Interaction of base excision repair gene polymorphism and estrogen-DNA adducts in breast cancer risk among East Asian women.

PURPOSE: In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. METHODS: We conducted a case-control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. RESULTS: Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). CONCLUSION: APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women.

Biomarkers of Toxic Exposure and Oxidative Stress Among U.S. Adult Users of Premium Cigar Versus Other Cigar Subtypes: 2013-2019.

INTRODUCTION: Cigars are currently the second-highest-used combustible tobacco product among U.S. adults, but knowledge about health effects of premium cigars versus other cigar subtype use is limited. AIMS AND METHODS: This study analyzed the biospecimen data (n = 31 875) from Waves 1-5 of the Population Assessment of Tobacco and Health Study, collected during 2013-2019. Multivariable generalized estimation equations, accounting for within-person clustering, were conducted to examine differences in urine biomarkers of exposure (BOE) from five classes of harmful and potentially harmful constituents along with a biomarker of oxidative stress (urine 8-isoprostane) among exclusive users of premium cigars versus other exclusive cigar subtypes (ie, non-premium large cigars, cigarillos, and filtered cigars), cigarettes, and non-tobacco users. RESULTS: In comparison to non-tobacco users, exclusive premium cigar users had higher geometric mean concentrations of the nicotine metabolite cotinine (5.8 vs. 0.5ng/mg, p < .0001), tobacco-specific nitrosamine (TSNA) (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL): 7.8 vs. 1.3pg/mg, p < .0001), and volatile organic compound (VOC) (N-Acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA, acrylonitrile): 4.7 vs. 1.6ng/mg, p < .0001). Exclusive premium cigar users were less likely to be daily users than other tobacco user groups and had comparable BOEs with exclusive non-premium large cigar users but generally lower BOEs than exclusive cigarillo, filtered cigar, and cigarette smokers. Daily exclusive premium cigar users had similar nicotine and TSNA exposure but lower exposure to polycyclic aromatic hydrocarbons and volatile organic compounds than exclusive cigarillo and filtered cigar users. CONCLUSIONS: Premium cigar use exhibits different exposure to toxicants from other cigar subtype users. Regulations of premium cigars need to formalize product definition and take the population's health effects into consideration. IMPLICATIONS: This population study provides important information on BOE and potential harm with premium cigar use and its potential health effects. At present, premium cigars appear to pose a relatively low overall population health risk due to low frequency of use. However, future regulation of other tobacco products might change the landscape of premium cigar use and alter the overall health impact.

Role of social determinants of health in differential respiratory exposure and health outcomes among children.

BACKGROUND: Attributes defining the Social Determinants of Health (SDoH) are associated with disproportionate exposures to environmental hazards and differential health outcomes among communities. The dynamics between SDoH, disproportionate environmental exposures, and differential health outcomes are often specific to micro-geographic areas. METHODS: This study focused on children less than 20 years of age who lived in Douglas County, Nebraska, during 2016-2019. To assess the role of SDoH in differential exposures, we evaluated the association between SDoH metrics and criteria pollutant concentrations and the association between SDoH and pediatric asthma exacerbations to quantify the role of SDoH in differential pediatric asthma outcomes. The Bayesian Poisson regression model with spatial random effects was used to evaluate associations. RESULTS: We identified significant positive associations between the annual mean concentration of criteria pollutants (carbon monoxide, particulate matter2.5, nitrogen dioxide, sulfur dioxide) with race (Non-Hispanic Black and Hispanic/Latino), financial stability, and literacy. Additionally, there were significant positive associations between higher rates of pediatric asthma emergency department visits and neighborhoods with more Non-Hispanic Black children, children without health insurance coverage, and households without access to a vehicle. CONCLUSIONS: Non-Hispanic Black and Hispanic/Latino children living in Douglas County, NE experience disproportionately higher exposure to criteria pollutant concentrations. Additionally, higher rates of asthma exacerbations among Non-Hispanic Black children could be due to reduced access to respiratory care that is potentially the result of financial instability and vehicle access. These results could inform city planners and health care providers to mitigate respiratory risks among these higher at-risk populations.

Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected.

Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.

The 3,4-Quinones of Estrone and Estradiol Are the Initiators of Cancer whereas Resveratrol and N-acetylcysteine Are the Preventers.

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.

Estrogen Metabolism in African-American Women with and without Breast Cancer: A Pilot Study.

Studies in Caucasian women have shown that the formation of estrogen-DNA adducts is greater in women at high risk for breast cancer or already diagnosed with the disease. To begin investigating whether the role of estrogens in the etiology of breast cancer is similar in African-American (AA) women, a saliva sample and a spot urine sample were collected from 19 AA women with breast cancer and 23 AA women not diagnosed with breast cancer. In the urine samples, 20 estrogen metabolites, conjugates, and DNA adducts were analyzed by using ultraperformance liquid chromatography/tandem mass spectrometry, and then the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and estrogen conjugates was significantly greater in cases compared to controls (92.4 ± 46.4 vs 38.5 ± 18.9, p < 0.0001). From the saliva samples, genomic DNA was purified and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes, catechol- O-methyltransferase (rs4680) and cytochrome P450 1B1 (rs1056836). There was no association between rs4680 and rs1056836 genotypes and adduct ratios or breast cancer status. This pilot study found higher DNA adduct ratios in women with breast cancer, which suggests that estrogen metabolism is out of balance, and the formation of estrogen-DNA adducts may exert a critical role in breast cancer initiation in AA women.

Critical depurinating DNA adducts: Estrogen adducts in the etiology and prevention of cancer and dopamine adducts in the etiology and prevention of Parkinson's disease.

Endogenous estrogens become carcinogens when dangerous metabolites, the catechol estrogen quinones, are formed. In particular, the catechol estrogen-3,4-quinones can react with DNA to produce an excess of specific depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from various types of studies. High levels of depurinating estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, as well as in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Formation of analogous depurinating dopamine-DNA adducts is hypothesized to initiate Parkinson's disease by affecting dopaminergic neurons. Two dietary supplements, N-acetylcysteine and resveratrol complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. When initiation of cancer is blocked, promotion, progression and development of the disease cannot occur. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.

IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line and CD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.

Unbalanced estrogen metabolism in ovarian cancer.

Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer.

Pesticide residues in adults living near a bioenergy plant with 85,000 tons of contaminated wetcake.

Neonicotinoid insecticide use is on the rise worldwide due to its broad-spectrum insecticidal action and exclusive approach of neurotoxic action. Besides application during the cultivation of several crops, all seed companies coat their seeds with neonicotinoids to have increased protection against insects during germination. Despite reduced mammalian toxicity, neonicotinoids have harmful effects on non-target non-mammalian organisms such as bees, an essential part of maintaining the ecosystem. In addition, epidemiologic studies have linked human exposure to neonicotinoids with poor developmental and neurological outcomes. Starting in 2015, the AltEn bioenergy plant near Mead, Nebraska, USA, used coated seeds for their ethanol production and failed to properly dispose of byproducts, causing environmental contamination that still exists. This pilot study reports the human urinary levels of neonicotinoids in samples collected during 2022-2023 in the population living in areas close to this now-closed bioenergy plant. Our results show that approximately 30% of the urine samples are contaminated with at least one of the targeted neonicotinoids or their transformed products. The most frequently detected parent neonicotinoid was clothianidin, which accounts for 13% of the samples. However, 5-hydroxy-imidacloprid, the transformed imidacloprid product, is detected in 27% of the samples, ranging from 1.2 to 42 ng/mL. In conclusion, the environmental contamination near Mead, Nebraska, due to improper storage and disposal of highly contaminated byproducts, puts the nearby population at risk from continuous exposure to neonicotinoids through air and dust particles and possible water contamination.

Pipeline emergency preparedness in Nebraska: Identifying interagency preparedness gaps and proposing solutions.

In Nebraska, there are over 28,000 miles of pipelines that carry various materials, which could impact human health and the natural environment in the event of a leak or spill. Nebraska is heavily reliant on its expansive groundwater supply from the large High Plains aquifer system as well as smaller secondary aquifers. Eighty-eight percent of Nebraska's population utilizes groundwater for personal use, and the state's agricultural sector depends on it for irrigation and livestock care. The ongoing challenges facing the implementation of the proposed Keystone XL pipeline system inspired re-searchers to examine the current state of pipeline emergency preparedness in Nebraska. To do this, a pipeline emergency preparedness workshop was held in November 2021 in Norfolk, Nebraska. Conference participants in-cluded county- and regional-level leadership, local public health departments, tribal representatives, and other organizations. Pipeline emergency responders and other stakeholders were invited to listen to plenary presenta-tions about inland oil spill responses and the current state of Nebraska pipelines and to participate in a facilitated discussion identifying pipeline response challenges and potential solutions. Through a facilitated discussion process, participants identified six general response challenge categories and 24 potential solutions. From those 24 solutions, three were selected as easily implementable solutions-increased joint/coordinated planning, increased pipeline emergency exercising, and increased pipeline emergency train-ing/education. Implementing this work will assist in reducing health risks associated with potential spills.

Estrogen genotoxicity causes preferential development of Fuchs endothelial corneal dystrophy in females.

Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, age-related, female-predominant disorder characterized by loss of post-mitotic corneal endothelial cells (CEnCs). Ultraviolet-A (UVA) light has been shown to recapitulate the morphological and molecular changes seen in FECD to a greater extent in females than males, by triggering CYP1B1 upregulation in females. Herein, we investigated the mechanism of greater CEnC susceptibility to UVA in females by studying estrogen metabolism in response to UVA in the cornea. Loss of NAD(P)H quinone oxidoreductase 1 (NQO1) resulted in increased production of estrogen metabolites and mitochondrial-DNA adducts, with a higher CEnC loss in Nqo1-/- female compared to wild-type male and female mice. The CYP1B1 inhibitors, trans-2,3',4,5'-tetramethoxystilbene (TMS) and berberine, rescued CEnC loss. Injection of wild-type male mice with estrogen (E2; 17ß-estradiol) increased CEnC loss, followed by increased production of estrogen metabolites and mitochondrial DNA (mtDNA) damage, not seen in E2-treated Cyp1b1-/-male mice. This study demonstrates that the endo-degenerative phenotype is driven by estrogen metabolite-dependent CEnC loss that is exacerbated in the absence of NQO1; thus, explaining the mechanism accounting for the higher incidence of FECD in females. The mitigation of estrogen-adduct production by CYP1B1 inhibitors could serve as a novel therapeutic strategy for FECD.

Reduced formation of depurinating estrogen-DNA adducts by sulforaphane or KEAP1 disruption in human mammary epithelial MCF-10A cells.

Sulforaphane (SFN) is a potent inducer of detoxication enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase (GST) via the Kelch-like erythroid-derived protein with CNC homology-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway. NQO1 reduces the carcinogenic estrogen metabolite, catechol estrogen-3,4-quinone, whereas GSTs detoxify it through conjugation with glutathione. These 3,4-quinones can react with DNA to form depurinating DNA adducts. Thus, SFN may alter estrogen metabolism and thus protect against estrogen-mediated DNA damage and carcinogenesis. Human breast epithelial MCF-10A cells were treated with either vehicle or SFN and either estradiol (E2) or its metabolite 4-hydroxyestradiol (4-OHE2). 4-Hydroxy-derived estrogen metabolites and depurinating DNA adducts formed from E2 and its interconvertable metabolite estrone (E1) were analyzed by mass spectrometry. Levels of the depurinated adducts, 4-OHE1/2-1-N3Adenine and 4-OHE1/2-1-N7Guanine, were reduced by 60% in SFN-treated cells, whereas levels of 4-OCH3E1/2 and 4-OHE1/2-glutathione conjugates increased. To constitutively enhance the expression of Nrf2-regulated genes, cells were treated with either scrambled or siKEAP1 RNA. Following E2 or 4-OHE2 treatments, levels of the adenine and guanine adducts dropped 60-70% in siKEAP1-treated cells, whereas 4-OHE1/2-glutathione conjugates increased. However, 4-OCH3E1/2 decreased 50% after siKEAP1 treatment. Thus, treatment with SFN or siKEAP1 has similar effects on reduction of depurinating estrogen-DNA adduct levels following estrogen challenge. However, these pharmacologic and genetic approaches have different effects on estrogen metabolism to O-methyl and glutathione conjugates. Activation of the Nrf2 pathway, especially elevated NQO1, may account for some but not all of the protective effects of SFN against estrogen-mediated DNA damage.

Unbalanced estrogen metabolism in thyroid cancer.

Well-differentiated thyroid cancer most frequently occurs in premenopausal women. Greater exposure to estrogens may be a risk factor for thyroid cancer. To investigate the role of estrogens in thyroid cancer, a spot urine sample was obtained from 40 women with thyroid cancer and 40 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed by using ultraperformance liquid chromatography/tandem mass spectrometry and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates significantly differed between cases and controls (p < 0.0001), demonstrating high specificity and sensitivity. These findings indicate that estrogen metabolism is unbalanced in thyroid cancer and suggest that formation of estrogen-DNA adducts might play a role in the initiation of thyroid cancer.

Characterization of Environmental Levels of Pesticide Residues in Household Air and Dust Samples near a Bioenergy Plant Using Treated Seed as Feedstock.

Exposure to neonicotinoid insecticides is associated with adverse human health outcomes. There is environmental contamination in Saunders County, Nebraska, due to the accumulation of fungicides and insecticides from a now-closed ethanol plant using seed corn as stock. A pilot study quantified environmental contamination in nearby houses from residual pesticides by measuring dust and air (indoor/outdoor) concentrations of neonicotinoids and fungicides at the study site (households within two miles of the plant) and control towns (20-30 miles away). Air (SASS® 2300 Wetted-Wall Air Sampler) and surface dust (GHOST wipes with 4 × 4-inch template) samples were collected from eleven study households and six controls. Targeted analysis quantified 13 neonicotinoids, their transformation products and seven fungicides. Sample extracts were concentrated using solid phase extraction (SPE) cartridges, eluted with methanol and evaporated. Residues were re-dissolved in methanol-water (1:4) prior to analysis, with an Acquity H-Class ultraperformance liquid chromatograph (UPLC) and a Xevo triple quadrupole mass spectrometer. We compared differences across chemicals in air and surface dust samples at the study and control sites by dichotomizing concentrations above or below the detection limit, using Fisher's exact test. A relatively higher detection frequency was observed for clothianidin and thiamethoxam at the study site for the surface dust samples, similarly for thiamethoxam in the air samples. Our results suggest airborne contamination (neonicotinoids and fungicides) from the ethanol facility at houses near the pesticide contamination.

Estrogen-DNA Adducts and Breast Cancer Risk in Premenopausal Asian Women.

The incidence of breast cancer among premenopausal women has been increasing rapidly in recent decades in East Asia. This case-control study investigated whether estrogen-DNA adducts were associated with breast cancer risk in Taiwan. The control group (n = 146) comprised healthy female volunteers and women with non-proliferative breast disease. The case group (n = 221) comprised women either with proliferative benign breast disease or breast cancer. The ratios of estrogen-DNA adducts to their respective metabolites and conjugates in plasma were analyzed using ultraperformance LC/MS-MS. The SNPs of CYP1A1, CYP1B1, and COMT were genotyped. Logistic regression model was used to compare the estrogen-DNA adduct ratios between the two groups. The estrogen-DNA adduct ratio in the case group was significantly higher than that in the control group (median ratio: 58.52 vs. 29.36, P = 0.004). A multiple logistic regression model demonstrated that a unit increase in the natural log of the estrogen-DNA adduct ratio in premenopausal women was a significant predictor of breast cancer risk, with an estimated hazard ratio of 1.718 (1.444-2.046, P < 0.001). However, the CYP1A1, CYP1B1, and COMT SNPs were not associated with the estrogen-DNA adduct ratios. In conclusion, plasma estrogen-DNA adduct ratio was associated with the presence of breast cancer or proliferating benign breast disease in premenopausal women in Taiwan. PREVENTION RELEVANCE: This study provides evidence that endogenous estrogen-induced genotoxicity may contribute to the carcinogenesis of breast cancer in premenopausal Asian women. This work could have important preventive implication for the emerging disease in East Asia.

Mechanism of DNA depurination by carcinogens in relation to cancer initiation.

Depurinating DNA adducts formed by aromatic hydrocarbons and catechol estrogen quinones play a major role in cancer initiation. Most of these adducts depurinate instantaneously, but some guanine adducts depurinate from DNA with half-lives of hours. We report here, that after 10 h at 37 °C, reaction of estradiol-3,4-quinone (E(2)-3,4-Q) with ds-DNA to yield N7Gua and N3Ade adducts was complete and more efficient than with ss-DNA. When E(2)-3,4-Q reacted with t-RNA, no adducts were detected after 10 h, and the level of N3Ade and N7Gua adducts after 10 days was less than half that with ss-DNA after 10 h. Reaction of E(2)-3,4-Q and dG yielded 4-OHE(2)-1-N7dG, which spontaneously depurinated to yield 4-OHE(2)-1-N7Gua. To investigate the mechanism of depurination, E(2)-3,4-Q was reacted with carbocyclicdeoxyguanosine, in which the ring oxygen of the deoxyribose moiety is substituted with CH(2) , and depurination was observed. The results from this experiment demonstrate that the oxocarbenium ion mechanism plays the major role in depurination and provides the first experimental evidence for this mechanism. A newly discovered ß-elimination mechanism also plays a minor role in depurination. Understanding why the depurinating estrogen-DNA adducts come from DNA, and not from RNA, underscores the critical role that these adducts play in initiating cancer.

The etiology and prevention of breast cancer.

Metabolism of estrogens via the catechol estrogen pathway is characterized by a balanced set of activating and protective enzymes (homeostasis). Disruption of homeostasis, with excessive production of catechol estrogen quinones, can lead to reaction of these quinones with DNA to form depurinating estrogen-DNA adducts. Some of the mutations generated by these events can lead to initiation of breast cancer. A wealth of evidence, from studies of metabolism, mutagenicity, cell transformation and carcinogenicity, demonstrates that estrogens are genotoxic. Women at high risk for breast cancer, or diagnosed with the disease, have relatively high levels of depurinating estrogen-DNA adducts compared to normal-risk women. The dietary supplements N-acetylcysteine and resveratrol can inhibit formation of catechol estrogen quinones and their reaction with DNA to form estrogen-DNA adducts, thereby preventing initiation of breast cancer.

Arsenic Exposure and Melanoma Among US Adults Aged 20 or Older, 2003-2016.

OBJECTIVES: Chronic exposure to arsenic has been reported as a risk factor for nonmelanoma skin cancer, notably squamous cell carcinoma. However, current knowledge is limited about the association between arsenic exposure and melanoma. Our objectives were to (1) measure the association between total urinary arsenic levels and melanoma compared with nonmelanoma skin cancer and no cancer and (2) analyze the association between water source and melanoma and nonmelanoma skin cancer. METHODS: We collected cross-sectional data from the 2003-2016 cycles of the National Health and Nutrition Examination Survey. We conducted univariate and multivariate logistic regressions. To evaluate the possible association of skin cancer with source of tap water, we calculated odds ratios for participants with melanoma and nonmelanoma skin cancer, compared with participants with no cancer. RESULTS: White race, higher education, higher socioeconomic status, and smoking history were associated with melanoma and nonmelanoma skin cancer in the full study population. After adjusting for age and race/ethnicity, the adjusted odds ratio of participants with >50 µg/L of total urinary arsenic for melanoma or nonmelanoma skin cancer was 1.87 (95% CI, 0.58-6.05) and 2.23 (95% CI, 1.12-4.45) times higher compared with no cancer, respectively. Participants with nonmelanoma skin cancer had 2.06 increased odds of reporting a nonmunicipal water source compared with participants without cancer. CONCLUSIONS: We did not find a relationship between the incidence of melanoma and exposure to arsenic among US adults. Nonmunicipal water sources were associated with nonmelanoma skin cancer and should be further investigated.

Joint association between ambient air pollutant mixture and pediatric asthma exacerbations.

Exposure to air pollutants is known to exacerbate asthma, with prior studies focused on associations between single pollutant exposure and asthma exacerbations. As air pollutants often exist as a complex mixture, there is a gap in understanding the association between complex air pollutant mixtures and asthma exacerbations. We evaluated the association between the air pollutant mixture (52 pollutants) and pediatric asthma exacerbations. Method: This study focused on children (age ≤ 19 years) who lived in Douglas County, Nebraska, during 2016-2019. A seasonal-scale joint association between the outdoor air pollutant mixture adjusting for potential confounders (temperature, precipitation, wind speed, and wind direction) in relation to pediatric asthma exacerbation-related emergency department (ED) visits was evaluated using the generalized weighted quantile sum (qWQS) regression with repeated holdout validation. Results: We observed associations between air pollutant mixture and pediatric asthma exacerbations during spring (lagged by 5 days), summer (lag 0-5 days), and fall (lag 1-3 days) seasons. The estimate of the joint outdoor air pollutant mixture effect was higher during the summer season (adjusted-ßWQS = 1.11, 95% confidence interval [CI]: 0.66, 1.55), followed by spring (adjusted-ßWQS = 0.40, 95% CI: 0.16, 0.62) and fall (adjusted-ßWQS = 0.20, 95% CI: 0.06, 0.33) seasons. Among the air pollutants, PM2.5, pollen, and mold contributed higher weight to the air pollutant mixture. Conclusion: There were associations between outdoor air pollutant mixture and pediatric asthma exacerbations during the spring, summer, and fall seasons. Among the 52 outdoor air pollutant metrics investigated, PM2.5, pollen (sycamore, grass, cedar), and mold (Helminthosporium, Peronospora, and Erysiphe) contributed the highest weight to the air pollutant mixture.