# Covalently Active Metabolites of Bisphenol A Analogs by Mass Spectrometry Diagnostic Ions: Possible Mechanisms of Their Toxicity

## TL;DR

This study explores how Bisphenol A analogs form reactive metabolites that can bind to proteins, potentially causing toxicity.

## Contribution

A novel nontargeted fragment screening strategy was developed to identify cysteine adducts and explore bioactivation mechanisms.

## Key findings

- A common activation pathway involving oxidation, ipso-addition, and ipso-substitution was identified across multiple BPs.
- Cysteine adduct abundances correlated with the metabolic rates of individual BPs, highlighting structure–reactivity relationships.
- The findings provide critical insights into the bioactivation and potential toxicity of BPs.

## Abstract

Bisphenol A analogs (BPs), used as BPA alternatives,
have drawn
great concerns due to their potential adverse effects. Studies have
shown that reactive metabolites (RMs) formed in vitro and in vivo
could covalently bind to nucleophilic macromolecules to elicit toxicity.
However, the bioactivation potential of BPs and their capacity to
covalently modify amino acid residues within proteins have been poorly
characterized. Thus, this study systematically characterized the metabolic
activation of eight BPs and their reactivity toward cysteine. Using N-acetylcysteine (NAC) as a trapping agent to capture RMs,
we developed a novel nontargeted fragment screening strategy for cysteine
adduct identification and mechanistic exploration. Integrating calculated
electron affinity results, mechanistic analyses revealed a common
activation pathway across multiple BPs involving oxidation, ipso-addition,
and ipso-substitution. Also, the abundances of cysteine adducts correlated
with metabolic rates of individual BPs, underscoring structure–reactivity
relationships. These results provided critical mechanistic insight
into BPs bioactivation, implicating their potential toxicity risk
and supporting environmental risk evaluation.