Metabolic activation of the plastic additive BPA, underlying mode of action

The risk plastic pollution poses to organisms depends on multiple factors such as particle size and additive composition. In some cases, additives account for up to 30% by weight, and it is well known that some of these additives generate adverse effects on organisms. Bisphenol A (BPA) is a widely used synthetic chemical found in various industries, including plastic. It is prevalent in aquatic environments, with concentrations reaching over 10 μg L⁻¹, and is recognized as a weak estrogenic endocrine disruptor (eEDC). BPA has been identified as a substance of concern due to its reproductive toxicity and has been added to the European Union's "Candidate List" for possible regulation under the REACH framework.The primary stablished mode of action of BPA is its binding to nuclear estrogen receptors, affecting the transcription of estrogen-responsive genes. However, its effects vary among species, often causing mild or inconsistent outcomes, which complicates regulatory measures.In vertebrates, BPA is primarily metabolized in the liver by the enzyme uridyl glucuronyl transferase (UGT). However, under specific conditions, UGT availability may be compromised, activating alternative secondary pathways. One such pathway involves the CYP450 enzyme, leading to the formation of the metabolite MBP. We have tested the estrogenic effects of MBP in the marine fish Cyprinodon variegatus, demonstrating elevated estrogenicity at both protein and gene expression levels, and have explored approaches to simulate in vivo scenarios of UGT deficiency.