Biomedical subjects

Ann M Richard

Publications and source records attributed to Ann M Richard.

11 recordsLinked to original sources

PubMed2006

The ToxCast program for prioritizing toxicity testing of environmental chemicals.

The U.S. Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS), and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. This chemical prioritization research program, entitled "ToxCast," is being initiated with the purpose of developing the ability to forecast toxicity based on bioactivity profiling. The proof-of-concept phase of ToxCast will focus upon chemicals with an existing, rich toxicological database in order to provide an interpretive context for the ToxCast data. This set of several hundred reference chemicals will represent numerous structural classes and phenotypic outcomes, including tumorigens, developmental and reproductive toxicants, neurotoxicants, and immunotoxicants. The ToxCast program will evaluate chemical properties and bioactivity profiles across a broad spectrum of data domains: physical-chemical, predicted biological activities based on existing structure-activity models, biochemical properties based on HTS assays, cell-based phenotypic assays, and genomic and metabolomic analyses of cells. These data will be generated through a series of external contracts, along with collaborations across EPA, with the National Toxicology Program, and with the National Institutes of Health Chemical Genomics Center. The resulting multidimensional data set provides an informatics challenge requiring appropriate computational methods for integrating various chemical, biological, and toxicological data into profiles and models predicting toxicity.

Animals↗

PubMed2006

Future of toxicology--predictive toxicology: An expanded view of "chemical toxicity".

A chemistry approach to predictive toxicology relies on structure-activity relationship (SAR) modeling to predict biological activity from chemical structure. Such approaches have proven capabilities when applied to well-defined toxicity end points or regions of chemical space. These approaches are less well-suited, however, to the challenges of global toxicity prediction, i.e., to predicting the potential toxicity of structurally diverse chemicals across a wide range of end points of regulatory and pharmaceutical concern. New approaches that have the potential to significantly improve capabilities in predictive toxicology are elaborating the "activity" portion of the SAR paradigm. Recent advances in two areas of endeavor are particularly promising. Toxicity data informatics relies on standardized data schema, developed for particular areas of toxicological study, to facilitate data integration and enable relational exploration and mining of data across both historical and new areas of toxicological investigation. Bioassay profiling refers to large-scale high-throughput screening approaches that use chemicals as probes to broadly characterize biological response space, extending the concept of chemical "properties" to the biological activity domain. The effective capture and representation of legacy and new toxicity data into mineable form and the large-scale generation of new bioassay data in relation to chemical toxicity, both employing chemical structure information to inform and integrate diverse biological data, are opening exciting new horizons in predictive toxicology.

Animals↗

PubMed2006

Chemical structure indexing of toxicity data on the internet: moving toward a flat world.

Standardized chemical structure annotation of public toxicity databases and information resources is playing an increasingly important role in the 'flattening' and integration of diverse sets of biological activity data on the Internet. This review discusses public initiatives that are accelerating the pace of this transformation, with particular reference to toxicology-related chemical information. Chemical content annotators, structure locator services, large structure/data aggregator web sites, structure browsers, International Union of Pure and Applied Chemistry (IUPAC) International Chemical Identifier (InChI) codes, toxicity data models and public chemical/biological activity profiling initiatives are all playing a role in overcoming barriers to the integration of toxicity data, and are bringing researchers closer to the reality of a mineable chemical Semantic Web. An example of this integration of data is provided by the collaboration among researchers involved with the Distributed Structure-Searchable Toxicity (DSSTox) project, the Carcinogenic Potency Project, projects at the National Cancer Institute and the PubChem database.

Abstracting and Indexing↗

PubMed2005

Genotoxicity and metabolism of the source-water contaminant 1,1-dichloropropene: activation by GSTT1-1 and structure-activity considerations.

1,1-Dichloropropene (1,1-DCPe) is a contaminant of some source waters used to make drinking water. Because of this and the fact that no toxicological data were available for this compound, which is structurally similar to the rodent carcinogen 1,3-dichloropropene (1,3-DCPe), 1,1-DCPe was placed on the Contaminant Candidate List of the US Environmental Protection Agency. Consequently, we have performed a hazard characterization of 1,1-DCPe by evaluating its mutagenicity in the Salmonella assay and its DNA damaging (comet assay) and apoptotic (caspase assay) activities in human lymphoblastoid cells. In Salmonella, 1,1-DCPe was not mutagenic in strains TA98, TA100, TA1535, or TA104 +/-S9 mix. However, it was clearly mutagenic in strain RSJ100, which expresses the rat GSTT1-1 gene. 1,1-DCPe did not induce DNA damage in GSTT1-1-deficient human lymphoblastoid cells, and it induced apoptosis in these cells only at 5 mM. Consistent with its mutagenesis in RSJ100, 1,1-DCPe reacted with glutathione (GSH) in vitro, suggesting an addition-elimination mechanism to account for the detected GSH conjugate. 1,1-DCPe was approximately 5000 times more mutagenic than its ethene congener 1,1-dichloroethylene (1,1-DCE or vinylidene chloride). Neither 1,1-DCE nor 1,3-DCPe showed enhanced mutagenicity in strain RSJ100, indicating a lack of activation of these congeners by GSTT1-1. Thus, 1,1-DCPe is a base-substitution mutagen requiring activation by GSTT1-1, possibly involving the production of a reactive episulfonium ion. This bioactivation mechanism of 1,1-DCPe is different from that of its congeners 1,1-DCE and 1,3-DCPe. The presence of 1,1-DCPe in source waters could pose an ecological or human health risk. Occurrence data for 1,1-DCPe in finished drinking water are needed to estimate human exposure to, and possible health risks from, this mutagenic compound.

Allyl Compounds↗

PubMed2004

Comparative mutagenicity of halomethanes and halonitromethanes in Salmonella TA100: structure-activity analysis and mutation spectra.

Halonitromethanes (HNMs) are a recently identified class of disinfection by-products (DPBs) in drinking water that are mutagenic in Salmonella and potent inducers of DNA strand breaks in mammalian cells. Here we compared the mutagenic potencies of the HNMs to those of their halomethane (HM) homologues by testing all nine HNMs and seven of the nine HMs (minus bromomethane and chloromethane) under the same conditions (the pre-incubation assay) in Salmonella TA100 +/- S9. We also determined the mutation spectra for several DBPs. In the presence of S9, all nine HNMs, but only three HMs, dibromomethane (DBM), dichloromethane (DCM), and bromochloromethane (BCM), were mutagenic. Only two DBPs of each class were mutagenic in the absence of S9. The HNMs were generally more potent mutagens than their HM homologues, and the brominated forms of both classes of DBPs were more mutagenic and cytotoxic than their chlorinated homologues. The HNMs were at least 10 times more cytotoxic than the HMs, and the cytotoxicity rankings in the presence of S9 were similar for the HNMs and the HMs. The addition of a nitro-group to BCM did not change the mutation spectra significantly, with both homologues inducing primarily (55-58%) GC --> AT transitions. The greater cytotoxic and mutagenic activities of the HNMs relative to the HMs are likely due to the greater intrinsic reactivity conferred by the nitro-group. Energy calculations predicted increased reactivity with increasing bromination and greater reactivity of the HNMs versus the HMs (Elumo values were approximately 20 kcal/mol lower for the HNMs compared to their HM homologues). Given that the HNMs also are potent genotoxins in mammalian cells [Environ. Sci. Technol. 38 (2004) 62] and are more mutagenic and 10x more cytotoxic in Salmonella than the HMs, whose levels are regulated in drinking water, further study of their occurrence and potential health effects is warranted.

Biotransformation↗

PubMed2004

Mutagenicity in Salmonella of halonitromethanes: a recently recognized class of disinfection by-products in drinking water.

Halonitromethanes (HNMs) are a recently identified class of disinfection by-products (DBPs) in drinking water. They include chloronitromethane (CHN), dichloronitromethane (DCNM), trichloronitromethane (TCNM), bromonitromethane (BNM), dibromonitromethane (DBNM), tribromonitromethane (TBNM), bromochloronitromethane (BCNM),dibromochloronitromethane (DBCNM), and bromodichloronitromethane (BDCNM). Previous studies of TCNM, DCNM, CNM, and TBNM found that all four were mutagenic in bacteria, and a recent study showed that all nine induced DNA damage in CHO cells. Here, all nine HNMs were evaluated in the Salmonella plate-incorporation assay +/- S9 using strains TA98, TA100, TA104, TPT100, and the glutathione transferase theta (GSTT1-1)-expressing strain RSJ100. All were mutagenic, most with and without S9. In the absence of S9, six were mutagenic in TA98, six in TA100, and three in TA104; in the presence of S9, these numbers were five, seven, and three, respectively. Thus, the HNMs-induced base substitutions primarily at GC sites as well as frameshifts. Although five HNMs were activated to mutagens in RSJ100 -S9, they produced < or =2-fold increases in revertants and potencies <506 rev/micromol. The rank order of the HNMs by mutagenic potency in TA100 +S9 was (BCNM DBNM) > (TBNM CNM > BNM DCNM BDCNM) > (TCNM = DBCNM). The mean rev/micromol for the three groupings, respectively, were 1423, 498, and 0, which classifies the HNMs as weak mutagens in Salmonella. Reaction of the dihalo and monohalo HNMs with GSH, possibly GSTT1-1, is a possible mechanism for formation of ultimate mutagenic products. Because the HNMs are mutagenic in Salmonella (present study) and potent clastogens in mammalian cells [Environ. Sci. Technol. 38 (2004) 62], their presence in drinking water warrants further research on their potential health effects.

Biotransformation↗

PubMed2004

Challenges in constructing statistically based structure-activity relationship models for developmental toxicity.

Regulatory agencies are increasingly called upon to review large numbers of environmental contaminants that have not been characterized for their potential to pose a health risk. Additionally, there is special interest in protecting potentially sensitive subpopulations and identifying developmental toxicants that may be present in the environment. Thus, there is an urgent need for efficient methods to screen large numbers of chemicals for their potential to pose a developmental hazard. One potential screening method involves the use of statistically based structure-activity relationship (SAR) tools to predict activity of untested chemicals. Such systems rely on statistical analyses to discern relationships between structure and activity for a training set of substances. Predictions can then be made for an untested substance as long as its structural features are encompassed by chemicals of the training set. In theory, such systems could assist regulatory agencies in their screening efforts; however, to date, there has been little independent evaluation of these tools for this use. To contribute to such an evaluation, the International Life Sciences Institute Risk Science Institute (ILSI RSI) convened a Working Group to examine methodology used to construct statistically based SAR systems for developmental toxicity. This document reports on the deliberations of the Working Group, which concluded that an improved process is needed for utilizing developmental toxicity data in the construction of statistically based SAR models. The process must be objective, reproducible, rational and transparent. Moreover, it must be informed by the expertise of developmental toxicologists and biologists and must be subject to peer review.

Congenital Abnormalities↗

PubMed2004

Identification and characterization of novel stable deoxyguanosine and deoxyadenosine adducts of benzo[a]pyrene-7,8-quinone from reactions at physiological pH.

Benzo[a]pyrene (B[a]P) is an archetypal member of the family of polycyclic aromatic hydrocarbons (PAHs) and is a widely distributed environmental pollutant. B[a]P is known to induce cancer in animals, and B[a]P-containing complex mixtures are human carcinogens. B[a]P exerts its genotoxic and carcinogenic effects through metabolic activation forming reactive intermediates that damage DNA. DNA adduction by B[a]P is a complex phenomenon that involves the formation of both stable and unstable (depurinating) adducts. One pathway by which B[a]P can mediate genotoxicity is through the enzymatic formation of B[a]P-7,8-quinone (BPQ) from B[a]P-7,8-diol by members of the aldo-keto-reductase (AKR) family. Once formed, BPQ can act as a reactive Michael acceptor that can alkylate cellular nucleophiles including DNA and peptides. Earlier studies have reported on the formation of stable and depurinating adducts from the reaction of BPQ with DNA and nucleosides, respectively. However, the syntheses and characterization of the stable adducts from these interactions have not been addressed. In this study, the reactivity of BPQ toward 2'-deoxyguanosine (dG) and 2'-deoxyadenosine (dA) nucleosides under physiological pH conditions is examined. The identification and characterization of six novel BPQ-nucleoside adducts obtained from the reaction of BPQ and dG or dA in a mixture of phosphate buffer and dimethylformamide are reported. The structures of these adducts were determined by ultraviolet spectroscopy, electrospray mass spectrometry, and NMR experiments including (1)H, (13)C, two-dimensional COSY, one-dimensional NOE, ROESY, HMQC, HSQC, and HMBC. The reaction of BPQ with dG afforded four unique Michael addition products: two diastereomers of 8-N(1),9-N(2)-deoxyguanosyl-8,10-dihydroxy-9,10-dihydrobenzo[a]pyren-7(8H)-one (BPQ-dG(1,2)) and two diastereomers of 10-(N(2)-deoxyguanosyl)-9,10-dihydro-9-hydroxybenzo[a]pyrene-7,8-dione (BPQ-dG(3,4)). The BPQ-dG(1,2)( )()adducts suggest a 1,6-Michael addition reaction of dG, an oxidation of the hydroquinone to the quinone, a 1,4-Michael addition of water, and an internal cyclization. The BPQ-dG(3,4)( )()adducts suggest a 1,4-Michael addition reaction of dG, an oxidation of the hydroquinone to the quinone, and a 1,6-Michael addition of water. Under similar but extended reaction conditions, the reaction of BPQ with dA produced only one diastereomeric pair of adducts identified as 8-N(6),10-N(1)-deoxyadenosyl-8,9-dihydroxy-9,10-dihydrobenzo[a]pyren-7(8H)-one (BPQ-dA(1,2)). The BPQ-dA(1,2)( )()adducts suggest a 1,4-Michael addition reaction of dA, an oxidation of the hydroquinone to the quinone, a 1,6-Michael addition of water, and an internal cyclization. As considerable efforts have been placed in documenting the genotoxic effects of BPQ, this first report of the identification and characterization of these stable adducts of BPQ formed under physiological pH conditions is expected to contribute significantly to the area of BPQ-mediated genotoxicity and carcinogenesis.

Benzo(a)pyrene↗

PubMed2003

Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern about adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist activity of the organophosphate (OP) pesticide fenitrothion. In this study, we characterized AR activity of analogues of fenitrothion to probe the structural requirements for AR activity among related chemicals. AR activity was measured using HepG2 human hepatoma cells transfected with human AR plus an androgen-responsive luciferase reporter gene, MMTV-luc. AR antagonist activity decreased as alkyl chain length of the phosphoester increased, whereas electron-donating properties of phenyl substituents of the tested compounds did not influence AR activity. Oxon derivatives of fenitrothion, which are more likely to undergo hydrolytic degradation, had no detectable AR antagonist activity. Molecular modeling results suggest that hydrogen-bond energies and the maximum achievable interatomic distance between two terminal H-bond capable sites may influence both the potential to interact with the AR and the nature of the interaction (agonist vs. antagonist) within this series of chemicals. This hypothesis is supported by the results of recent AR homology modeling and crystallographic studies relative to agonist- and antagonist-bound AR complexes. The present results are placed in the context of structure-activity knowledge derived from previous modeling studies as well as studies aimed toward designing nonsteroidal antiandrogen pharmaceuticals. Present results extend understanding of the structural requirements for AR activity to a new class of nonsteroidal, environmental, OP-related chemicals.

Carcinoma, Hepatocellular↗

PubMed2002

Distributed structure-searchable toxicity (DSSTox) public database network: a proposal.

The ability to assess the potential genotoxicity, carcinogenicity, or other toxicity of pharmaceutical or industrial chemicals based on chemical structure information is a highly coveted and shared goal of varied academic, commercial, and government regulatory groups. These diverse interests often employ different approaches and have different criteria and use for toxicity assessments, but they share a need for unrestricted access to existing public toxicity data linked with chemical structure information. Currently, there exists no central repository of toxicity information, commercial or public, that adequately meets the data requirements for flexible analogue searching, Structure-Activity Relationship (SAR) model development, or building of chemical relational databases (CRD). The distributed structure-searchable toxicity (DSSTox) public database network is being proposed as a community-supported, web-based effort to address these shared needs of the SAR and toxicology communities. The DSSTox project has the following major elements: (1) to adopt and encourage the use of a common standard file format (structure data file (SDF)) for public toxicity databases that includes chemical structure, text and property information, and that can easily be imported into available CRD applications; (2) to implement a distributed source approach, managed by a DSSTox Central Website, that will enable decentralized, free public access to structure-toxicity data files, and that will effectively link knowledgeable toxicity data sources with potential users of these data from other disciplines (such as chemistry, modeling, and computer science); and (3) to engage public/commercial/academic/industry groups in contributing to and expanding this community-wide, public data sharing and distribution effort. The DSSTox project's overall aims are to effect the closer association of chemical structure information with existing toxicity data, and to promote and facilitate structure-based exploration of these data within a common chemistry-based framework that spans toxicological disciplines.

Carcinogens↗

PubMed2002

Improving structure-linked access to publicly available chemical toxicity information.

Publicly available toxicity databases serve as the central resource in efforts to develop algorithms for assessing potential chemical toxicity. File standardization and linkage of chemical structures with chemical toxicity information are essential first steps in providing broad access to existing toxicity information, for deriving useful structure-activity relationship (SAR) models, performing analog searches, and estimating the potential toxicity of new chemicals. This review will focus on current efforts to improve structure-linked access to publicly available sources of toxicity information, outlining current web-based resources as well as two new database initiatives for standardizing and consolidating public chemical toxicity information.

Computer Communication Networks↗