Assessing the safety of Bisphenol A, its substitutes, and associated detoxification methods using the alternative animal model Caenorhabditis elegans
Bisphenol A (BPA) is widely used for producing consumer products such as plastics, receipts, and food packaging. Increased concerns about its safety has led to its replacement with substitutes. However, most of these substitutes share a high degree of structural similarity with BPA, suggesting that they may possess comparable bioactivity and toxicity. Using the model organism Caenorhabditis elegans (C. elegans), the consequences on normal reproduction of the BPA substitute bisphenol S (BPS) was investigated. Similar to BPA, BPS resulted in severe reproductive defects, including germline apoptosis and embryonic lethality. However, analysis of meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast database analysis indicate that BPS exposure caused reproductive defects are partially achieved via mechanisms distinct from those mediated by BPA. Our findings here not only raise new concerns about the safety of BPA alternatives but also highlight the value of C. elegans as a valuable and relevant model organism for evaluating the toxicity of BPA and its substitutes. Therefore, in the second part of this study, we utilized C. elegans as the model organism to evaluate the detoxification efficiency and safety of a novel enzymatic bisphenol biodegradation system developed by Dr. Shaily Mahendra at UCLA. Manganese peroxidase (MnP) was utilized in this system to degrade bisphenol compounds (BPs) in water. Packaging MnP with vault nanoparticles (vMnP) increases its biodegradation efficiency. To answer whether this encapsulation altered enzyme kinetics and resulted in products with different toxicity, a product profile analysis was conducted. Experiments revealed that encapsulation resulted in considerable division in product species and abundance, consistent with the observed changes in the estrogenic activities of BPs. The reproductive toxicity of vMnP-treated samples, as measured in C. elegans, were dramatically reduced for all tested BPs, evidenced by significantly reduced embryonic lethality and germline apoptosis. Collectively, these results indicate that the vMnP system represents an efficient and effective strategy for the removal of environmental BPs. Finally, although exposure to BPA associates with alterations in hormone production, its effect on mitochondrial cholesterol uptake, the crucial step for hormone biosynthesis, remains unknown. Therefore, the relationship between BPA and mitochondrial cholesterol transporters was investigated in C. elegans as well. Results indicate that BPA reduced the efficiency of steroidogenic acute regulatory protein (StAR) in cholesterol transport, disturbed intracellular cholesterol homeostasis and resulted in mitochondrial cholesterol deficiency. These changes were positively associated with the reproductive damage observed in worms following BPS exposure, since restoring mitochondrial cholesterol level through exogenous cholesterol supplementation rescued BPA-induced reproductive dysfunctions in nematodes. The findings reported in this study here provide important mechanistic evidence on the effect of BPA on intracellular cholesterol transport and reproduction. They also suggest that the reproductive system of individuals with StAR deficiency or low cholesterol level may be sensitive to BPA’s toxicity. In summary, this study not only expands our knowledge of the toxicity of bisphenol compounds but also clearly highlight the value of C. elegans as a powerful in vivo assay model in toxicology research.