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Current Highlight from April 24, 2015

Effects of Orally Administered BPA on Gene Expression in Prostate and Female Mammary Glands of Rats

NCTR scientists reported that no apparent dose-related gene expression or epigenetic effects were detected in prostates or female mammary glands from rat pups that were daily administered BPA across a wide range of doses below the no-adverse-effect level currently used by the FDA.  However, a BPA dose of 500,000 times the mean human-exposure level induced gene-expression changes that overlapped partially with those induced by ethinyl estradiol (reference estrogen control), suggesting that BPA has some estrogenic potential at this high dose.  These results are consistent with previously reported toxicology endpoints from the same study.  This study was conducted at NCTR under the auspices and funding of the Interagency Agreement between FDA/NCTR and NIEHS/NTP.  A manuscript describing this study is available online at Food and Chemical Toxicology.

For additional information, please contact Luisa Camacho, Ph.D., or Barry Delclos, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

Effects of oral exposure to bisphenol A on gene expression and global genomic DNA methylation in the prostate, female mammary gland, and uterus of NCTR Sprague-Dawley rats

• Luísa Camacho^a, , , 
• Mallikarjuna S. Basavarajappa^a, 
• Ching-Wei Chang^b, 
• Tao Han^c, 
• Tetyana Kobets^a, 1, 
• Igor Koturbash^a, 2, 
• Gordon Surratt^a, 
• Sherry M. Lewis^d, 
• Michelle M. Vanlandingham^a, 
• James C. Fuscoe^c, 
• Gonçalo Gamboa da Costa^a, 
• Igor P. Pogribny^a, 
• K. Barry Delclos^a

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doi:10.1016/j.fct.2015.04.009

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Highlights

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The effects of seven “low BPA”, two “high BPA”, and two EE₂ doses versus vehicle control were assessed at the molecular level.

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Prostate and mammary glands, tissues previously identified as potential BPA targets, from Sprague-Dawley rats were analyzed.

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Postnatal day 4 microarray data showed gene expression changes induced by “high BPA” overlapped par tially with those of EE₂.

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Genes were modulated also in “low BPA” dose range, but lack of dose response reduced likelihood these are treatment-related.

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These results are consistent with the toxicity outcomes reported previously for this animal cohort.

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Abstract

Bisphenol A (BPA), an industrial chemical used in the manufacture of polycarbonate and epoxy resins, binds to the nuclear estrogen receptor with an affinity 4–5 orders of magnitude lower than that of estradiol. We reported previously that “high BPA” [100,000 and 300,000 µg/kg body weight (bw)/day], but not “low BPA” (2.5–2700 µg/kg bw/day), induced clear adverse effects in NCTR Sprague-Dawley rats gavaged daily from gestation day 6 through postnatal day (PND) 90. The “high BPA” effects partially overlapped those of ethinyl estradiol (EE₂, 0.5 and 5.0 µg/kg bw/day). To evaluate further the potential of “low BPA” to induce biological effects, here we assessed the global genomic DNA methylation and gene expression in the prostate and female mammary glands, tissues identified previously as potential targets of BPA, and uterus, a sensitive estrogen-responsive tissue. Both doses of EE₂ modulated gene expression, including of known estrogen-responsive genes, and PND 4 global gene expression data showed a partial overlap of the “high BPA” effects with those of EE₂. The “low BPA” doses modulated the expression of several genes; however, the absence of a dose response reduces the likelihood that these changes were causally linked to the treatment. These results are consistent with the toxicity outcomes.

Abbreviations

• BPA, bisphenol A; 
• bw, body weight; 
• C3, complement component 3-coding gene; 
• CMC,carboxymethylcellulose; 
• Ct, threshold cycle; 
• Dnmt, DNA methyltransferase-coding gene; 
• EE₂, ethinyl estradiol; 
• ER, estrogen receptor; 
• Esr, estrogen receptor-coding gene; 
• FDR, false discovery rate; 
• GO,gene ontology; 
• GPER, G-protein-coupled ER; 
• LC-MS/MS, liquid chromatography tandem mass spectrometry; 
• NCTR, National Center for Toxicological Research; 
• NTP, National Toxicology Program;
• PCA, principal component analysis; 
• PND, postnatal day; 
• Pgr, progesterone receptor-coding gene; 
• qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; 
• RIN, RNA integrity number;
• S100g, calbindin D9K-coding gene; 
• Vegfa, vascular endothelial growth factor A-coding gene

Keywords

• Bisphenol A; 
• Ethinyl estradiol; 
• Global genomic DNA methylation; 
• Microarray; 
• Prostate; 
• Mammary gland

Corresponding author. Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA. Tel.: +1 870 543 7588; fax: +1 870 543 7136.

1

Present address: Department of Pathology, New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595, USA.

2

Present address: Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.

Published by Elsevier Ltd.

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