Low-dose BPA exposure alters the mesenchymal and epithelial transcriptomes of the mouse fetal mammary gland

Exposure of rodent fetuses to low doses of the endocrine disruptor bisphenol A (BPA) causes subtle morphological changes in the prenatal mammary gland and results in pre-cancerous and cancerous lesions during adulthood. To examine whether the BPA-induced morphological alterations of the fetal mouse...

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Published in:	PloS one 2013-05, Vol.8 (5), p.e63902
Main Authors:	Wadia, Perinaaz R, Cabaton, Nicolas J, Borrero, Michael D, Rubin, Beverly S, Sonnenschein, Carlos, Shioda, Toshi, Soto, Ana M
Format:	Article
Language:	eng
Subjects:	Adipogenesis Animal tissues Animals Apoptosis Apoptosis - drug effects Apoptosis - genetics Benzhydryl Compounds - toxicity Biology Bisphenol A Breast cancer Cell adhesion & migration Cellular biology Cluster Analysis Comparative analysis Developmental stages Dosage and administration Drug dosages Embryos Epithelium Epithelium - drug effects Epithelium - metabolism Estradiol Estrogen Receptor alpha - metabolism Estrogens Ethinyl estradiol Ethinyl Estradiol - pharmacology Ethinylestradiol Exposure Female Fetus - drug effects Fetus - metabolism Fetuses Focal Adhesions - drug effects Focal Adhesions - metabolism Gene expression Gene Expression Profiling Gene Expression Regulation, Developmental - drug effects Genes Glands Laboratory animals Lesions Life Sciences Mammary gland Mammary glands Mammary Glands, Animal - drug effects Mammary Glands, Animal - embryology Mammary Glands, Animal - metabolism Mammary Glands, Animal - pathology Medicine Mesenchyme Mesoderm - drug effects Mesoderm - metabolism Mice Mice, Inbred C57BL Morphogenesis Phenols Phenols - toxicity Pregnancy Pregnant women Prenatal Exposure Delayed Effects - genetics Prenatal Exposure Delayed Effects - pathology Principal Component Analysis Puberty RNA RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Signal Transduction - drug effects Signal Transduction - genetics Stem cells Stroma Stromal Cells - drug effects Stromal Cells - metabolism Studies Thyroid gland Transcription, Genetic - drug effects Transcriptome - genetics Troponin C - metabolism Urine Xenoestrogens
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Summary:	Exposure of rodent fetuses to low doses of the endocrine disruptor bisphenol A (BPA) causes subtle morphological changes in the prenatal mammary gland and results in pre-cancerous and cancerous lesions during adulthood. To examine whether the BPA-induced morphological alterations of the fetal mouse mammary glands are a) associated with changes in mRNA expression reflecting estrogenic actions and/or b) dependent on the estrogen receptor α (ERα), we compared the transcriptomal effects of BPA and the steroidal estrogen ethinylestradiol (EE2) on fetal mammary tissues of wild type and ERα knock-out mice. Mammary glands from fetuses of dams exposed to vehicle, 250 ng BPA/kg BW/d or 10 ng EE2/kg BW/d from embryonic day (E) 8 were harvested at E19. Transcriptomal analyses on the ductal epithelium and periductal stroma revealed altered expression of genes involved in the focal adhesion and adipogenesis pathways in the BPA-exposed stroma while genes regulating the apoptosis pathway changed their expression in the BPA-exposed epithelium. These changes in gene expression correlated with previously reported histological changes in matrix organization, adipogenesis, and lumen formation resulting in enhanced maturation of the fat-pad and delayed lumen formation in the epithelium of BPA-exposed fetal mammary glands. Overall similarities in the transcriptomal effects of BPA and EE2 were more pronounced in the epithelium, than in the stroma. In addition, the effects of BPA and EE2 on the expression of various genes involved in mammary stromal-epithelial interactions were suppressed in the absence of ERα. These observations support a model whereby BPA and EE2 act directly on the stroma, which expresses ERα, ERβ and GPR30 in fetal mammary glands, and that the stroma, in turn, affects gene expression in the epithelium, where ERα and ERβ are below the level of detection at this stage of development.
ISSN:	1932-6203 1932-6203