Low-dose environmental endocrine disruptors, increase aromatase activity, estradiol biosynthesis and cell proliferation in human breast cells

• Published in: Molecular and cellular endocrinology 2019-04, Vol.486, p.55-64
• Main Authors: Williams, Graeme P., Darbre, Philippa D.
• Format: Article
• Language: English
• Subjects: Aromatase - genetics; Aromatase - metabolism; Aromatase up-regulation; Breast - pathology; Breast cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Endocrine disruption; Endocrine Disruptors - chemistry; Endocrine Disruptors - toxicity; Estradiol - biosynthesis; Female; Fulvestrant - pharmacology; Humans; Letrozole - pharmacology; Receptors, Estrogen - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Testosterone - pharmacology; ‘Phenolic’ EDCs
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2019.02.016

Phenolic endocrine-disrupting compounds (EDCs) have long been suspected of increasing human breast cancer risk, via aromatase up-regulation; however, the metabolic effects upon aromatase in human breast cells exposed to environmentally relevant concentrations of phenolic compounds, have not been addressed. To examine the mechanistic responses of aromatase CYP19A1 mRNA, aromatase activity, estradiol biosynthesis and cellular proliferation, in three human breast cell lines, exposed to seven phenolic compounds, at environmentally relevant concentrations. MCF-7 and ZR-75-1 breast cancer cells, and HMF3A breast fibroblasts were treated with specific concentrations of p,p’-DDT, methoxychlor, benzophenone-2, bisphenol A, bisphenol S, 4-phenylphenol and n-butylparaben, with and without the presence of aromatase inhibitors and estrogen receptor inhibitors. All test EDCs up-regulated aromatase mRNA, increased aromatase activity, significantly increased the aromatase-induced biosynthesis of the breast carcinogen 17β-estradiol, and increased ERα-positive breast cell proliferation. Inadvertent exposures to ‘phenolic’ EDCs, increase estradiol biosynthesis, and estrogen-sensitive breast cancer proliferation. •Breast cancer is linked to aromatase up-regulation and increased estradiol biosynthesis.•Phenolic EDCs significantly up-regulate aromatase in breast cells (in-vitro).•Phenolic EDCs significantly increase the biosynthesis of the carcinogen, 17β-estradiol.•Exposure to phenolic EDCs increase ER-positive breast cancer cell proliferation.