Isomer-specific metabolism and novel metabolite identification of bisphenol A and its isomer o, p’-BPA in humans

Studies have identified bisphenol A (BPA) and its isomer o, p'-BPA in environmental and human samples, indicating their potential risks to human health. Yet, the risks of their co-exposure cannot be extrapolated from individual profiles, as interactions of BPA and o, p'-BPA may critically alter metabolic fate and toxicity. However, the metabolic interactions between these two co-occurring compounds in the human body remain poorly understood. To address this knowledge gap, the present study examined the concurrent metabolic behaviors of BPA and o, p'-BPA using human liver S9 fraction. Furthermore, this study analyzed their identified metabolites in collected human urine samples (n = 103). The results demonstrated that BPA (mean rate constant 0.020-0.028 min⁻¹) was metabolized more rapidly than o, p'-BPA (0.014-0.021 min⁻¹) by the human liver S9 fraction. We identified multiple Phase I and Phase II metabolites of both compounds, including oxidative metabolites, conjugated metabolites, and dimerization products formed between BPA and o, p'-BPA. In the collected human urine, five different BPA metabolites were detected, among which BPA-glucuronide (4.0 ng/mL) showed higher mean urinary concentrations than both BPA-sulfate (1.8 ng/mL) and 4-(2-(4-hydroxyphenyl)propan-2-yl)benzene-1,2-diol (BPA-O; 0.37 ng/mL). Notably, this study first demonstrates the presence of BPA-O and 2,2-bis(4-hydroxyphenyl)propanol in human urine. In total, 17 % of human urine samples contained measurable o, p'-BPA, with the highest level of 0.58 ng/mL. The o, p'-BPA-glucuronide was found in 22 % of human urine samples, displaying the highest level of 1.0 ng/mL. Findings of this study provide critical novel insights into the simultaneous metabolic fate of BPA and o, p'-BPA in humans. These results also emphasize the necessity of including o, p'-BPA in future biomonitoring studies and health risk assessments to enable more accurate evaluation of human exposure and potential health risks.