Archives of Toxicology

, Volume 93, Issue 10, pp 2773–2785 | Cite as

A nongenomic mechanism for “metalloestrogenic” effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor

  • Jingli Liu
  • Linda Yu
  • Lysandra Castro
  • Yitang Yan
  • Maria I. Sifre
  • Carl D. Bortner
  • Darlene DixonEmail author
Inorganic Compounds


Cadmium (Cd) is a ubiquitous environmental metal that is reported to be a “metalloestrogen.” Uterine leiomyomas (fibroids) are estrogen-responsive gynecologic neoplasms that can be the target of xenoestrogens. Previous epidemiology studies have suggested Cd may be associated with fibroids. We have shown that Cd can stimulate proliferation of human uterine leiomyoma (ht-UtLM) cells, but not through classical estrogen receptor (ER) binding. Whether nongenomic ER pathways are involved in Cd-induced proliferation is unknown. In the present study, by evaluating G protein-coupled estrogen receptor (GPER), ERα36, and phospho-epidermal growth factor receptor (EGFR) expression in human tissues, we found that GPER, ERα36 and phospho-EGFR were all highly expressed in fibroids compared to patient-matched myometrial tissues. In ht-UtLM cells, cell proliferation was increased by low doses of Cd (0.1 µM and 10 µM), and this effect could be inhibited by GPER-specific antagonist (G15) pretreatment, or silencing (si) GPER, but not by siERα36. Cd-activated MAPK was dependent on GPER/EGFR transactivation, through significantly increased phospho-Src, matrix metalloproteinase-2 (MMP2) and MMP9, and heparin-binding EGF-like growth factor (HB-EGF) expression/activation. Also, phospho-Src could interact directly to phosphorylate EGFR. Overall, Cd-induced proliferation of human fibroid cells was through a nongenomic GPER/p-src/EGFR/MAPK signaling pathway that did not directly involve ERα36. This suggests that Cd may be a risk factor for uterine fibroids through cross talk between hormone and growth factor receptor pathways.


Cadmium EGFR Uterine leiomyomas GPER ERα36 



The authors sincerely thank Mr. Charles J. Tucker (Fluorescence Microscopy and Imaging Center), NIEHS for helping set up confocal analysis software and Drs. Jerry J. Liu and Wendy Jefferson for their critical review and comments on the manuscript. J.L. thanks the Natural Science Foundation of China (81500613) and Jiangsu Province (BK20150108) for their support. This work was funded by the Intramural Research Program of the NIH, NIEHS and DNTP.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The collection of human uterine tissues in the present study was in accordance with the approval of Institutional Review Board (IRB) of the NIEHS.

Informed consent

Every patient had signed the informed consent prior to their inclusion in the study.

Supplementary material

204_2019_2544_MOESM1_ESM.pdf (4.1 mb)
Supplementary material 1 (PDF 4242 kb)


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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection  2019

Authors and Affiliations

  1. 1.Molecular Pathogenesis Group, National Toxicology Program (NTP) Laboratory, Division of the NTP (DNTP)National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Research Triangle ParkUSA
  2. 2.Signal Transduction LaboratoryDivision of Intramural Research (DIR), NIEHS, NIHResearch Triangle ParkUSA

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