The objectives of this study were to determine whether differences in the size and composition of coarse (2.5-10 micro m), fine (< 2.5 microm), and ultrafine (< 0.1 microm) particulate matter (PM) are related to their uptake in macrophages and epithelial cells and their ability to induce oxidative stress. The premise for this study is the increasing awareness that various PM components induce pulmonary inflammation through the generation of oxidative stress. Coarse, fine, and ultrafine particles (UFPs) were collected by ambient particle concentrators in the Los Angeles basin in California and used to study their chemical composition in parallel with assays for generation of reactive oxygen species (ROS) and ability to induce oxidative stress in macrophages and epithelial cells. UFPs were most potent toward inducing cellular heme oxygenase-1 (HO-1) expression and depleting intracellular glutathione. HO-1 expression, a sensitive marker for oxidative stress, is directly correlated with the high organic carbon and polycyclic aromatic hydrocarbon (PAH) content of UFPs. The dithiothreitol (DTT) assay, a quantitative measure of in vitro ROS formation, was correlated with PAH content and HO-1 expression. UFPs also had the highest ROS activity in the DTT assay. Because the small size of UFPs allows better tissue penetration, we used electron microscopy to study subcellular localization. UFPs and, to a lesser extent, fine particles, localize in mitochondria, where they induce major structural damage. This may contribute to oxidative stress. Our studies demonstrate that the increased biological potency of UFPs is related to the content of redox cycling organic chemicals and their ability to damage mitochondria.

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Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage.

Papillomavirus infections — a major cause of human cancers

HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.

Molecular biology of human papillomavirus infection and cervical cancer.

Less than 10 years after publication of the hypothesis of a papillomavirus etiology of cancer of the cervix (zur Hausen 1975, 1976, 1977), the DNAs of the first cervical cancer-associated human papillomavirus (HPV) types were cloned and characterized. These DNAs are regularly and frequently found in biopsies obtained from cervical cancer patients throughout the world (Durst et al. 1983; Boshart et al. 1984).

Molecular pathogenesis of cancer of the cervix and its causation by specific human papillomavirus types.

OBJECTIVE. Autism is a developmental disorder defined by impaired social interaction, communication, and behavior. Causes and correlates of autism are largely unknown, but elevated frequencies of psychiatric disorders and distinct personality traits have been reported among the family members of individuals with autism. Linkage of data from Swedish registries was used to investigate whether hospitalization for psychiatric conditions was higher among parents of children with autism compared with control subjects. METHODS. Data sources included the Swedish Medical Birth Register (child9s birth), the Swedish Multi-Generation Register (linking parents to children), and Swedish Hospital Discharge Register (hospitalization records). Children born between 1977 and 2003 who had a hospitalization record indicating autism before 10 years of age (n = 1227) were matched with 30 693 control subjects from the Swedish Medical Birth Register by gender, year of birth, and hospital. Parent diagnoses were based on an inpatient hospital diagnostic evaluation and included schizophrenia, other nonaffective psychoses, affective disorders, neurotic and personality disorders and other nonpsychotic disorders, alcohol and drug addiction and abuse, and autism. Odds ratios and 95% confidence intervals were estimated by using conditional logistic regression, adjusted for child9s age, gender, hospital of birth, parents’ age, country of birth and socioeconomic status, and diagnosis of a mental disorder in the other parent. RESULTS. Parents of children with autism were more likely to have been hospitalized for a mental disorder than parents of control subjects. Schizophrenia was more common among case mothers and fathers compared with respective control parents. Depression and personality disorders were more common among case mothers but not fathers. CONCLUSIONS. This large population study supports the potential for familial aggregation of psychiatric conditions that may provide leads for future investigations of heritable forms of autism.

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Parental psychiatric disorders associated with autism spectrum disorders in the offspring.

We have previously identified in the long control region of the genome of human papillomavirus type 16 (HPV-16) a DNA segment which functions as a cell-type-specific enhancer as well as mediating glucocorticoid response. It contains multiple transcription-factor-binding sites, including several for nuclear factor I and one for the glucocorticoid receptor, which binds to the partially palindromic sequence TGTACANNNTGTCAT. We report here that this sequence element, when separated from the surrounding transcription-factor-binding sites and placed as an oligonucleotide into a test vector, retains its function as a glucocorticoid response element (GRE) in HeLa cells. In T47D cells, which express the progesterone receptor, the HPV-16 enhancer fragment mediates progesterone responsiveness. A point mutant in this fragment and the response of the oligonucleotide clone to both steroids prove the identity of the progesterone response element (PRE) with the GRE. The antiprogesterone and antiglucocorticoid RU486 interferes with both hormonal responses. In SiHa cells, the HPV-16 GRE mediates an increase in transcripts encoding E6 and E7 proteins, which are involved in transformation by HPV-16. Hormonal regulation is not restricted to HPV-16: DNA segments containing the cell-type-specific enhancers of HPV-11 and HPV-18 also mediate glucocorticoid and progesterone response. We identified sequence elements in the long control regions of HPV-11 and HPV-18 which function as GRE/PREs when tested as oligonucleotides. These findings suggest that GRE/PREs are an integral part of gene expression regulation in genital HPVs.

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Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia.

G. Klock

Papers

Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia.