Format

Send to

Choose Destination
Environ Int. 2019 Jul 13;131:104969. doi: 10.1016/j.envint.2019.104969. [Epub ahead of print]

Determining the endocrine disruption potential of industrial chemicals using an integrative approach: Public databases, in vitro exposure, and modeling receptor interactions.

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
2
Department of Product Stewardship and Toxicology, Group Health, Safety, Security and Environment, Petroliam Nasional Berhad, Kuala Lumpur, Malaysia; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
3
Department of Product Stewardship and Toxicology, Group Health, Safety, Security and Environment, Petroliam Nasional Berhad, Kuala Lumpur, Malaysia.
4
Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale School of Medicine, New Haven, CT, USA.
5
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, USA.
6
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
7
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA; Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA. Electronic address: shannon.whirledge@yale.edu.

Abstract

Environmental and occupational exposure to industrial chemicals has been linked to toxic and carcinogenic effects in animal models and human studies. However, current toxicology testing does not thoroughly explore the endocrine disrupting effects of industrial chemicals, which may have low dose effects not predicted when determining the limit of toxicity. The objective of this study was to evaluate the endocrine disrupting potential of a broad range of chemicals used in the petrochemical sector. Therefore, 139 chemicals were classified for reproductive toxicity based on the United Nations Globally Harmonized System for hazard classification. These chemicals were evaluated in PubMed for reported endocrine disrupting activity, and their endocrine disrupting potential was estimated by identifying chemicals with active nuclear receptor endpoints publicly available databases. Evaluation of ToxCast data suggested that these chemicals preferentially alter the activity of the estrogen receptor (ER). Four chemicals were prioritized for in vitro testing using the ER-positive, immortalized human uterine Ishikawa cell line and a range of concentrations below the reported limit of toxicity in humans. We found that 2,6-di-tert-butyl-p-cresol (BHT) and diethanolamine (DEA) repressed the basal expression of estrogen-responsive genes PGR, NPPC, and GREB1 in Ishikawa cells, while tetrachloroethylene (PCE) and 2,2'-methyliminodiethanol (MDEA) induced the expression of these genes. Furthermore, low-dose combinations of PCE and MDEA produced additive effects. All four chemicals interfered with estradiol-mediated induction of PGR, NPPC, and GREB1. Molecular docking demonstrated that these chemicals could bind to the ligand binding site of ERα, suggesting the potential for direct stimulatory or inhibitory effects. We found that these chemicals altered rates of proliferation and regulated the expression of cell proliferation associated genes. These findings demonstrate previously unappreciated endocrine disrupting effects and underscore the importance of testing the endocrine disrupting potential of chemicals in the future to better understand their potential to impact public health.

KEYWORDS:

Endocrine disrupting chemical (EDC); Environmental chemical; Estrogen receptor; Risk assessment; Uterus

PMID:
31310931
DOI:
10.1016/j.envint.2019.104969
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center