Lignin-derivable alternatives to bisphenol A with potentially undetectable estrogenic activity and minimal developmental toxicity

Abstract

Lignin-derivable bisguaiacols/bissyringols are viable alternatives to commercial bisphenols; however, many bisguaiacols/bissyringols (e.g., bisguaiacol F [BGF]) have unsubstituted bridging carbons between the aromatic rings, making them more structurally similar to bisphenol F (BPF) than bisphenol A (BPA) – both of which are suspected endocrine disruptors. Herein, we investigated the estrogenic activity (EA) and developmental toxicity of dimethyl-substituted bridging carbon-based lignin-derivable bisphenols (bisguaiacol A [BGA] and bissyringol A [BSA]). Notably, BSA showed undetectable EA at seven test concentrations (from 10−12 M to 10−6 M) in the MCF-7 cell proliferation assay, whereas BPA had detectable EA at five concentrations (from 10−10 M to 10−6 M). In silico results indicated that BSA had the lowest binding affinity with estrogen receptors. Moreover, in vivo chicken embryonic assay results revealed that lignin-derivable monomers had minimal developmental toxicity vs. BPA at environmentally relevant test concentrations (8.7–116 μg/kg). Additionally, all lignin-derivable compounds showed significantly lower expression fold changes (from ∼1.81 to ∼4.41) in chicken fetal liver tests for an estrogen-response gene (apolipoprotein II) in comparison to BPA (fold change of ∼11.51), which was indicative of significantly reduced estrogenic response. Altogether, the methoxy substituents on lignin-derivable bisphenols appeared to be a positive factor in reducing the EA of BPA alternatives.