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Endocr Relat Cancer. 2017 Jul;24(7):365-378. doi: 10.1530/ERC-17-0006. Epub 2017 May 9.

Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk.

Leung YK1,2,3, Govindarajah V1,2, Cheong A1,2, Veevers J1,2,3, Song D1,2, Gear R2,4, Zhu X1,2, Ying J1,2,3, Kendler A5, Medvedovic M1,2,3, Belcher S2,4, Ho SM6,2,3,7.

Author information

1
Department of Environmental HealthCincinnati, Ohio, USA.
2
Center for Environmental GeneticsUniversity of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
3
Cincinnati Cancer CenterCincinnati, Ohio, USA.
4
Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
5
Department of Pathology and Laboratory MedicineUniversity of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
6
Department of Environmental HealthCincinnati, Ohio, USA shuk-mei.ho@uc.edu.
7
Cincinnati Veteran Affairs Hospital Medical CenterCincinnati, Ohio, USA.

Abstract

In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose-response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.

KEYWORDS:

DNA methylation; RNA-seq; TCGA; bisphenol A; breast cancer; developmental origin of health and disease (DOHaD); high-butter fat diet; in utero exposure; non-monotonic response; patient survival; transcriptomics; windows of susceptibility

PMID:
28487351
PMCID:
PMC5488396
DOI:
10.1530/ERC-17-0006
[Indexed for MEDLINE]
Free PMC Article

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