The Organophosphate Esters Used as Flame Retardants and Plasticizers Affect H295R Adrenal Cell Phenotypes and Functions

Author:

Li Zixuan1,Robaire Bernard12ORCID,Hales Barbara F1ORCID

Affiliation:

1. Department of Pharmacology & Therapeutics, McGill University , Montreal, QC, H3G 1Y6 , Canada

2. Department of Obstetrics & Gynecology, McGill University , Montreal, QC, H3G 1Y6 , Canada

Abstract

Abstract Adverse effects associated with exposure to brominated flame retardants have led to regulations for their use and their replacement with organophosphate esters (OPEs). However, little is known about the impact of OPEs on the adrenal, a vital endocrine gland. Here, we used a high-content screening approach to elucidate the effects of OPEs on H295R human adrenal cell phenotypic endpoints and function. The effects of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a legacy brominated flame retardant, on H295R cell cytotoxicity, oxidative stress, mitochondria, lysosomes, and lipid droplets were compared with those of 6 OPEs. Most OPEs reduced oxidative stress, increased the numbers of mitochondria, decreased lysosomes, and increased lipid droplets. Two potency ranking approaches, the lowest benchmark concentration/administered equivalent dose methods and Toxicological Prioritization Index analyses, revealed that the triaryl-OPEs (isopropylated triphenyl phosphate [IPPP], tris(methylphenyl) phosphate [TMPP], and triphenyl phosphate [TPHP]) and 1 nontriaryl OPE (tris(1,3-dichloro-2-propyl) phosphate [TDCIPP]) were more potent than BDE-47. The steroidogenic activity of adrenal cells in the presence or absence of forskolin, a steroidogenic stimulus, was determined after exposure to triaryl-OPEs. The basal production of cortisol and aldosterone was increased by IPPP but decreased by TPHP or TMPP exposure; the response to forskolin was not affected by these OPEs. All 3 triaryl OPEs altered the expression of rate-limiting enzymes involved in cholesterol and steroid biosynthesis; CYP11B1 and CYP11B2 were the most prominently affected targets. The OPE chemical-specific effects on cortisol and aldosterone production were best explained by alterations in STAR expression. Thus, the adrenal may be an important target for these endocrine-disrupting chemicals.

Funder

Institute for Population and Public Health

Canadian Institutes of Health Research

McGill University

McGill University and the Centre for Research in Reproduction and Development

Publisher

The Endocrine Society

Subject

Endocrinology

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