs can affect DNA methylation patterns 33,54,55 and gene expression, [56][57][58][59][60] it is hypothesized that these hormonelike chemicals can alter the reciprocal epigenetic states of the two parental chromosomes at imprinted genes or their DMRs and those epigenetic changes would alter the allele-specific expression in the embryonic or extraembryonic organs. To test this hypothesis we generated multiplex allele-specific assays and measured the effects of BPA, VZ and DEHP on the maintenance of imprinted gene expression of a representative set of imprinted transcripts in the embryo and in extraembryonic organs after in utero exposure to these chemicals.…”