How neighborhood environment modified the effects of power outages on multiple health outcomes in New York state?

Background: Although power outage (PO) is one of the most important consequences of increasing weather extremes and the health impact of POs has been reported previously, studies on the neighborhood environment underlying the population vulnerability in such situations are limited. This study aimed to identify dominant neighborhood environmental predictors which modified the impact of POs on multiple health outcomes in New York State. Methods: We applied a two-stage approach. In the first stage, we used time series analysis to determine the impact of POs (versus non-PO periods) on multiple health outcomes in each power operating division in New York State, 2001-2013. In the second stage, we classified divisions as risk-elevated and non-elevated, then developed predictive models for the elevation status based on 36 neighborhood environmental factors using random forest and gradient boosted trees. Results: Consistent across different outcomes, we found predictors representing greater urbanization, particularly, the proportion of residents having access to public transportation (importance ranging from 4.9-15.6%), population density (3.3-16.1%), per capita income (2.3-10.7%), and the density of public infrastructure (0.8-8.5%), were associated with a higher possibility of risk elevation following power outages. Additionally, the percent of minority (-6.3-27.9%) and those with limited English (2.2-8.1%), the percent of sandy soil (6.5-11.8%), and average soil temperature (3.0-15.7%) were also dominant predictors for multiple outcomes. Spatial hotspots of vulnerability generally were located surrounding New York City and in the northwest, the pattern of which was consistent with socioeconomic status. Conclusion: Population vulnerability during power outages was dominated by neighborhood environmental factors representing greater urbanization.

Surface coatings alter transcriptional responses to silver nanoparticles following oral exposure.

Silver nanoparticles (AgNPs) are used in food packaging materials, dental care products and other consumer goods and can result in oral exposure. To determine whether AgNP coatings modulate transcriptional responses to AgNP exposure, we exposed mice orally to 20 nm citrate (cit)-coated AgNPs (cit-AgNPs) or polyvinylpyrrolidone (PVP)-coated AgNPs (PVP-AgNPs) at a 4 mg/kg dose for 7 consecutive days and analyzed changes in the expression of protein-coding genes and long noncoding RNAs (lncRNAs), a new class of regulatory RNAs, in the liver. We identified unique and common expression signatures of protein-coding and lncRNA genes, altered biological processes and signaling pathways, and coding-non-coding gene interactions for cit-AgNPs and PVP-AgNPs. Commonly regulated genes comprised only about 10 and 20 percent of all differentially expressed genes in PVP-AgNP and cit-AgNP exposed mice, respectively. Commonly regulated biological processes included glutathione metabolic process and cellular oxidant detoxification. Commonly regulated pathways included Keap-Nrf2, PPAR, MAPK and IL-6 signaling pathways. The coding-non-coding gene co-expression analysis revealed that protein-coding genes were co-expressed with a variable number of lncRNAs ranging from one to twenty three and may share functional roles with the protein-coding genes. PVP-AgNP exposure induced a more robust transcriptional response than cit-AgNP exposure characterized by more than two-fold higher number of differentially expressed both protein- coding and lncRNA genes. Our data demonstrate that the surface coating strongly modulates the spectrum and the number of differentially expressed genes after oral AgNP exposure. On the other hand, our data suggest that AgNP exposure can alter drug and chemical sensitivity, metabolic homeostasis and cancer risk irrespective of the coating type, warranting further investigations.

Evaluation of Genotoxicity of Nanoparticles in Mouse Models.

Owing to new and unique properties, engineered nanoparticles (NPs) likely pose different risks than their constituent chemicals and these risks need to be understood. In particular, it is important to assess genotoxicity, since genotoxicity is a precursor to carcinogenicity. Here we describe a battery of tests for the assessment of genotoxicity of NPs in vivo in mice. Mice can be exposed to NPs for various exposure durations and by any route of exposure, provided NPs are absorbed into the systemic blood circulation. The testing battery measures three well-established markers of DNA damage: oxidative DNA damage, double strand breaks (DSBs) and chromosomal damage. These markers are measured in peripheral blood cells by microscopic techniques. 8-oxo-7,8-dihydro-2-deoxyguanine (8-oxoG), indicative of oxidative DNA damage, and phosphorylated histone 2AX (γ-H2AX) foci, indicative of DSBs, are determined in white blood cells by immunofluorescence. Micronuclei, indicative of chromosomal damage, are examined in erythrocytes on Giemsa-stained peripheral blood smears. This testing battery can be easily integrated in general toxicology studies or studies examining carcinogenic potential of NPs.

Pomegranate Extract Alters Breast Cancer Stem Cell Properties in Association with Inhibition of Epithelial-to-Mesenchymal Transition.

Cancer stem cells (CSCs) have become an important target population in cancer therapy and prevention due to their ability to self-renew, initiate tumors, and resist therapy. We examined whether pomegranate extract (PE) alters characteristics of breast CSCs. Ability to grow as mammospheres is a hallmark of breast CSCs. PE inhibited mammosphere formation in two different cell lines, neoplastic mammary epithelial HMLER and breast cancer Hs578T. In addition, mammosphere-derived cells from PE treatment groups showed reduced mammosphere formation for at least two serial passages. These data indicate that PE inhibits CSC's ability to self-renew. In addition, incubation of mammospheres with PE reversed them into adherent cultures, indicating promotion of CSC differentiation. Epithelial-to-mesenchymal transition (EMT) is a key program in generating CSCs and maintaining their characteristics. Thus, we examined the effect of PE on EMT. PE reduced cell migration, a major feature of the EMT phenotype. In addition, PE downregulated genes involved in EMT, including the EMT-inducing transcription factor Twist family basic helix-loop-helix transcription factor 1 (TWIST1). This suggests that PE suppresses CSC characteristics in part due to inhibition of EMT. The ability of PE to suppress CSCs can be exploited in the prevention of breast cancer.

Differential effects of silver nanoparticles on DNA damage and DNA repair gene expression in Ogg1-deficient and wild type mice.

Due to extensive use in consumer goods, it is important to understand the genotoxicity of silver nanoparticles (AgNPs) and identify susceptible populations. 8-Oxoguanine DNA glycosylase 1 (OGG1) excises 8-oxo-7,8-dihydro-2-deoxyguanine (8-oxoG), a pro-mutagenic lesion induced by oxidative stress. To understand whether defects in OGG1 is a possible genetic factor increasing an individual's susceptibly to AgNPs, we determined DNA damage, genome rearrangements, and expression of DNA repair genes in Ogg1-deficient and wild type mice exposed orally to 4 mg/kg of citrate-coated AgNPs over a period of 7 d. DNA damage was examined at 3 and 7 d of exposure and 7 and 14 d post-exposure. AgNPs induced 8-oxoG, double strand breaks (DSBs), chromosomal damage, and DNA deletions in both genotypes. However, 8-oxoG was induced earlier in Ogg1-deficient mice and 8-oxoG levels were higher after 7-d treatment and persisted longer after exposure termination. AgNPs downregulated DNA glycosylases Ogg1, Neil1, and Neil2 in wild type mice, but upregulated Myh, Neil1, and Neil2 glycosylases in Ogg1-deficient mice. Neil1 and Neil2 can repair 8-oxoG. Thus, AgNP-mediated downregulation of DNA glycosylases in wild type mice may contribute to genotoxicity, while upregulation thereof in Ogg1-deficient mice could serve as an adaptive response to AgNP-induced DNA damage. However, our data show that Ogg1 is indispensable for the efficient repair of AgNP-induced damage. In summary, citrate-coated AgNPs are genotoxic in both genotypes and Ogg1 deficiency exacerbates the effect. These data suggest that humans with genetic polymorphisms and mutations in OGG1 may have increased susceptibility to AgNP-mediated DNA damage.

Particle coatings but not silver ions mediate genotoxicity of ingested silver nanoparticles in a mouse model.

Incorporation of silver nanoparticles (AgNPs) in toothpaste, food containers, dietary supplements and other consumer products can result in oral exposure to AgNPs and/or silver ions (Ag+) released from the surface of AgNPs. To examine whether ingestion of AgNPs or Ag+ results in genotoxic damage and whether AgNP coatings modulate the effect, we exposed mice orally to 20 nm citrate-coated AgNPs, polyvinylpyrrolidone (PVP)-coated AgNPs, silver acetate or respective vehicles at a 4 mg/kg dose (equivalent to 800x the EPA reference dose for Ag) for 7 days. Genotoxicity was examined in the systemic circulation and bone marrow at 1, 7, and 14 days post-exposure. We found that citrate-coated AgNPs induced chromosomal damage in bone marrow and oxidative DNA damage and double strand breaks in peripheral blood. These damages persisted for at least 14 days after exposure termination. Because oxidative DNA damage and strand breaks are repaired rapidly, their presence after exposure cessation indicates that citrate-coated AgNPs persist in the body. In contrast, PVP-coated AgNPs and silver acetate did not induce DNA or chromosomal damage at any time point measured. To determine whether coating-dependent genotoxicity is related to different AgNP changes in the gastrointestinal tract, we examined AgNP behavior and fate in an in vitro gastrointestinal digestion model using UV-visible spectroscopy and DLS. Citrate-coated AgNPs were more susceptible to agglomeration than PVP-coated AgNPs in digestive juices with or without proteins. In summary, AgNPs but not Ag+ are genotoxic following oral ingestion. Nanoparticle coatings modulate gastrointestinal transformation and genotoxicity of AgNPs, where higher agglomeration of AgNPs in gastrointestinal juices is associated with higher genotoxicity in tissues. Since genotoxicity is a strong indicator of cancer risk, further long-term studies focusing on cancer are warranted.

Pomegranate Intake Protects Against Genomic Instability Induced by Medical X-rays In Vivo in Mice.

Ionizing radiation (IR) is a well-documented human carcinogen. The increased use of IR in medical procedures has doubled the annual radiation dose and may increase cancer risk. Genomic instability is an intermediate lesion in IR-induced cancer. We examined whether pomegranate extract (PE) suppresses genomic instability induced by x-rays. Mice were treated orally with PE and exposed to an x-ray dose of 2 Gy. PE intake suppressed x-ray-induced DNA double-strand breaks (DSBs) in peripheral blood and chromosomal damage in bone marrow. We hypothesized that PE-mediated protection against x-ray-induced damage may be due to the upregulation of DSB repair and antioxidant enzymes and/or increase in glutathione (GSH) levels. We found that expression of DSB repair genes was not altered (Nbs1 and Rad50) or was reduced (Mre11, DNA-PKcs, Ku80, Rad51, Rad52 and Brca2) in the liver of PE-treated mice. Likewise, mRNA levels of antioxidant enzymes were reduced (Gpx1, Cat, and Sod2) or were not altered (HO-1 and Sod1) as a function of PE treatment. In contrast, PE-treated mice with and without IR exposure displayed higher hepatic GSH concentrations than controls. Thus, ingestion of pomegranate polyphenols is associated with inhibition of x-ray-induced genomic instability and elevated GSH, which may reduce cancer risk.

Nanoencapsulation of pomegranate bioactive compounds for breast cancer chemoprevention.

Pomegranate polyphenols are potent antioxidants and chemopreventive agents but have low bioavailability and a short half-life. For example, punicalagin (PU), the major polyphenol in pomegranates, is not absorbed in its intact form but is hydrolyzed to ellagic acid (EA) moieties and rapidly metabolized into short-lived metabolites of EA. We hypothesized that encapsulation of pomegranate polyphenols into biodegradable sustained release nanoparticles (NPs) may circumvent these limitations. We describe here the development, characterization, and bioactivity assessment of novel formulations of poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs loaded with pomegranate extract (PE) or individual polyphenols such as PU or EA. Monodispersed, spherical 150-200 nm average diameter NPs were prepared by the double emulsion-solvent evaporation method. Uptake of Alexa Fluor-488-labeled NPs was evaluated in MCF-7 breast cancer cells over a 24-hour time course. Confocal fluorescent microscopy revealed that PLGA-PEG NPs were efficiently taken up, and the uptake reached the maximum at 24 hours. In addition, we examined the antiproliferative effects of PE-, PU-, and/or EA-loaded NPs in MCF-7 and Hs578T breast cancer cells. We found that PE, PU, and EA nanoprototypes had a 2- to 12-fold enhanced effect on cell growth inhibition compared to their free counterparts, while void NPs did not affect cell growth. PU-NPs were the most potent nanoprototype of pomegranates. Thus, PU may be the polyphenol of choice for further chemoprevention studies with pomegranate nanoprototypes. These data demonstrate that nanotechnology-enabled delivery of pomegranate polyphenols enhances their anticancer effects in breast cancer cells. Thus, pomegranate polyphenols are promising agents for nanochemoprevention of breast cancer.

Oral ingestion of silver nanoparticles induces genomic instability and DNA damage in multiple tissues.

Silver nanoparticles (AgNPs) are widely used in consumer and medical products. However, most AgNP toxicity data are based on in vitro studies. Only a few studies were performed in mammals and no studies systematically assessed cancer risk of AgNPs. In this study, we examined whether oral exposure to polyvinylpyrrolidone (PVP)-coated AgNPs induces DNA damage and permanent genome alterations, and modulates DNA repair gene expression in vivo in mice. We found that AgNPs induced large DNA deletions in developing embryos, irreversible chromosomal damage in bone marrow, and double strand breaks and oxidative DNA damage in peripheral blood and/or bone marrow. DNA Repair RT Profiler PCR Array showed that AgNPs altered expression of 36 of the 84 genes from which 24 genes were downregulated and 12 genes were upregulated. In particular, AgNPs downregulated a significant proportion of base excision repair (BER) genes. We hypothesized that downregulation of BER by AgNPs contributes to oxidative DNA damage and subsequent genomic instability, which predicts that BER defects enhance sensitivity to AgNPs. We tested this hypothesis in mice deficient in MutY homologue (Myh). Myh excises adenine mispaired with 8-oxoguanine to counteract its promutagenic activity and also has a role in cell cycle check points and apoptosis. MYH mutations are common in humans and predispose to colorectal and other types of cancer. Myh deficient mice were hypersensitive to AgNP-induced chromosomal damage. In summary, oral ingestion of AgNPs induces permanent genome alterations and may therefore cause cancer. In addition, BER defects, especially, Myh mutations, enhance sensitivity to AgNPs.

Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks.

Pomegranate extract (PE) inhibits the proliferation of breast cancer cells and stimulates apoptosis in MCF-7 breast cancer cells. While PE is a potent antioxidant, the present studies were conducted to examine the mechanisms of action of PE beyond antioxidation by studying cellular and molecular mechanisms underlying breast tumorigenesis. PE inhibited cell growth by inducing cell cycle arrest in G2 /M followed by the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and cell proliferation. Both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA double strand break (DSB) repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2, and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate miRNAs involved in DNA repair processes. Further, PE treatment increased the frequency of DSBs. These data suggest that PE downregulates HR which sensitizes cells to DSBs, growth inhibition and apoptosis. Because HR represents a novel target for cancer therapy, downregulation of HR by PE may be exploited for sensitization of tumors to anticancer drugs.

Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity.

Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress.

Effects of 1 GeV/nucleon 56Fe particles on longevity, carcinogenesis and neuromotor ability in Atm-deficient mice.

As therapeutic uses of high-LET radiation become more prevalent and human space exploration continues to be a focus of NASA, it is important to understand the biological effects of high-LET radiation and the role of genetics in sensitivity to high-LET radiation. To study genetic susceptibility to radiation, we used mice deficient in Atm activity (AtmΔSRI). ATM is important in DNA repair, apoptosis and cell cycle regulation. Although homozygous mutations in ATM are rare, the prevalence of ATM heterozygosity is estimated to be 1% and results in an increased cancer risk. We found that the effects of 1 Gy 1 GeV/nucleon 56Fe particles on life span and tumorigenesis are genotype- and sex-specific. Significant effects of 1 Gy 1 GeV/nucleon 56Fe particles on incidence of non-cancer end points were seen; however, 2 Gy 1 GeV/nucleon 56Fe particles significantly affected neuromotor ability. Our results represent an extensive investigation into the late effects of high-LET radiation exposure in a sex- and genotype-dependent manner and provide a baseline for understanding the long-term risks of high-LET radiation.

Genomic instability in mice is greater in Fanconi anemia caused by deficiency of Fancd2 than Fancg.

Fanconi anemia (FA) results from mutations in the FANC genes and is characterized by bone marrow failure, birth defects, and a high incidence of cancer. FANCG is a part of the FA core complex that is responsible for monoubiquitination of FANCD2 and FANCI. The precise role of the FA pathway is not well understood, although it may be involved in homologous recombination (HR), nonhomologous end joining, and translesion synthesis (TLS). Fancd2(-/-) mice have a more severe phenotype than Fancg(-/-), and other FA core complex-deficient mice, although both Fancg and Fancd2 belong to the same FA pathway. We hypothesized that Fancd2 deficiency results in a more severe phenotype because Fancd2 also has a FA pathway-independent function in the maintenance of genomic integrity. To test this hypothesis, we determined the level of DNA damage and genomic instability in Fancd2(-/-), Fancg(-/-), and wild-type controls. Fancd2(-/-) mice displayed a higher magnitude of chromosomal breakage and micronucleus formation than the wild-type or Fancg(-/-) mice. Also, DNA strand breaks were increased in Fancd2(-/-) but not in Fancg(-/-) mice. In addition, Fancd2(-/-) mice displayed an elevated frequency of DNA deletions, resulting from HR at the endogenous p(un) locus. In contrast, in Fancg(-/-) mice, the frequency of DNA deletions was decreased. Thus, Fancd2 but not Fancg deficiency results in elevated chromosomal/DNA breakage and permanent genome rearrangements. This provides evidence that Fancd2 plays an additional role in the maintenance of genomic stability than Fancg, which might explain the higher predisposition to cancer seen in the Fancd2(-/-) mice.

Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice.

Titanium dioxide (TiO(2)) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO(2) is chemically inert, TiO(2) nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO(2)-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO(2) nanoparticles-induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO(2) nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the gamma-H2AX immunostaining assay and by measuring 8-hydroxy-2'-deoxyguanosine levels and, as a genetic instability endpoint, DNA deletions. We also determined mRNA levels of inflammatory cytokines in the peripheral blood. Our results show that TiO(2) nanoparticles induced 8-hydroxy-2'-deoxyguanosine, gamma-H2AX foci, micronuclei, and DNA deletions. The formation of gamma-H2AX foci, indicative of DNA double-strand breaks, was the most sensitive parameter. Inflammation was also present as characterized by a moderate inflammatory response. Together, these results describe the first comprehensive study of TiO(2) nanoparticles-induced genotoxicity in vivo in mice possibly caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the growing use of TiO(2) nanoparticles, these findings raise concern about potential health hazards associated with TiO(2) nanoparticles exposure.

N-acetyl cysteine protects against ionizing radiation-induced DNA damage but not against cell killing in yeast and mammals.

Ionizing radiation (IR) induces DNA strand breaks leading to cell death or deleterious genome rearrangements. In the present study, we examined the role of N-acetyl-L-cysteine (NAC), a clinically proven safe agent, for it's ability to protect against gamma-ray-induced DNA strand breaks and/or DNA deletions in yeast and mammals. In the yeast Saccharomyces cerevisiae, DNA deletions were scored by reversion to histidine prototrophy. Human lymphoblastoid cells were examined for the frequency of gamma-H2AX foci formation, indicative of DNA double strand break formation. DNA strand breaks were also measured in mouse peripheral blood by the alkaline comet assay. In yeast, NAC reduced the frequency of IR-induced DNA deletions. However, NAC did not protect against cell death. NAC also reduced gamma-H2AX foci formation in human lymphoblastoid cells but had no protective effect in the colony survival assay. NAC administration via drinking water fully protected against DNA strand breaks in mice whole-body irradiated with 1Gy but not with 4Gy. NAC treatment in the absence of irradiation was not genotoxic. These data suggest that, given the safety and efficacy of NAC in humans, NAC may be useful in radiation therapy to prevent radiation-mediated genotoxicity, but does not interfere with efficient cancer cell killing.

Effects of human Werner helicase on intrachromosomal homologous recombination mediated DNA deletions in mice.

Werner syndrome (WS) is a rare genetic disorder characterized by accelerated aging and aging-related diseases including cancer. WS is caused by autosomal recessive mutations in the WRN gene, which is involved in genome maintenance although precise functions of WRN are not well understood. To further investigate the role of WRN, we used transgenic mice over-expressing a human helicase mutant WRN gene (hMW). We determined homologous recombination (HR) events leading to 70 kb deletions in the p(un) locus visualized as pigmented cells in the retinal pigment epithelium. hMW mice had an increased spontaneous frequency of DNA deletions compared to control mice, consistent with WRN involvement in HR suppression. In addition, 4-nitroquinoline 1-oxide (4-NQO), which can cause both oxidative stress and DNA adduct formation, significantly increased the frequency of DNA deletions in both control and hMW mice. In order to assess how oxidative stress may modulate this phenotype, we treated mice with the glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO). The frequency of DNA deletions increased significantly in control mice, but not in hMW littermates. To elucidate the cause of this discrepancy, we determined total GSH levels as a measure of anti-oxidative defense. BSO significantly decreased GSH levels in both hMW mice and control mice, while 4-NQO increased GSH levels in all mice. These findings suggest that the reduction of GSH by BSO or compensatory increase of GSH by 4-NQO had little impact on hMW mice in which HR repair is compromised. Therefore, oxidative stress impacts HR repair in hMW mice less than control mice and effects of the mutated gene may be exacerbated by direct DNA damage from 4-NQO. This mouse model of WS in conjunction with different DNA damaging agents may provide insight into mechanisms of genomic instability, DNA repair, and carcinogenesis.

Experimental antioxidant therapy in ataxia telangiectasia.

Ataxia telangiectasia (AT) is a rare genetic disorder characterized by immunodeficiency, early onset neurological degeneration, hypersensitivity to ionizing radiation and a high incidence of lymphoid cancers. The disease results from bi-allelic mutations in the AT mutated (ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidant therapy may mitigate the symptoms of AT, especially neurological degeneration and tumorigenesis. Consequently, several studies examined the effect of antioxidants in Atm deficient mice used as an animal model of AT. N-acetyl-L-cysteine (NAC), EUK-189, tempol and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested for their chemopreventive properties and had some beneficial effects. In addition to antioxidants, cancer therapeutic agent dexamethasone was examined for cancer prevention in Atm deficient mice. Of the tested antioxidants, only NAC has wide clinical applications due to safety and efficacy and is available as an over-the-counter dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. The short-tem study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced both the incidence and multiplicity of lymphoma.

Sex difference in neural tube defects in p53-null mice is caused by differences in the complement of X not Y genes.

To shed light on the biological origins of sex differences in neural tube defects (NTDs), we examined Trp53-null C57BL/6 mouse embryos and neonates at 10.5 and 18.5 days post coitus (dpc) and at birth. We confirmed that female embryos show more NTDs than males. We also examined mice in which the testis-determining gene Sry is deleted from the Y chromosome but inserted onto an autosome as a transgene, producing XX and XY gonadal females and XX and XY gonadal males. At birth, Trp53 nullizygous mice were predominantly XY rather than XX, irrespective of gonadal type, showing that the sex difference in the lethal effect of Trp53 nullizygosity by postnatal day 1 is caused by differences in sex chromosome complement. At 10.5 dpc, the incidence of NTDs in Trp53-null progeny of XY* mice, among which the number of the X chromosomes varies independently of the presence or absence of a Y chromosome, was higher in mice with two copies of the X chromosome than in mice with a single copy. The presence of a Y chromosome had no protective effect, suggesting that sex differences in NTDs are caused by sex differences in the number of X chromosomes.

Effects of antioxidants on cancer prevention and neuromotor performance in Atm deficient mice.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by immunodeficiency, neurodegeneration and cancer. The disease results from bi-allelic mutations in the AT mutated (ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidants may alleviate the symptoms of AT. Consequently, several studies were conducted in Atm deficient mice to examine the role of antioxidants in cancer prevention and/or correction of neuromotor performance. N-acetyl-l-cysteine (NAC), EUK-189, tempol, and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested in Atm deficient mice. In contrast to other antioxidants, NAC has been used in the clinical practice for many decades and is available as a dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. Our short-term study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced the incidence and multiplicity of lymphoma and improved some aspects of motor performance.

Involvement of homologous recombination in carcinogenesis.

DNA alterations of every type are associated with the incidence of carcinogenesis, often on the genomic scale. Although homologous recombination (HR) is an important pathway of DNA repair, evidence is accumulating that deleterious genomic rearrangements can result from HR. It therefore follows that HR events may play a causative role in carcinogenesis. HR is elevated in response to carcinogens. HR may also be increased or decreased when its upstream regulation is perturbed or components of the HR machinery itself are not fully functional. This chapter summarizes research findings that demonstrate an association between HR and carcinogenesis. Increased or decreased frequencies of HR have been found in cancer cells and cancer-prone hereditary human disorders characterized by mutations in genes playing a role in HR, such as ATM, Tp53, BRCA, BLM, and WRN genes. Another evidence linking perturbations in HR and carcinogenesis is provided by studies showing that exposure to carcinogens results in an increased frequency of HR resulting in DNA deletions in yeast, human cells, or mice.