Papers by William H Bisson
Frontiers in Oncology, 2024
A healthy lifestyle, pharmacological strategies, or decreased exposure to environmental
carcinoge... more A healthy lifestyle, pharmacological strategies, or decreased exposure to environmental
carcinogens can reduce risk or delay the development of cancer (1). Several decades of
research have explored mechanisms of carcinogenesis, characterized carcinogenicity
hazards, and identified novel targets for intervention. Many of these integral discoveries
contributed to the identification of the 15 hallmarks of cancer and the 10 key characteristics
of carcinogens, KCCs (2–4) Leveraging these findings has the potential to foster the design
and the implementation of precision prevention strategies on multiple levels (5).
This Research Topic aimed to produce a collection of articles that discuss known and
novel biological targets and biomarkers in vitro, in vivo, and in human cohorts, including
the emerging role of the cancer hallmarks phenotypic plasticity and circulating cell-derived
biomarkers. The importance of integrating mechanistic and epidemiological data-driven
approaches was highlighted. Particularly, these articles focused on identified early
mechanisms of molecular and chemical carcinogenesis aiming to inform precision
prevention and to reduce the burden of cancer health disparities
Frontiers in Oncology, 2024
The complexity of cancer requires a comprehensive approach to understand its
diverse manifestatio... more The complexity of cancer requires a comprehensive approach to understand its
diverse manifestations and underlying mechanisms. Initially outlined by Hanahan
and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a
conceptual basis for understanding inherent variability in cancer biology. Recent
expansions have further elucidated additional hallmarks, including phenotypic
plasticity and senescent cells. The International Agency for Research on Cancer
(IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate
their carcinogenic potential. We analyzed chemicals of concern for
environmental exposure that interact with specific receptors to induce
genomic instability, epigenetic alterations, immune suppression, and receptormediated effects, thereby contributing to chronic inflammation. Despite their
varying degrees of carcinogenicity, these chemicals have similar KCC profiles.
Our analysis highlights the pivotal role of receptor binding in activating most
other KCCs, underscoring their significance in cancer initiation. Although KCCs
are associated with early molecular or cellular events, they do not encompass
processes directly linked to full cellular malignancy. Thus, there is a need to
integrate clear endpoints that anchor KCCs to the acquisition of a complete
malignant phenotype into chemical testing. From the perspective of toxicology
and cancer research, an all-encompassing strategy that incorporates both
existing and novel KCCs and cancer hallmarks is essential to enable the
targeted identification of prevalent carcinogens and facilitate zone-specific
prevention strategies. To achieve this goal, collaboration between the KCC and
cancer hallmarks communities becomes essential.
Biology, 2017
We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the ... more We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We performed structure-activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis. We identified Y134 as a raloxifene analog that activates AhR-mediated transcriptional activity and induces apoptosis in MDA-MB-231 human triple negative breast cancer cells. Suppression of AhR expression strongly reduced apoptosis induced by Y134, indicating the requirement of AhR for Y134-induced apoptosis. Y134 also induced apoptosis in hepatoma cells without having an effect on cell cycle regulation. Toxicity testing on zebrafish embryos revealed that Y134 has a significantly better safety profile than raloxifene. Our studies also identified an analog of ralox...
Toxicological sciences : an official journal of the Society of Toxicology, 2015
Polycyclic aromatic hydrocarbons (PAHs) are priority environmental contaminants that exhibit muta... more Polycyclic aromatic hydrocarbons (PAHs) are priority environmental contaminants that exhibit mutagenic, carcinogenic, proinflammatory, and teratogenic properties. Oxygen-substituted PAHs (OPAHs) are formed during combustion processes and via phototoxidation and biological degradation of parent (unsubstituted) PAHs. Despite their prevalence both in contaminated industrial sites and in urban air, OPAH mechanisms of action in biological systems are relatively understudied. Like parent PAHs, OPAHs exert structure-dependent mutagenic activities and activation of the aryl hydrocarbon receptor (AHR) and cytochrome p450 metabolic pathway. Four-ring OPAHs 1,9-benz-10-anthrone (BEZO) and benz(a)anthracene-7,12-dione (7,12-B[a]AQ) cause morphological aberrations and induce markers of oxidative stress in developing zebrafish with similar potency, but only 7,12-B[a]AQ induces robust Cyp1a protein expression. We investigated the role of the AHR in mediating the toxicity of BEZO and 7,12-B[a]AQ, a...
Nature Chemistry , 2023
Non-destructive fluorophore diffusion across cell membranes to provide an unbiased fluorescence i... more Non-destructive fluorophore diffusion across cell membranes to provide an unbiased fluorescence intensity readout is critical for quantitative imaging applications in live cells and tissues. Commercially available small-molecule fluorophores have been engineered for biological compatibility, imparting high water solubility by modifying rhodamine and cyanine dye scaffolds with multiple sulfonate groups. The resulting net negative charge, however, often renders these fluorophores cell-membrane-impermeant. Here we report the design and development of our biologically compatible, water-soluble and cell-membrane-permeable fluorophores, termed OregonFluor (ORFluor). By adapting previously established ratiometric imaging methodology using bio-affinity agents, it is now possible to use small-molecule ORFluor-labelled therapeutic inhibitors to quantitatively visualize their intracellular distribution and protein target-specific binding, providing a chemical toolkit for quantifying drug target availability in live cells and tissues.
Exposome, 2024
This paper explores the exposome concept and its role in elucidating the interplay between enviro... more This paper explores the exposome concept and its role in elucidating the interplay between environmental exposures and human health. We introduce two key concepts critical for exposomics research. Firstly, we discuss the joint impact of genetics and environment on phenotypes, emphasizing the variance attributable to shared and nonshared environmental factors, underscoring the complexity of quantifying the exposome's influence on health outcomes. Secondly, we introduce the importance of advanced datadriven methods in large cohort studies for exposomic measurements. Here, we introduce the exposome-wide association study (ExWAS), an approach designed for systematic discovery of relationships between phenotypes and various exposures, identifying significant associations while controlling for multiple comparisons. We advocate for the standardized use of the term "exposomewide association study, ExWAS," to facilitate clear communication and literature retrieval in this field. The paper aims to guide future health researchers in understanding and evaluating exposomic studies. Our discussion extends to emerging topics, such as FAIR Data Principles, biobanked healthcare datasets, and the functional exposome, outlining the future directions in exposomic research. This abstract provides a succinct overview of our comprehensive approach to understanding the complex dynamics of the exposome and its significant implications for human health.
Carcinogenesis, Jan 22, 2015
An increasing number of studies suggest an important role of host immunity as a barrier to tumor ... more An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides...
Carcinogenesis, 2015
Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect... more Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through ...
Molecular Nutrition & Food Research, 2016
Toxicological sciences : an official journal of the Society of Toxicology, Jan 13, 2017
FICZ and TCDD, two high affinity AhR ligands, are reported to have opposite effects on T cell dif... more FICZ and TCDD, two high affinity AhR ligands, are reported to have opposite effects on T cell differentiation with TCDD inducing regulatory T cells and FICZ inducing Th17 cells. This dichotomy has been attributed to ligand-intrinsic differences in AhR activation, although differences in sensitivity to metabolism complicates the issue. TCDD is resistant to AhR-induced metabolism and produces sustained AhR activation following a single dose in the μg/kg range while FICZ is rapidly metabolized and AhR activation is transient. Nonetheless, prior studies comparing FICZ with TCDD have generally used the same 10-50μg/kg dose range, and thus the two ligands would not equivalently activate AhR. We hypothesized that high-affinity AhR ligands can promote CD4+ T cell differentiation into both Th17 cells and Tregs, with fate depending on the extent and duration of AhR activation. We compared the immunosuppressive effects of TCDD, FICZ, and several other rapidly metabolized ligands in an acute al...
Toxicological sciences : an official journal of the Society of Toxicology, May 10, 2017
Nitrated polycyclic aromatic hydrocarbons (NPAHs) and heterocyclic PAHs (HPAHs) are recognized en... more Nitrated polycyclic aromatic hydrocarbons (NPAHs) and heterocyclic PAHs (HPAHs) are recognized environmental pollutants. However, the health risks of NPAHs and HPAHs to humans and environmental systems are not well-studied. The developmental zebrafish (Danio rerio) model was used to evaluate the toxicity of a structurally diverse set of 27 NPAHs and 10 HPAHs. The individual activity of each compound towards the aryl hydrocarbon receptor (AHR), including the role of the AHR in observed toxicity, and genetic markers of oxidative stress and cardiac toxicity were evaluated. Zebrafish embryos were exposed from 6 to 120 hours post fertilization (hpf), to a broad concentration range of individual compounds, and evaluated for 22 developmental endpoints. The potential role of AHR was determined using the transgenic Tg(cyp1a:nls-egfp) reporter zebrafish line. All compounds were screened computationally through molecular docking using a previously developed AHR models of zebrafish isoforms 1A,...
Journal of Medicinal Chemistry, 2005
The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and... more The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha3beta4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha4beta2 nAChR subtype ligands.
Cell death & disease, 2014
Identification of new molecular targets for the treatment of breast cancer is an important clinic... more Identification of new molecular targets for the treatment of breast cancer is an important clinical goal, especially for triple-negative breast cancer, which is refractory to existing targeted treatments. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, and thus may be a potential anticancer target. To investigate the AhR as an anticancer target, we conducted a small molecule screen to discover novel AhR ligands with anticancer properties. We identified raloxifene, a selective estrogen receptor (ER) modulator currently used in the clinic for prevention of ER-positive breast cancer and osteoporosis in post-menopausal women, as an AhR activator. Raloxifene directly bound the AhR and induced apoptosis in ER-negative mouse and human hepatoma cells in an AhR-dependent manner, indicati...
Current topics in medicinal chemistry, 2012
Current topics in medicinal chemistry
Toxicological Sciences, 2011
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Papers by William H Bisson
carcinogens can reduce risk or delay the development of cancer (1). Several decades of
research have explored mechanisms of carcinogenesis, characterized carcinogenicity
hazards, and identified novel targets for intervention. Many of these integral discoveries
contributed to the identification of the 15 hallmarks of cancer and the 10 key characteristics
of carcinogens, KCCs (2–4) Leveraging these findings has the potential to foster the design
and the implementation of precision prevention strategies on multiple levels (5).
This Research Topic aimed to produce a collection of articles that discuss known and
novel biological targets and biomarkers in vitro, in vivo, and in human cohorts, including
the emerging role of the cancer hallmarks phenotypic plasticity and circulating cell-derived
biomarkers. The importance of integrating mechanistic and epidemiological data-driven
approaches was highlighted. Particularly, these articles focused on identified early
mechanisms of molecular and chemical carcinogenesis aiming to inform precision
prevention and to reduce the burden of cancer health disparities
diverse manifestations and underlying mechanisms. Initially outlined by Hanahan
and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a
conceptual basis for understanding inherent variability in cancer biology. Recent
expansions have further elucidated additional hallmarks, including phenotypic
plasticity and senescent cells. The International Agency for Research on Cancer
(IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate
their carcinogenic potential. We analyzed chemicals of concern for
environmental exposure that interact with specific receptors to induce
genomic instability, epigenetic alterations, immune suppression, and receptormediated effects, thereby contributing to chronic inflammation. Despite their
varying degrees of carcinogenicity, these chemicals have similar KCC profiles.
Our analysis highlights the pivotal role of receptor binding in activating most
other KCCs, underscoring their significance in cancer initiation. Although KCCs
are associated with early molecular or cellular events, they do not encompass
processes directly linked to full cellular malignancy. Thus, there is a need to
integrate clear endpoints that anchor KCCs to the acquisition of a complete
malignant phenotype into chemical testing. From the perspective of toxicology
and cancer research, an all-encompassing strategy that incorporates both
existing and novel KCCs and cancer hallmarks is essential to enable the
targeted identification of prevalent carcinogens and facilitate zone-specific
prevention strategies. To achieve this goal, collaboration between the KCC and
cancer hallmarks communities becomes essential.
carcinogens can reduce risk or delay the development of cancer (1). Several decades of
research have explored mechanisms of carcinogenesis, characterized carcinogenicity
hazards, and identified novel targets for intervention. Many of these integral discoveries
contributed to the identification of the 15 hallmarks of cancer and the 10 key characteristics
of carcinogens, KCCs (2–4) Leveraging these findings has the potential to foster the design
and the implementation of precision prevention strategies on multiple levels (5).
This Research Topic aimed to produce a collection of articles that discuss known and
novel biological targets and biomarkers in vitro, in vivo, and in human cohorts, including
the emerging role of the cancer hallmarks phenotypic plasticity and circulating cell-derived
biomarkers. The importance of integrating mechanistic and epidemiological data-driven
approaches was highlighted. Particularly, these articles focused on identified early
mechanisms of molecular and chemical carcinogenesis aiming to inform precision
prevention and to reduce the burden of cancer health disparities
diverse manifestations and underlying mechanisms. Initially outlined by Hanahan
and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a
conceptual basis for understanding inherent variability in cancer biology. Recent
expansions have further elucidated additional hallmarks, including phenotypic
plasticity and senescent cells. The International Agency for Research on Cancer
(IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate
their carcinogenic potential. We analyzed chemicals of concern for
environmental exposure that interact with specific receptors to induce
genomic instability, epigenetic alterations, immune suppression, and receptormediated effects, thereby contributing to chronic inflammation. Despite their
varying degrees of carcinogenicity, these chemicals have similar KCC profiles.
Our analysis highlights the pivotal role of receptor binding in activating most
other KCCs, underscoring their significance in cancer initiation. Although KCCs
are associated with early molecular or cellular events, they do not encompass
processes directly linked to full cellular malignancy. Thus, there is a need to
integrate clear endpoints that anchor KCCs to the acquisition of a complete
malignant phenotype into chemical testing. From the perspective of toxicology
and cancer research, an all-encompassing strategy that incorporates both
existing and novel KCCs and cancer hallmarks is essential to enable the
targeted identification of prevalent carcinogens and facilitate zone-specific
prevention strategies. To achieve this goal, collaboration between the KCC and
cancer hallmarks communities becomes essential.