Identification of candidate reference chemicals for in vitro steroidogenesis assays

Toxicol In Vitro. 2018 Mar:47:103-119. doi: 10.1016/j.tiv.2017.11.003. Epub 2017 Nov 13.

Abstract

The Endocrine Disruptor Screening Program (EDSP) is transitioning from traditional testing methods to integrating ToxCast/Tox21 in vitro high-throughput screening assays for identifying chemicals with endocrine bioactivity. The ToxCast high-throughput H295R steroidogenesis assay may potentially replace the low-throughput assays currently used in the EDSP Tier 1 battery to detect chemicals that alter the synthesis of androgens and estrogens. Herein, we describe an approach for identifying in vitro candidate reference chemicals that affect the production of androgens and estrogens in models of steroidogenesis. Candidate reference chemicals were identified from a review of H295R and gonad-derived in vitro assays used in methods validation and published in the scientific literature. A total of 29 chemicals affecting androgen and estrogen levels satisfied all criteria for positive reference chemicals, while an additional set of 21 and 15 chemicals partially fulfilled criteria for positive reference chemicals for androgens and estrogens, respectively. The identified chemicals included pesticides, pharmaceuticals, industrial and naturally-occurring chemicals with the capability to increase or decrease the levels of the sex hormones in vitro. Additionally, 14 and 15 compounds were identified as potential negative reference chemicals for effects on androgens and estrogens, respectively. These candidate reference chemicals will be informative for performance-based validation of in vitro steroidogenesis models.

Keywords: Androgens; Estrogens; Gonadal models; H295R; Sex hormones; Steroidogenesis.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Adrenal Cortex / cytology
  • Adrenal Cortex / drug effects*
  • Adrenal Cortex / metabolism
  • Adrenal Cortex Hormones / agonists
  • Adrenal Cortex Hormones / antagonists & inhibitors
  • Adrenal Cortex Hormones / biosynthesis*
  • Adrenal Cortex Hormones / metabolism
  • Animals
  • Cell Line
  • Cells, Cultured
  • Endocrine Disruptors / standards
  • Endocrine Disruptors / toxicity*
  • Estradiol / agonists
  • Estradiol / biosynthesis*
  • Estradiol / chemistry
  • Estradiol / metabolism
  • Female
  • Guidelines as Topic
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Osmolar Concentration
  • Ovary / cytology
  • Ovary / drug effects*
  • Ovary / metabolism
  • Reference Standards
  • Small Molecule Libraries
  • Testis / cytology
  • Testis / drug effects*
  • Testis / metabolism
  • Testosterone / agonists
  • Testosterone / antagonists & inhibitors
  • Testosterone / biosynthesis*
  • Testosterone / metabolism
  • Toxicity Tests, Acute / methods
  • Toxicity Tests, Acute / standards
  • Validation Studies as Topic

Substances

  • Adrenal Cortex Hormones
  • Endocrine Disruptors
  • Small Molecule Libraries
  • Testosterone
  • Estradiol