Effects of In Utero Exposure to Bisphenol A on mRNA Expression of Arylhydrocarbon and Retinoid Receptors in Murine Embryos

Abstract

Abstract.To evaluate the effects of bisphenol A (BPA), a candidate endocrine disruptor (ED), on embryonic development, we examined the mRNA expression levels of the arylhydrocarbon receptor (AhR), which binds with many EDs and plays crucial roles in xenobiotic metabolism, and of the retinoic acid receptor (RAR) α and retinoid X receptor (RXR) α, key factors in nuclear receptordependent retinoid signal transduction, in murine embryos exposed in utero to BPA (0.02, 2, 200, and 20,000 µg/kg/day) at 6.5-13.5 or 6.5-17.5 days post coitum (dpc), using the real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Extremely low-dose BPA (0.02 µg/kg/ day; 1/100 the dose of environmental exposure) remarkably increased AhR mRNA expression in the cerebra, cerebella, and gonads (testes and ovaries) of male and female 14.5-and 18.5-dpc-embryos. In utero exposure to BPA at 2, 200, and 20,000 µg/kg/day also increased levels of AhR mRNA. In gonads of 14.5-dpc-embryos, AhR mRNA levels were elevated and showed diphasic (U) dose-response curves following exposure to BPA, but inverted U dose-response curves were obtained for 18.5-dpcembryos. Exposure to BPA increased expression levels of RARα and RXRα mRNAs in the cerebra, cerebella, and gonads of male and female 14.5-and 18.5-dpc-embryos. Extremely low-dose BPA (0.02 µg/kg/day) increased RARα mRNA expression in the cerebella of male and female 14.5-and 18.5-dpc-embryos and in the gonads of female 14.5-dpc-embryos, and significantly increased RXRα mRNA expression in the cerebra and cerebella of male and female 14.5-dpc-embryos. The present findings confirm that in utero exposure to an extremely low dose of BPA up-regulates the mRNA expression of AhR, RARα, and RXRα in murine embryos and disrupts the receptor-dependent signal transducing systems, and will contribute to the assessment of the toxic effects of BPA on xenobiotic metabolism and retinoid signals in embryogenesis. Key words: Arylhydrocarbon receptor (AhR), Bisphenol A, Murine embryo, Retinoic acid receptor (RAR) α, Retinoid X receptor (RXR) α (J. Reprod. Dev. 51: [315][316][317][318][319][320][321][322][323][324] 2005) isphenol A [BPA; 2,2-bis (4-hydroxyphenyl) p r o p a n e ] , a c o m m o n p l a s t i c i z e r a n d a candidate environmental endocrine disruptor (ED), has toxicological effects on the reproductive, immunological, and nervous systems of mammals [1][2][3][4]. BPA binds to estrogen receptor-α (ERα; NR3A1) and -β (ERβ; NR3A2), and induces

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

“…Nishizawa et al (2005b), supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology and by the Japan Society for the Promotion of Science, examined the effects of bisphenol A exposure on expression of mRNA for arylhydrocarbon and retinoid receptors in mouse embryos. ICR mice were fed standard diet (CM; Oriental Yeast).…”

“…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)]. …”

“…Gestational and lactational exposures in rats have reported subtle effects on sexually-dimorphic brain nuclei (Funabashi et al, 2004a), hormonal receptors in brain (Nishizawa et al, , 2005b, and certain sexually-dimorphic or reproductively relevant behaviors (Negishi et al, 2004a;Ryan and Vandenbergh, 2006). Most of this work has utilized single doses across the range of 2-40 mg/kg, and none has been confirmed or linked to other functional or clearly adverse effects.…”

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

“…Although actual BPA lowest observed adverse effects level (LOAEL) established by the National Toxicology Program's report (US Environmental Protection Agency 1993) is 50 mg/kg per day, there are several reports indicating that perinatal exposure to BPA in doses below LOAEL affects reproductive parameters in adult animals, such as neuroendocrine axis development (Khurana et al 2000, Ramos et al 2003, mammary gland and prostate morphology (Ramos et al 2001, Durando et al 2006, estrous cyclicity patterns (Rubin et al 2001), and sexual behavior (Carr et al 2003, Kubo et al 2003, Negishi et al 2004, Porrini et al 2005, Fujimoto et al 2006. This apparent controversy could be explained by the fact that BPA shows an inverted-U-shaped dose-response curve (Nishizawa et al 2005, Wetherill et al 2005, Zsarnovszky et al 2005, where much of the effects observed with low-dose treatments are absent in traditional high-dose toxicological studies.…”

Chlorination by-products of bisphenol A enhanced retinoid X receptor disrupting effects

“…The antagonistic activities of environmental pollutions may induced antagonist activity to RXRs. BPA has been identified as a RXR disruptor, an extremely low concentration of BPA significantly increased RXR mRNA expression in the cerebra and cerebella of murine embryos [28]. Our previous work also has demonstrated that BPA exhibiting antagonistic activities to RXR␤ at micromolar concentrations in vitro [29].…”