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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2018)

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.

    Cover page: Assessing the safety of Bisphenol A, its substitutes, and associated detoxification methods using the alternative animal model Caenorhabditis elegans
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2019)
    Bisphenol A is an endocrine disruptor associated with hormone synthesis and reproduction alterations. However, the initiating events underpinning these dysfunctions are still unclear. Here, we address the hypothesis that BPA interferes with the highly evolutionary conserved process of mitochondrial cholesterol transport, a crucial step in steroid hormone biosynthesis, by using the model organism C. elegans. We observed that embryonic lethality and germline apoptosis, hallmarks of BPA's reproductive toxicity in C. elegans, are fully rescued by low exogenous cholesterol supplementation. We also observed that increasing BPA concentrations proportionally reduced mitochondrial cholesterol levels. Mutants for strl-1 (ortholog of StAR), but not C41G7.9 (ortholog of TSPO), show reproductive defects similar to BPA's while BPA exposure in a strl-1 background did not worsen these effects. Finally, cholesterol supplementation rescued these defects for all strl-1 genotype/BPA combinations assessed. Together, these results uncover a novel mechanism underlying BPA's germline toxicity through the alteration of cholesterol transport.
      Cover page: BPA interferes with StAR-mediated mitochondrial cholesterol transport to induce germline dysfunctions
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2019)
      We report an effective and environmentally sustainable water treatment approach using enzymes encapsulated in biogenic vault nanoparticles. Manganese peroxidase (MnP), whose stability was remarkably extended by encapsulating into vaults, rapidly catalyzed the biotransformation of endocrine-disrupting compounds, including bisphenol A (BPA), bisphenol F (BPF), and bisphenol AP (BPAP). The vault-encapsulated MnP (vMnP) treatment removed 80-95% of each of the tested bisphenols (BPs) at lower enzyme dosage, while free native MnP (nMnP) only resulted in a 19-36% removal, over a 24-h period. Treatment by vMnP and nMnP resulted in considerable disparities in product species and abundance, which were consistent with the observed changes in the estrogenic activities of BPs. To test if vMnP-catalyzed transformations generated toxic intermediates, we assessed biological hallmarks of BP toxicity, namely, the ability to disrupt reproductive processes. The toxicity of vMnP-treated samples, as measured in the model organism, Caenorhabditis elegans, was dramatically reduced for all three BPs, including the reproductive indicators of BPA exposure such as reduced fertility and increased germ cell death. Collectively, our results indicate that the vMnP system represents an efficient and safe approach for the removal of BPs and promise the development of vault-encapsulated customized enzymes for treating other targeted organic compounds in contaminated waters.
        Cover page: A Vault-Encapsulated Enzyme Approach for Efficient Degradation and Detoxification of Bisphenol A and Its Analogues
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2016)
        Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures.
          Cover page: Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function
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