Estimation of bisphenol A—Human toxicity by 3D cell culture arrays, high throughput alternatives to animal tests

Dong Woo Lee, Woo Yeon Oh, Sang Hyun Yi, Bosung Ku, Moo Yeal Lee, Yoon Hee Cho, Mihi Yang

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Bisphenol A (BPA) has been widely used for manufacturing polycarbonate plastics and epoxy resins and has been extensively tested in animals to predict human toxicity. In order to reduce the use of animals for toxicity assessment and provide further accurate information on BPA toxicity in humans, we encapsulated Hep3B human hepatoma cells in alginate and cultured them in three dimensions (3D) on a micropillar chip coupled to a panel of metabolic enzymes on a microwell chip. As a result, we were able to assess the toxicity of BPA under various metabolic enzyme conditions using a high-throughput and micro assay; sample volumes were nearly 2,000 times less than that required for a 96-well plate. We applied a total of 28 different enzymes to each chip, including 10 cytochrome P450s (CYP450s), 10 UDP-glycosyltransferases (UGTs), 3 sulfotransferases (SULTs), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase 2 (ALDH2). Phase I enzyme mixtures, phase II enzyme mixtures, and a combination of phase I and phase II enzymes were also applied to the chip. BPA toxicity was higher in samples containing CYP2E1 than controls, which contained no enzymes (IC50, 184 ± 16 μM and 270 ± 25.8 μM, respectively, p < 0.01). However, BPA-induced toxicity was alleviated in the presence of ADH (IC50, 337 ± 17.9 μM), ALDH2 (335 ± 13.9 μM), and SULT1E1 (318 ± 17.7 μM) (p < 0.05). CYP2E1-mediated cytotoxicity was confirmed by quantifying unmetabolized BPA using HPLC/FD. Therefore, we suggest the present micropillar/microwell chip platform as an effective alternative to animal testing for estimating BPA toxicity via human metabolic systems.

Original languageEnglish
Pages (from-to)87-94
Number of pages8
JournalToxicology Letters
StatePublished - Sep 30 2016


  • 3D cell microarray
  • Bisphenol A
  • Cytotoxicity
  • Metabolism


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