History of environmental and molecular mutagenesis

Environmental and Molecular Mutagenesis, the journal of the Environmental Mutagen Society (EMS), marks its 25th anniversary in 2004. The journal, originally called Environmental Mutagenesis, was established in 1979 with Seymour Abrahamson as its first editor. The development of the journal is closely linked to the evolution of the fields of mutation research and genetic toxicology. This perspective traces the founding of the journal and discusses its editorial history, growth, content, style, administration, and relationship to the EMS.     

History and rationale of genetic toxicity testing: an impersonal, and sometimes personal, view

Genetic toxicity testing is a necessary and pivotal component of product development and registration. This article traces the historical development and evolution of genetic toxicity testing, and the rationale for such testing, and identifies some of the individuals who played key roles in this process. The evolution of the present test batteries and some of the research and rationales behind the decisions to accept or reject tests are described.     

The mutagenesis moonshot: The propitious beginnings of the environmental mutagenesis and genomics society

A mutagenesis moonshot addressing the influence of the environment on our genetic wellbeing was launched just 2 months before astronauts landed on the moon. Its impetus included the discovery that X-rays (Muller HJ. [1927]: Science 64:84–87) and chemicals (Auerbach and Robson. [1946]: Nature 157:302) were germ-cell mutagens, the introduction of a growing number of untested chemicals into the environment after World War II, and an increasing awareness of the role of environmental pollution on human health. Due to mounting concern from influential scientists that germ-cell mutagens might be ubiquitous in the environment, Alexander Hollaender and colleagues founded in 1969 the Environmental Mutagen Society (EMS), now the Environmental Mutagenesis and Genomics Society (EMGS); Frits Sobels founded the European EMS in 1970. As Fred de Serres noted, such societies were necessary because protecting populations from environmental mutagens could not be addressed by existing scientific societies, and new multidisciplinary alliances were required to spearhead this movement. The nascent EMS gathered policy makers and scientists from government, industry, and academia who became advocates for laws requiring genetic toxicity testing of pesticides and drugs and helped implement those laws. They created an electronic database of the mutagenesis literature; established a peer-reviewed journal; promoted basic and applied research in DNA repair and mutagenesis; and established training programs that expanded the science worldwide. Despite these successes, one objective remains unfulfilled: identification of human germ-cell mutagens. After 50 years, the voyage continues, and a vibrant EMGS is needed to bring the mission to its intended target of protecting populations from genetic hazards. Environ. Mol. Mutagen. 61:8–24, 2020. © 2019 Wiley Periodicals, Inc.     

Building on the past,shaping the future: The environmental mutagenesis and genomics society

In late 2012, the members of the Environmental Mutagen Society voted to change its name to the Environmental Mutagenesis and Genomics Society. Here, we describe the thought process that led to adoption of the new name, which both respects the rich history of a Society founded in 1969 and reflects the many advances in our understanding of the nature and breadth of gene‐environment interactions during the intervening 43 years. Environ. Mol. Mutagen. 54:153–157, 2013. © 2013 Wiley Periodicals, Inc.     

Mutagenicity of products from coal gasification and liquefaction in the salmonella/microsome assay

As a first step in the assessment of their possible bio-effects, coal-related materials were tested for mutagenicity in the Salmonella/microsome assay. Of three coal gasification by-products tested, only a tar was mutagenic for any of four Salmonella strains. The following liquefaction materials were mutagenic for strains TA1538, TA98, and/or TA100: A liquefaction vehicle oil and coal hydrogenation filtered liquid, separated bottoms, vacuum overhead, and vacuum bottoms. Neither powdered coal nor water produced as a by-product of the hydrogenation process was positive in the Salmonella test. No coal-related material was mutagenic for the missense mutant TA1535 or for any strain in the absence of metabolic activation provided by rat hepatic homogenates (S9). In all but one instance Aroclor 1254-induced S9 provided the maximum activation for mutagenesis. Fractionation of all samples was undertaken by serial extraction with organic solvents of increasing polarity (hexane, toluene, methylene chloride, acetonitrile). Highly mutagenic materials were found in fractions of the hydrogenation filtered liquid, vacuum overhead, and vacuum bottoms. Thus far non-mutagenic samples have not yielded mutagenic components upon fractionation.     

The metabolic activation of 4,4′-methylene-bis-(2-chlorobenzeneamine) to a bacterial mutagen by hepatic postmitochondrial supernatant from human and other species

4,4′-Methylene-bis-(2-chlorobenzeneamine) (MbOCA) is a commercially important industrial chemical that is carcinogenic in three animal species and mutagenic in the Ames test. The ability of hepatic postmitochondrial supernatant from humans, dogs, mice, and rats to activate MbOCA to a bacterial mutagen has been investigated using the Ames plate incorporation test and a bacterial fluctuation test. In the Ames plate test, hepatic S9 preparations from mice and Aroclor 1254-induced rats only were sufficiently active to produce a significant mutagenic response. Preincubation of MbOCA with S9 from human liver produced a slight increase in the number of revertants but not a doubling as compared to controls. However, using the more sensitive bacterial fluctuation test, liver S9 from all species activated MbOCA to a bacterial mutagen. The responses produced were dose-related and, for at least part of the dose range, were double the background levels observed in controls. The increases in the mutagenicity of MbOCA produced by liver S9 from humans, dogs, and rats were significant at the 0.1% level of probability. Liver S9 preparations from all species in which MbOCA is carcinogenic have now been demonstrated to be capable of activating this compound to a bacterial mutagen. The finding that S9 from human liver can also activate MbOCA to a mutagen increases the concern that it may be a human carcinogen.     

Study of mutational specificity in the lacl gene of Escherichia coli as a window on the mechanisms of mutation

Whereas in the past we had to be content with mutation induction and survival curves, the recently developed technologies permitting the rapid cloning and sequencing of mutant alleles have provided a new window through which to examine the nature of mutation. These technologies make it possible to determine the precise nature of the mutational alteration as well as the local DNA context. This information has contributed significantly to our knowledge of the mutational process including the identification of likely pre-mutagenic lesions and the influence of DNA sequence and structure of the distribution of damage and its subsequent repair. This article discusses these issues as they relate to mutagenesis by alkylating agents.     

Predicting the mutagenicity of tobacco-related N-nitrosamines in humans using 11 strains of Salmonella typhimurium YG7108, each coexpressing a form of human cytochrome P450 along with NADPH-cytochrome P450 reductase.

Tobacco, including snuff and chewing tobacco, contains N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), N-nitrosopiperidine (NPIP), N-nitrosomorpholine (NMOR), N-nitrosonornicotine (NNN), N-nitrosoanabasine (NABS), and N-nitrosoanatabine (NATB). The role of human cytochrome P450 (CYP) in the metabolic activation of these tobacco-related N-nitrosamines was examined by a Salmonella mutation test using genetically engineered Salmonella typhimurium (S. typhimurium) YG7108 cells each expressing a form of human CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, or CYP3A5) together with human NADPH-cytochrome P450 reductase. Mutagen production from NNK was catalyzed by CYP in the following order: CYP1A2, CYP1A1, CYP1B1, CYP2A6, CYP2C19, CYP3A4. The metabolic activation of one of the N-alkylnitrosamines, NDEA, was mediated by CYP2A6, followed by CYP2E1. Cyclic N-nitrosamines such as NPYR, NPIP, and NMOR were also primarily activated by CYP2A6, and to a lesser extent by CYP2E1. NNN, a pyridine derivative of NPYR, was activated by CYP1A1 at an efficiency similar to that of CYP2A6. NABS, a pyridine derivative of NPIP, was mainly activated by CYP3A4, followed by CYP1A1 and CYP2A6. Thus, the addition of a pyridine ring to NPYR or NPIP altered the forms of CYP primarily responsible for mutagenic activation. NATB was metabolically activated solely by CYP2A6, whereas the genotoxicity of NATB was much lower than that of NNN or NPYR. Based on these data, we conclude that CYP2A6 was responsible for the mutagenic activation of essentially all tobacco-related N-nitrosamines tested in the present study.     

Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity

A relatively rare type of mutation causing human genetic disease is the indel, a complex lesion that appears to represent a combination of micro-deletion and micro-insertion. In the absence of meta-analytical studies of indels, the mutational mechanisms underlying indel formation remain unclear. Data from the Human Gene Mutation Database (HGMD) were therefore used to compare and contrast 211 different indels underlying genetic disease in an attempt to deduce the processes responsible for their genesis. Each indel was treated as if it were the result of a two-step insertion/deletion process and was assessed in the context of 10 base-pairs DNA sequence flanking the lesion on either side. Several indel hotspots were noted and a GTAAGT motif was found to be significantly over-represented in the vicinity of the indels studied. Previously postulated mechanisms underlying micro-deletions and micro-insertions were initially explored in terms of local DNA sequence regularity as measured by its complexity. The change in complexity consequent to a mutation was found to be indicative of the type of repeat sequence involved in mediating the event, thereby providing clues as to the underlying mutational mechanism. Complexity analysis was then employed to examine the possible intermediates through which each indel could have occurred and to propose likely mechanisms and pathways for indel generation on an individual basis. Manual analysis served to confirm that the majority of indels (>90%) are explicable in terms of a two-step process involving established mutational mechanisms. Indels equivalent to double base-pair substitutions (22% of the total) were found to be mechanistically indistinguishable from the remainder and may therefore be regarded as a special type of indel. The observed correspondence between changes in local DNA sequence complexity and the involvement of specific mutational mechanisms in the insertion/deletion process, and the ability of generated models to account for both the number and identity of the bases deleted and/or inserted, makes this approach invaluable not only for the analysis of indel formation, but also for the study of other types of complex lesion.     

医学科技论文影响力相关因素分析

目的探讨医学科技论文影响力的相关因素方法采用回归分析方法,研究安医大附院1996-2003年间1146篇科技论文影响力与作者背景、论文来源等因素之间的关系。结果影响因子、是否为基金或成果论文,以及作者是否入选人才培养对象、是否承担课题等9个因素与论文影响力有明显的相关性,其中影响因子、是否为基金或成果论文、论文发表年限和作者学历,不仅与论文是否被引用有关,而且影响着论文被引频次和自引他引倾向。结论论文影响力的提高,不仅需要科研管理部门引导科技人员在高影响因子期刊发表科技论文,更需要从人才培养、学位教育、项目和成果管理等诸方面去努力,只有建立起一支具有良好素质和有所作为的科技队伍作支撑,才能从根本上保证论文水平和论文影响力的稳步提高。     

门诊病历科学管理探讨

门诊病历的科学管理是医院现代化管理和建设和谐医患关系的一个重要标志。基于门诊病历的特点和书写规范的特殊性．门诊病历的科学管理在当前没有引起足够重视，使其成为被忽视和浪费的医疗资源。本文探讨了当前门诊病历的现状和存在的问题，提出了对门诊病历进行科学管理的对策和方法，同时对门诊病历”一本通”和门诊病历质量控制进行了讨论。科学地管理门诊病历，将会推动医院管理水平和医疗水平的提高，同时促进社会进步及和谐医患关系的发展。     

Morphological transformation of BALB/3T3 cells by various procarcinogens in the presence of a rat liver S-9 activation system

An Aroclor-induced rat hepatic S-9 metabolic activation system was incorporated into the BALB/3T3 cell transformation assay to increase its sensitivity to a wide range of procarcinogens. S-9 was prepared from Aroclor 1254-induced (500 mg/kg) Fischer 344 rats. Cyclophosphamide, dimethylnitrosamine, 2-aminofluorene, and 2-naphthylamine were metabolized to reactive forms capable of inducing both dose-dependent toxicity and morphological transformation of BALB/3T3 cells. Treatments without an exogenous metabolic activation system were nontoxic and nontransforming. Adaptation of this commonly used exogenous metabolic activation system to BALB/3T3 cells will allow detection of the transforming potential of procarcinogens which test negative in a standard assay.     

信息对医学发展的影响给我们的启示

本文对信息的产生、概念、特性及作用进行了概括性描述，以中西医学发展中重大成功的发明发现和失误、失败教训为线索，阐述了信息时医学的巨大影响，并指出科学对待、处理、发现、利用信息的方法和途径。提出了医学研究中信息安全的重要性及揭露、批判、清理伪科学、虚假、有害信息的必要性。     

Mutation screening of the LDLR gene and ApoB gene in patients with a phenotype of familial hypercholesterolemia and normal values in a functional LDL receptor/apolipoprotein B assay

Mutations in the LDL receptor (LDLR) or the apolipoprotein B-100 genes causing familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB), two of the most frequent inherited diseases, are the underlying genetic defects in a small proportion of patients suffering from premature atherosclerotic heart disease.
Consequently, secure diagnostic tools for these conditions allowing early preventive measures are needed. Since clinical and biochemical diagnosis often is inaccurate, assays analyzing patient LDLR function and LDL affinity have been established. These assays are, however, not able clearly to differentiate between suspected FH/FDB samples and normal controls. To evaluate if this may be caused by other hitherto undescribed genetic defects or to failure of the functional assays, we undertook denaturing gradient gel electrophoresis based mutation screening of the LDLR gene and the codon 3456–3553 region of the apolipoprotein B gene in six French FH/FDB patients with normal outcomes on functional assays. In all six patients, pathogenic LDLR mutations were found, including three previously undescribed mutations, suggesting that failure of the functional assays explains the normal results found in some phenotypic FH/FDB patients and illustrating the need for DNA based screening techniques for routine genetic diagnosis in FH/FDB.     

Expression of cloned envelope protein genes from the flavivirus tick-borne encephalitis virus in mammalian cells and random mutagenesis by PCR

The structural membrane proteins prM and E of the flavivirus tick-borne encephalitis (TBE) virus were expressed in mammalian cells for the purpose of probing the structure and molecular interactions of these proteins. Advantage was taken of the natural error frequency of the Taq polymerase used in the PCR amplification to generate a randomly mutated population of genes that were then cloned directly into plasmid expression vectors under the control of an SV40 promoter. Analysis of the mutation frequency by direct sequencing of 22 separate clones showed that the PCR produced mutations at a rate yielding an average of one to two amino acid changes per clone in the 496 amino acid long protein E. This is an ideal rate for assessing the importance of individual amino acid residues within protein domains, thus demonstrating the potential value of the PCR as a random mutagenesis method. Clones encoding wild-type prM and E proteins, and a truncated form of E, were also constructed by recombining portions of selected PCR clones. Transfection of COS-1 cells with these constructs resulted in expression of the prM and E proteins, which was demonstrated by indirect immunofluorescence using monoclonal antibodies (Mabs). The intracellular level of TBE virus antigen, measured in lysates of transfected cells by ELISA, reached approximately 25% of that found in virusinfected COS cells. Furthermore, it was shown by immunofluoresence using a panel of 19 anti-E Mabs that the antigenic structure of the expressed E proteins was nearly identical to that of E protein in infected cells, thus confirming the suitability of this model system as a tool for studying flavivirus protein structure.