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Toxicity Screening of Bisphenol A Replacement Compounds: Cytotoxicity and mRNA Expression in Primary Hepatocytes of Chicken and Double‐Crested Cormorant

A market for bisphenol A (BPA) replacement compounds has emerged as a result of restrictions on the use of BPA. Some of these compounds have been detected in the environment; however, little is known about their toxicological properties. In the present study, an avian in vitro toxicogenomic approach was used to compare the effects of 5 BPA alternatives. Cell viability and mRNA expression were compared in primary embryonic hepatocytes of chicken (CEH) and double‐crested cormorant (DCEH) exposed to 4,4′‐(propane‐2,2‐diyl) diphenol (BPA), bis (4‐hydroxyphenyl) methane (BPF), bis (3‐allyl‐4‐hydroxyphenyl) sulfone (TGSH), 7‐bis (4‐hydroxyphenylthio)‐3,5‐dioxaheptane (DD‐70), 2,2‐bis (4‐hydroxyphenyl) hexafluoropropane (BPAF), and 4‐hydroxyphenyl 4‐isoprooxyphenylsulfone (BPSIP). Changes in gene expression were determined using 2 polymerase chain reaction (PCR) arrays: 1) species‐specific ToxChips that contain genes representing toxicologically relevant pathways, and 2) chicken‐specific AestroChip that measures estrogen responsive genes. In CEH and DCEH, BPA alternatives TGSH, DD‐70, and BPAF were most cytotoxic. Some of the replacement compounds changed the expression of genes related to xenobiotic metabolism, bile acid, and cholesterol regulation. The rank order based on the number of genes altered on the chicken ToxChip array was TGSH > DD‐70 > BPAF = BPF > 17β estradiol (E2) > BPSIP > BPA. On the cormorant ToxChip array, BPSIP altered the greatest number of genes. Based on the chicken AestroChip data, BPSIP and BPF were slightly estrogenic. These results suggest that the replacement compounds have comparable or even greater toxicity than BPA and act via different mechanisms. Environ Toxicol Chem 2021;40:1368–1378. © 2021 Her Majesty the Queen in Right of Canada. Reproduced with the permission of the Minister of Environment and Climate Change Canada.