RESUMO
Conflicting findings have been reported regarding the association between Agent Orange (AO) exposure and type 2 diabetes. This study aimed to examine whether AO exposure is associated with the development of type 2 diabetes and to verify the causal relationship between AO exposure and type 2 diabetes by combining DNA methylation with DNA genotype analyses. An epigenome-wide association study and DNA genotype analyses of the blood of AO-exposed and AO-unexposed individuals with type 2 diabetes and that of healthy controls were performed. Methylation quantitative trait locus and Mendelian randomisation analyses were performed to evaluate the causal effect of AO-exposure-identified CpGs on type 2 diabetes. AO-exposed individuals with type 2 diabetes were associated with six hypermethylated CpG sites (cg20075319, cg21757266, cg05203217, cg20102280, cg26081717, and cg21878650) and one hypo-methylated CpG site (cg07553761). Methylation quantitative trait locus analysis showed the methylation levels of some CpG sites (cg20075319, cg20102280, and cg26081717) to be significantly different. Mendelian randomisation analysis showed that CpG sites that were differentially methylated in AO-exposed individuals were causally associated with type 2 diabetes; the reverse causal effect was not significant. These findings reflect the need for further epigenetic studies on the causal relationship between AO exposure and type 2 diabetes.
Assuntos
Agente Laranja , Metilação de DNA , Diabetes Mellitus Tipo 2 , Epigênese Genética , Veteranos , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Masculino , República da Coreia/epidemiologia , Pessoa de Meia-Idade , Ilhas de CpG , Feminino , Estudo de Associação Genômica Ampla , Idoso , Locos de Características Quantitativas , Análise da Randomização Mendeliana , Estudos de Casos e ControlesRESUMO
BACKGROUND: The US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk. PATIENTS AND METHODS: Participants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. RESULTS AND INTERPRETATION: On univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09, <10-6) but not with metastatic PCa (HR: 1.07, 95% CI: 0.98-1.15, p = 0.10) or PCa death (HR: 1.02, 95% CI: 0.83-1.23, p = 0.09). Similar results were found when accounting for genetic risk. Agent Orange exposure history may not improve modern PCa risk stratification.
Assuntos
Agente Laranja , Neoplasias da Próstata , Veteranos , Guerra do Vietnã , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/mortalidade , Veteranos/estatística & dados numéricos , Pessoa de Meia-Idade , Idoso , Estados Unidos/epidemiologia , Desfolhantes Químicos/efeitos adversos , Fatores de Risco , Ácido 2,4,5-Triclorofenoxiacético/efeitos adversos , Ácido 2,4-Diclorofenoxiacético/efeitos adversos , Ácido 2,4-Diclorofenoxiacético/toxicidade , Dibenzodioxinas Policloradas/efeitos adversosRESUMO
Among the congener of dioxin, 2,3,7,8-TCDD is the most toxic, having a serious long-term impact on the environment and human health. UDP-glucuronosyltransferase 1A1 (UGT1A1) plays a crucial role in the detoxification and excretion of endogenous and exogenous lipophilic compounds, primarily in the liver and gastrointestinal tract. This study aimed to investigate the association of UGT1A1 gene polymorphisms, expression levels, and enzyme concentration with Agent Orange/Dioxin exposure. The study included 100 individuals exposed to Agent Orange/Dioxin nearby Da Nang and Bien Hoa airports in Vietnam and 100 healthy controls. UGT1A1 SNP rs10929303, rs1042640 and rs8330 were determined by Sanger sequencing, mRNA expression was quantified by RT-qPCR and plasma UGT1A1 concentrations were measured by ELISA. The results showed that UGT1A1 polymorphisms at SNPs rs10929303, rs1042640 and rs8330 were associated with Agent Orange/Dioxin exposure (OR = 0.55, P = 0.018; OR = 0.55, P = 0.018 and OR = 0.57, P = 0.026, respectively). UGT1A1 mRNA expression levels and enzyme concentration were significantly elevated in individuals exposed to Agent Orange/Dioxin compared to controls (P < 0.0001). Benchmark dose (BMD) analyses showed that chronic exposure to 2,3,7,8-TCDD contamination affects the UGT1A1 mRNA and protein levels. Furthermore, UGT1A1 polymorphisms affected gene expression and enzyme concentrations in individuals exposed to Agent Orange/Dioxin. In conclusion, UGT1A1 gene polymorphisms, UGT1A gene expression levels and UGT1A1 enzyme concentrations were associated with Agent Orange/Dioxin exposure. The metabolism of 2,3,7,8-TCDD may influence UGT1A gene expression and enzyme concentrations.
Assuntos
Dioxinas , Dibenzodioxinas Policloradas , Humanos , Agente Laranja , Dibenzodioxinas Policloradas/toxicidade , Ácido 2,4-Diclorofenoxiacético , Ácido 2,4,5-Triclorofenoxiacético/análise , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genéticaRESUMO
Background: Agent Orange (AO) is a Vietnam War-era herbicide that contains a 1â:â1 ratio of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Emerging evidence suggests that AO exposures cause toxic and degenerative pathologies that may increase the risk for Alzheimer's disease (AD). Objective: This study investigates the effects of the two main AO constituents on key molecular and biochemical indices of AD-type neurodegeneration. Methods: Long Evans rat frontal lobe slice cultures treated with 250µg/ml of 2,4-D, 2,4,5-T, or both (Dâ+âT) were evaluated for cytotoxicity, oxidative injury, mitochondrial function, and AD biomarker expression. Results: Treatment with the AO constituents caused histopathological changes corresponding to neuronal, white matter, and endothelial cell degeneration, and molecular/biochemical abnormalities indicative of cytotoxic injury, lipid peroxidation, DNA damage, and increased immunoreactivity to activated Caspase 3, glial fibrillary acidic protein, ubiquitin, tau, paired-helical filament phosphorylated tau, AßPP, Aß, and choline acetyltransferase. Nearly all indices of cellular injury and degeneration were more pronounced in the Dâ+âT compared with 2,4-D or 2,4,5-T treated cultures. Conclusions: Exposures to AO herbicidal chemicals damage frontal lobe brain tissue with molecular and biochemical abnormalities that mimic pathologies associated with early-stage AD-type neurodegeneration. Additional research is needed to evaluate the long-term effects of AO exposures in relation to aging and progressive neurodegeneration in Vietnam War Veterans.
Assuntos
Doença de Alzheimer , Herbicidas , Ratos , Animais , Agente Laranja , Herbicidas/toxicidade , Doença de Alzheimer/metabolismo , Ratos Long-Evans , Ácido 2,4,5-TriclorofenoxiacéticoRESUMO
Herbicide and pesticide exposure [e.g., agent orange (AO)] is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, it is unclear whether TCDD/AO exposure (AO exposure hereafter) increases the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. We sought to evaluate the association in a nationwide study of US Veterans. A natural language processing algorithm was used to confirm MGUS and progression to MM. We included Veterans who were diagnosed with MGUS from 10/1/1999 to 12/31/2021 and served during the Vietnam War Era from 1/9/1962 to 5/7/1975. AO exposure was stratified according to three TCDD exposure levels: high (1/9/1962-11/30/1965), medium (12/1/1965-12/31/1970), or low (1/1/1971-5/7/1975). The association between AO exposure and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. The analytic cohort included 10,847 Veterans with MGUS, of whom 26.3% had AO exposure and 7.4% progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, high exposure was associated with an increased progression rate (multivariable-adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. This information is critical to inform progression risk in patients diagnosed with MGUS and prior AO exposure. It is also applicable to MGUS patients with occupational TCDD exposure from herbicides and pesticides.
Assuntos
Herbicidas , Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Dibenzodioxinas Policloradas , Veteranos , Humanos , Mieloma Múltiplo/induzido quimicamente , Mieloma Múltiplo/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/induzido quimicamente , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Agente Laranja , Vietnã , Herbicidas/efeitos adversos , Dibenzodioxinas Policloradas/toxicidadeRESUMO
OBJECTIVE: Approximately 3 million Americans served in the armed forces during the Vietnam War. Veterans have a higher incidence rate of lung cancer compared with the general population, which may be related to exposures sustained during service. Agent Orange, one of the tactical herbicides used by the armed forces as a means of destroying crops and clearing vegetation, has been linked to the development of several cancers including non-small cell lung cancer. However, traditional risk models of lung cancer survival and recurrence often do not include such exposures. We aimed to examine the relationship between Agent Orange exposure and overall survival and disease recurrence for surgically treated stage I non-small cell lung cancer. METHODS: We performed a retrospective cohort study using a uniquely compiled dataset of US Veterans with pathologic I non-small cell lung cancer. We included adult patients who served in the Vietnam War and underwent surgical resection between 2010 and 2016. Our 2 comparison groups included those with identified Agent Orange exposure and those who were unexposed. We used multivariable Cox proportional hazards and Fine and Gray competing risk analyses to examine overall survival and disease recurrence for patients with pathologic stage I disease, respectively. RESULTS: A total of 3958 Vietnam Veterans with pathologic stage I disease were identified (994 who had Agent Orange exposure and 2964 who were unexposed). Those who had Agent Orange exposure were more likely to be male, to be White, and to live a further distance from their treatment facility (P < .05). Tumor size distribution, grade, and histology were similar between cohorts. Multivariable Cox proportional hazards modeling identified similar overall survival between cohorts (Agent Orange exposure hazard ratio, 0.97; 95% CI, 0.86-1.09). Patients who had Agent Orange exposure had a 19% increased risk of disease recurrence (hazard ratio, 1.19; 95% CI, 1.02-1.40). CONCLUSIONS: Veterans with known Agent Orange exposure who undergo surgical treatment for stage I non-small cell lung cancer have an approximately 20% increased risk of disease recurrence compared with their nonexposed counterparts. Agent Orange exposure should be taken into consideration when determining treatment and surveillance regimens for Veteran patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Dibenzodioxinas Policloradas , Veteranos , Adulto , Humanos , Masculino , Estados Unidos/epidemiologia , Feminino , Agente Laranja , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Ácido 2,4-Diclorofenoxiacético/efeitos adversos , Ácido 2,4-Diclorofenoxiacético/análise , Estudos Retrospectivos , Ácido 2,4,5-Triclorofenoxiacético/efeitos adversos , Ácido 2,4,5-Triclorofenoxiacético/análise , Dibenzodioxinas Policloradas/efeitos adversos , Dibenzodioxinas Policloradas/análise , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/epidemiologiaAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Agente Laranja , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Intervalo Livre de Doença , Estadiamento de Neoplasias , Recidiva Local de NeoplasiaRESUMO
Importance: Hepatocellular carcinoma (HCC) and its mortality are on the rise. Viral hepatitis and alcohol are leading risk factors; however, other risk factors among veterans are less defined, including Agent Orange (AO), an herbicide linked to several cancers. Objective: To assess the association of AO exposure and HCC in a national cohort of Vietnam veterans. Design, Setting, and Participants: This retrospective cohort study included Vietnam veterans who served between 1966 and 1975, were male, were older than 18 years at the time of deployment, and had established follow-up in the Veterans Affairs (VA) between 2000 and 2019. Veterans with AO exposure were identified in the disability data via validated clinical surveys. Relevant clinical risk factors for cirrhosis and HCC were collected. Patients were stratified based on cirrhosis status, as defined by consecutive diagnosis found by documented International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision scores or calculated Fibrosis-4 scores. Data were collected from January 1, 2019, to December 31, 2020, and analyzed from December 2020 to October 2023. Main Outcome and Measures: Incident HCC was the primary outcome. AO and HCC association was estimated using a multivariable Cox regression analysis, with death and liver transplant as competing events. Results: Of the 296â¯505 eligible veterans (222â¯545 [75.1%] White individuals and 44â¯342 [15.0%] Black individuals), 170â¯090 (57%) had AO exposure (mean [SD] age, 21.62 [3.49] years; 131â¯552 White individuals [83.2%] and 22â¯767 Black individuals [14.4%]) and 35â¯877 (12.1%) had cirrhosis. Veterans who were not exposed to AO were more likely to smoke (109â¯689 of 126â¯413 [86.8%] vs 146â¯061 of 170â¯090 [85.9%]); use alcohol (54â¯147 of 126â¯413 [42.8%] vs 71â¯951 of 170â¯090 [42.3%]) and have viral hepatitis (47â¯722 of 126â¯413 [37.8%] vs 58â¯942 of 170â¯090 [34.7%]). In a multivariable competing risk model, AO exposure was not associated with HCC. Among veterans with cirrhosis, self-identification as Hispanic individuals (aHR, 1.51; 95% CI, 1.30-1.75; P <.001) or Black individuals (aHR, 1.18; 95% CI, 1.05-1.32; P = .004), and having a diagnosis of viral hepatitis (aHR, 3.71; 95% CI, 3.26-4.24; P <.001), alcohol-associated liver disease (aHR, 1.32; 95% CI, 1.19-1.46; P <.001), and nonalcoholic fatty liver disease (NAFLD) (aHR, 1.92; 95% CI, 1.72-2.15; P <.001) were associated with HCC. Among veterans without cirrhosis, hypertension (aHR, 1.63; 95% CI, 1.23-2.15; P <.001) and diabetes (aHR, 1.52; 95% CI, 1.13-2.05; P = .005) were also associated with HCC. Early smoking and alcohol use were significant risk factors for HCC. Conclusions and Relevance: In this large nationwide cohort study of Vietnam veterans, AO exposure was not associated with HCC. Smoking, alcohol, viral hepatitis, and NAFLD were the most important clinical risk factors for HCC.
Assuntos
Carcinoma Hepatocelular , Hepatite Viral Humana , Neoplasias Hepáticas , Militares , Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Adulto Jovem , Adulto , Feminino , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/epidemiologia , Agente Laranja , Estudos de Coortes , Estudos Retrospectivos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/epidemiologia , Cirrose Hepática/epidemiologia , EtanolRESUMO
BACKGROUND: Vietnam-era veterans were exposed to Agent Orange (AO), which is associated with a high prevalence of Parkinson's disease (PD). However, little is known about the development of PD-like symptoms caused by drug-induced parkinsonism (DIP) in such populations. This study aimed to investigate PD incidence and PD risk following exposure to AO or DIP-risk drugs in veterans. METHODS: A retrospective cohort study was conducted using 12 years (2009-2020) of electronic medical records of the Veterans Health Service Medical Center, the largest Veterans Affairs hospital in South Korea (n = 37,246; 100% male; age, 65.57 ± 8.12 years). Exposure to AO or DIP-risk drugs, including antipsychotic, prokinetic, anti-epileptic, dopamine-depleting and anti-anginal agents, was assessed in veterans with PD, operationally defined as having a PD diagnosis and one or more prescriptions for PD treatment. The PD risk was calculated using multiple logistic regression analysis adjusted for age and comorbidities. RESULTS: The rates of DIP-risk drug use and AO exposure were 37.92% and 62.62%, respectively. The PD incidence from 2010 to 2020 was 3.08%; 1.30% with neither exposure, 1.63% with AO exposure, 4.38% with DIP-risk drug use, and 6.33% with both. Combined exposure to AO and DIP-risk drugs increased the PD risk (adjusted odds ratio = 1.68, 95% confidence interval, 1.36-2.08, P < 0.001). CONCLUSIONS: The PD incidence was 1.31 times higher with AO exposure alone and 1.68 times higher with AO exposure and DIP-risk drug use. The results suggest the necessity for careful monitoring and DIP-risk drug prescription in patients with AO exposure.
Assuntos
Doença de Parkinson Secundária , Doença de Parkinson , Veteranos , Humanos , Masculino , Idoso , Feminino , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Estudos Retrospectivos , Agente Laranja/efeitos adversos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/diagnósticoRESUMO
OBJECTIVE: To explore the effect of Agent Orange (AO) exposure on bladder cancer (BCa) outcomes in patients receiving Bacillus Calmette-Guérin (BCG) for non-muscle invasive BCa (NMIBC). METHODS: We retrospectively examined the association between AO exposure in patients with NMIBC in national veterans affairs databases who were being treated with BCG. Patients were diagnosed with NMIBC from 2000 to 2010 with follow-up through 2018. Clinical, pathological, and demographic variables were compared by AO exposure. Associations of AO exposure with recurrence, progression, and cancer-specific survival were performed using Cox proportional hazard models after inverse propensity score weighting and competing risks adjustments. We also assessed the association of AO exposure on grade and stage via multivariable logistic regression models. RESULTS: A total of 7651 patients were identified of which 753 (9.8%) were exposed to AO. The median follow-up time was 130 months. The AO-exposed patients were younger (age 61 vs 71 years, P <.001), but had similar Charlson comorbidity scores and stage/grade distribution as the non-AO exposed patients. AO exposure was not associated with higher grade or stage. In our Cox multivariable analyses, AO exposure was not associated with worse recurrence (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.72-1.10, P = .29), progression (HR 1.08, 95% CI 0.86-1.36, P = .51), or cancer-specific survival (HR 1.31, 95% CI 0.92-1.87, P = .13). CONCLUSION: AO exposure was not associated with worse oncologic outcomes in patients receiving BCG for NMIBC. While this is reassuring, additional research is needed in other patient populations and disease states to determine if the effect is consistent.
Assuntos
Agente Laranja , Neoplasias não Músculo Invasivas da Bexiga , Neoplasias da Bexiga Urinária , Humanos , Pessoa de Meia-Idade , Adjuvantes Imunológicos/uso terapêutico , Administração Intravesical , Agente Laranja/uso terapêutico , Vacina BCG/efeitos adversos , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias não Músculo Invasivas da Bexiga/complicações , Neoplasias não Músculo Invasivas da Bexiga/terapia , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/terapia , IdosoRESUMO
Importance: To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. Objective: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. Design, Setting, and Participants: This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2â¯517â¯926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Exposure: Agent Orange. Main Outcomes and Measures: Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Results: Among the 2â¯517â¯926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629â¯907 veterans (25.0%) with Agent Orange exposure and 1â¯888â¯019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). Conclusions and Relevance: In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.
Assuntos
Dibenzodioxinas Policloradas , Neoplasias da Bexiga Urinária , Veteranos , Masculino , Humanos , Pessoa de Meia-Idade , Agente Laranja , Ácido 2,4-Diclorofenoxiacético/efeitos adversos , Estudos Retrospectivos , Estudos de Coortes , Ácido 2,4,5-Triclorofenoxiacético/efeitos adversos , Dibenzodioxinas Policloradas/efeitos adversos , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologiaRESUMO
2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is the most toxic congener of dioxin and has serious long-term effects on the environment and human health. Pyruvate Kinase L/R (PKLR) gene expression levels and gene variants are associated with pyruvate kinase enzyme deficiency, which has been identified as the cause of several diseases linked to dioxin exposure. In this study, we estimated PKLR gene copy number and gene expression levels using real-time quantitative PCR (RT-qPCR) assays, genotyped PKLR SNP rs3020781 by Sanger sequencing, and quantified plasma pyruvate kinase enzyme activity in 100 individuals exposed to Agent Orange/Dioxin near Bien Hoa and Da Nang airfields in Vietnam and 100 healthy controls. The means of PKLR copy numbers and PKLR gene expression levels were significantly higher, while pyruvate kinase enzyme activity was significantly decreased in Agent Orange/Dioxin-exposed individuals compared to healthy controls (P < 0.0001). Positive correlations of PKLR gene copy number and gene expression with 2,3,7,8-TCDD concentrations were observed (r = 0.2, P = 0.045 and r = 0.54, P < 0.0001, respectively). In contrast, pyruvate kinase enzyme activity was inversely correlated with 2,3,7,8-TCDD concentrations (r = -0.52, P < 0.0001). PKLR gene copy number and gene expression levels were also inversely correlated with pyruvate kinase enzyme activity. Additionally, PKLR SNP rs3020781 was found to be associated with 2,3,7,8-TCDD concentrations and PKLR gene expression. In conclusion, PKLR copy number, gene expression levels, and pyruvate kinase enzyme activity are associated with 2,3,7,8-TCDD exposure in individuals living in Agent Orange/Dioxin-contaminated areas.
Assuntos
Dioxinas , Dibenzodioxinas Policloradas , Humanos , Agente Laranja , Dibenzodioxinas Policloradas/análise , Dioxinas/toxicidade , Dioxinas/análise , Vietnã , Piruvato Quinase/genética , Ácido 2,4-Diclorofenoxiacético/análise , Ácido 2,4,5-Triclorofenoxiacético/análise , Dosagem de GenesRESUMO
Thyroid cancer incidence has been steadily rising since the 1970s and exposure to environmental pollutants, including persistent organic pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins, has emerged as a potential explanation for this increase. This study aimed to summarize available human studies on the association between TCDD exposure and thyroid cancer. A systematic review of the literature was performed searching the National Library of Medicine and National Institutes of Health PubMed, Embase, and Scopus databases, through January 2022, using the following keywords: "thyroid", "2,3,7,8-tetrachlorodibenzo-p-dioxin", "TCDD", "dioxin", and "Agent Orange". Six studies were included in this review. Three studies evaluated the acute exposure to the chemical factory accident in Seveso, Italy, and found a non-significant increase in the risk of thyroid cancer. Two studies investigating Agent Orange exposure among United States Vietnam War veterans found a significant risk of thyroid cancer following exposure. No association was found in one study evaluating TCDD exposure through herbicides. The current study highlights the limited information on the potential association between TCDD exposure and thyroid cancer and thus the need for future human studies, especially considering the persistent human exposure to dioxins in the environment.
Assuntos
Dioxinas , Herbicidas , Dibenzodioxinas Policloradas , Neoplasias da Glândula Tireoide , Humanos , Agente Laranja , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Dibenzodioxinas Policloradas/toxicidade , Neoplasias da Glândula Tireoide/induzido quimicamente , Neoplasias da Glândula Tireoide/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Analyses were conducted of the occurrence of eight general categories of birth defects and developmental disabilities for children fathered by participants of the Air Force Heath Study (AFHS). Participants were male Air Force veterans of the Vietnam War. Children were categorized into conceived before and after the start of the participant's Vietnam War service. Analyses accounted for correlation between outcomes for multiple children fathered by each of the participants. For each of the eight general categories of birth defects and developmental disabilities, the probability of its occurrence increased substantially for children conceived after compared to before the start of Vietnam War service. These results support the conclusion of an adverse effect on reproductive outcomes due to Vietnam War service. Data for children conceived after the start of Vietnam War service for participants with measured dioxin values were used to estimate dose-response curves for the effect of dioxin exposure on the occurrence of each of the eight general categories of birth defects and developmental disabilities. These curves were assumed to be constant up to a threshold and then monotonic after that threshold. For seven of the eight general categories of birth defects and developmental disabilities, the estimated dose-response curves increased nonlinearly after associated thresholds. These results support the conclusion that the adverse effect to conception after the start of Vietnam War service may be attributable to high enough exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War.
Assuntos
Dioxinas , Dibenzodioxinas Policloradas , Humanos , Masculino , Criança , Feminino , Ácido 2,4-Diclorofenoxiacético , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/induzido quimicamente , Ácido 2,4,5-Triclorofenoxiacético/efeitos adversos , Agente Laranja , Exposição AmbientalRESUMO
The 2,3,7,8-tetrachlorodibenzodioxin (TCDD), a contaminant in Agent Orange released during the US-Vietnam War, led to a severe environmental crisis. Approximately, 50 years have passed since the end of this war, and vegetation has gradually recovered from the pollution. Soil bacterial communities were investigated by 16S metagenomics in habitats with different vegetation physiognomies in Central Vietnam, namely, forests (S0), barren land (S1), grassland (S2), and developing woods (S3). Vegetation complexity was negatively associated with TCDD concentrations, revealing the reasoning behind the utilization of vegetation physiognomy as an indicator for ecological succession along the gradient of pollutants. Stark changes in bacterial composition were detected between S0 and S1, with an increase in Firmicutes and a decrease in Acidobacteria and Bacteroidetes. Notably, dioxin digesters Arthrobacter, Rhodococcus, Comamonadaceae, and Bacialles were detected in highly contaminated soil (S1). Along the TCDD gradients, following the dioxin decay from S1 to S2, the abundance of Firmicutes and Actinobacteria decreased, while that of Acidobacteria increased; slight changes occurred at the phylum level from S2 to S3. Although metagenomics analyses disclosed a trend toward bacterial communities before contamination with vegetation recovery, non-metric multidimensional scaling analysis unveiled a new trajectory deviating from the native state. Recovery of the bacterial community may have been hindered, as indicated by lower bacterial diversity in S3 compared to S0 due to a significant loss of bacterial taxa and recruitment of fewer colonizers. The results indicate that dioxins significantly altered the soil microbiomes into a state of disorder with a deviating trajectory in restoration.
Assuntos
Dioxinas , Microbiota , Dibenzodioxinas Policloradas , Agente Laranja , Solo , Dibenzodioxinas Policloradas/análise , Bactérias/genética , Acidobacteria/genética , Firmicutes , Microbiologia do Solo , RNA Ribossômico 16S/genéticaRESUMO
Rationale: There is limited literature exploring the relationship between military exposures and idiopathic pulmonary fibrosis (IPF). Objectives: To evaluate whether exposure to Agent Orange is associated with an increased risk of IPF among veterans. Methods: We used Veterans Health Administration data to identify patients diagnosed with IPF between 2010 and 2019. We restricted the cohort to male Vietnam veterans and performed multivariate logistic regression to examine the association between presumptive Agent Orange exposure and IPF. We conducted sensitivity analyses restricting the cohort to army veterans (highest theoretical burden of exposure, surrogate for dose response) and a more specific case definition of IPF. Fine-Gray competing risk models were used to evaluate age to IPF diagnosis. Measurements and Main Results: Among 3.6 million male Vietnam veterans, 948,103 (26%) had presumptive Agent Orange exposure. IPF occurred in 2.2% of veterans with Agent Orange exposure versus 1.9% without exposure (odds ratio, 1.14; 95% confidence interval [CI], 1.12-1.16; P < 0.001). The relationship persisted after adjusting for known IPF risk factors (odds ratio, 1.08; 95% CI, 1.06-1.10; P < 0.001). The attributable risk among exposed veterans was 7% (95% CI, 5.3-8.7%; P < 0.001). Numerically greater risk was observed when restricting the cohort to 1) Vietnam veterans who served in the army and 2) a more specific definition of IPF. After accounting for the competing risk of death, veterans with Agent Orange exposure were still more likely to develop IPF. Conclusions: Presumptive Agent Orange exposure is associated with greater risk of IPF. Future research should validate this association and investigate the biological mechanisms involved.
Assuntos
Fibrose Pulmonar Idiopática , Dibenzodioxinas Policloradas , Veteranos , Ácido 2,4,5-Triclorofenoxiacético/efeitos adversos , Ácido 2,4-Diclorofenoxiacético/efeitos adversos , Agente Laranja , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Masculino , Dibenzodioxinas Policloradas/toxicidadeRESUMO
Bien Hoa airbase is the most dioxin-polluted hotspot in Vietnam. In 2012, a birth cohort living around Bien Hoa airbase was recruited for assessment of physical and neurological development. In the present study, neurodevelopment scores at 5 years of age were assessed by the Kaufman Assessment Battery for Children, Second Edition and the Movement Assessment Battery for Children, Second Edition for 185 children in Bien Hoa and 104 children in Ha Dong (unexposed control group) to clarify the effects of dioxin. 2,3,7,8-tetrachlorodibenzo-p-dioxin concentrations in breast milk of women in Bien Hoa were approximately three times higher than those of women in Ha Dong (2.33 vs. 0.69 pg/g fat, p < 0.001). In general, neurodevelopment scores were lower in Bien Hoa children than in Ha Dong children. In boys, scores differed for number recall (12.6 vs. 14.0, p = 0.036), triangles (10.7 vs. 12.4, p = 0.005), manual dexterity (8.3 vs. 9.7, p = 0.037), balance (7.4 vs. 10.3, p < 0.001), and total movement scores (8.0 vs. 10.1, p = 0.003). After adjusting for covariates, linear regression analysis indicated that the scores of the triangles, balance, and total movement tests were inversely associated with levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin and of toxic equivalency of polychlorinated dibenzodioxins and polychlorinated dibenzofurans. In girls, scores differed for the triangles test (11.0 vs. 12.6, p = 0.005), hand movement test (9.6 vs. 11.3, p = 0.003), and balance test (9.1 vs. 10.7, p = 0.050); toxic equivalency of polychlorinated dibenzofurans was inversely associated with hand movement and balance scores. Overall, perinatal dioxin exposure appears to have a long-term impact on neurodevelopment.