1,3-Butadiene: a ubiquitous environmental mutagen and its associations with diseases

Abstract1,3-Butadiene (BD) is a petrochemical manufactured in high volumes. It is a human carcinogen and can induce lymphohematopoietic cancers, particularly leukemia, in occupationally-exposed workers. BD is an air pollutant with the major environmental sources being automobile exhaust and tobacco smoke. It is one of the major constituents and is considered the most carcinogenic compound in cigarette smoke. The BD concentrations in urban areas usually vary between 0.01 and 3.3 μg/m3 but can be significantly higher in some microenvironments. For BD exposure of the general population, microenvironments, particularly indoor microenvironments, are the primary determinant and environmental tobacco smoke is the main contributor. BD has high cancer risk and has been ranked the second or the third in the environmental pollutants monitored in most urban areas, with the cancer risks exceeding 10-5. Mutagenicity/carcinogenicity of BD is mediated by its genotoxic metabolites but the specific metabolite(s) responsible for the effects in humans have not been determined. BD can be bioactivated to yield three mutagenic epoxide metabolites by cytochrome P450 enzymes, or potentially be biotransformed into a mutagenic chlorohydrin by myeloperoxidase, a peroxidase almost specifically present in neutrophils and monocytes. Several urinary BD biomarkers have been developed, among which N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine is the most sensitive and is suitable for biomonitoring BD exposure in the general population. Exposure to BD has been associated with leukemia, cardiovascular disease, and possibly reproductive effects, and may be associated with several cancers, autism, and asthma in children. Collectively, BD is a ubiquitous pollutant that has been associated with a range of adverse health effects and diseases with children being a subpopulation with potentially greater susceptibility. Its adverse effects on human health may have been underestimated and more studies are needed.

Evaluation of risk due to chronic low dose ionizing radiation exposure on the birth prevalence of congenital heart diseases (CHD) among the newborns from high-level natural radiation areas of Kerala coast, India

Background The human population residing in monazite bearing Kerala coast are exposed to chronic low dose and low dose rate external gamma radiation due to Th232 deposits in its beach sand. The radiation level in this area varies from < 1.0 to 45.0 mGy/year. This area serves as an ideal source for conducting large-scale epidemiological studies for assessing risk of low dose and low dose rate radiation exposure on human population. The areas with a dose level of ≤1.50 mGy/year are considered as normal level natural radiation areas (NLNRAs) and areas with > 1.50 mGy/year, as high level natural radiation areas (HLNRAs). HLNRAs were further stratified into three dose groups of 1.51-3.0 mGy/year, 3.01-6.00 mGy/year and > 6.0 mGy/year. The present study evaluates the effects of chronic low dose radiation (LDR) exposure on the birth prevalence of Congenital Heart Diseases (CHD) among the live newborns monitored in hospital based prospective study from NLNRAs and HLNRAs of Kerala coast, India. Methodology Consecutive newborns were monitored from two hospital units located in the study area for congenital malformations. Referred CHD cases among the newborns screened were confirmed by conducting investigations such as pulse oximetry, chest X-ray, electrocardiogram and echocardiogram etc. Results Among the newborns screened, 289 CHDs were identified with a frequency of 1.49‰ among 193,634 livebirths, which constituted 6.03% of overall malformations and 16.29% of major malformations. Multiple logistic regression analysis suggested that the risk of CHD among the newborns of mothers from HLNRAs with a dose group of 1.51-3.0 mGy/year was significantly lower as compared to NLNRA (OR = 0.72, 95% CI: 0.57-0.92), whereas it was similar in HLNRA dose groups of 3.01-6.00 mGy/year (OR = 0.55, 95% CI: 0.31-1.00) and ≥ 6.0 mGy/year (OR = 0.96, 95% CI: 0.50-1.85). The frequency of CHDs did not show any radiation dose related increasing trend. However, a significant (P = 0.005) reduction was observed in the birth prevalence of CHDs among the newborns from HLNRA (1.28‰) as compared to NLNRA (1.79‰). Conclusion Chronic LDR exposure did not show any increased risk on the birth prevalence of CHDs from high-level natural radiation areas of Kerala coast, India. No linear increasing trend was observed with respect to different background dose groups. The frequency of CHD was observed to be 1.49 per 1000 livebirths, which was similar to the frequency of severe CHD rate reported elsewhere in India and was much less than the reported frequency of 9 per thousand.

Detection of hepatocarcinogens by combination of liver micronucleus assay and histopathological examination in 2-week or 4-week repeated dose studies

Background Currently, revisions to the ICH S1 guidance on rodent carcinogenicity testing are being proposed. Application of this approach would reduce the use of animals in accordance with the 3Rs principles (reduce/refine/replace). The method would also shift resources to focus on more scientific mechanism-based carcinogenicity assessments and promote safe and ethical development of new small molecule pharmaceuticals. In the revised draft, findings such as cellular hypertrophy, diffuse and/or focal cellular hyperplasia, persistent tissue injury and/or chronic inflammation, preneoplastic changes, and tumors are listed as histopathology findings of particular interest for identifying carcinogenic potential. In order to predict hepatocarcinogenicity of test chemicals based on the results from 2- or 4-week repeated dose studies, we retrospectively reanalyzed the results of a previous collaborative study on the liver micronucleus assay. We focused on liver micronucleus induction in combination with histopathological changes including hypertrophy, proliferation of oval cells or bile duct epithelial cells, tissue injuries, regenerative changes, and inflammatory changes as the early responses of hepatocarcinogenesis. For these early responses, A total of 20 carcinogens, including 14 genotoxic hepatocarcinogens (Group A) and 6 non-liver-targeted genotoxic carcinogens (Group B) were evaluated. Results In the Group A chemicals, 5 chemicals (NPYR, MDA, NDPA, 2,6-DNT, and NMOR) showed all of the 6 early responses in hepatocarcinogenesis. Five chemicals (DMN, 2,4-DNT, QUN, 2-AAF, and TAA) showed 4 responses, and 4 chemicals (DAB, 2-NP, MCT, and Sudan I) showed 3 responses. All chemicals exhibited at least 3 early responses. Contrarily, in the Group B chemicals (6 chemicals), 3 of the 6 early responses were observed in 1 chemical (MNNG). No more than two responses were observed in 3 chemicals (MMC, MMS, and KA), and no responses were observed in 2 chemicals (CP and KBrO3). Conclusion Evaluation of liver micronucleus induction in combination with histopathological examination is useful for detecting hepatocarcinogens. This assay takes much less time than routine long-term carcinogenicity studies.

A DNA adductome analysis revealed a reduction in the global level of C5-hydroxymethyl-2′-deoxycytidine in the non-tumoral upper urinary tract mucosa of urothelial carcinoma patients

Background DNA adducts, covalent modifications to DNA due to exposure to specific carcinogens, cause the mispairing of DNA bases, which ultimately results in DNA mutations. DNA methylation in the promoter region, another type of DNA base modification, alters the DNA transcription process, and has been implicated in carcinogenesis in humans due to the down-regulation of tumor suppressor genes. Difficulties are associated with demonstrating the existence of DNA adducts or chemically modified bases in the human urological system. Apart from aristolochic acid-DNA adducts, which cause urothelial carcinoma and endemic nephropathy in a particular geographical area (Balkan), limited information is currently available on DNA adduct profiles in renal cell carcinoma and upper urinary tract urothelial carcinoma, including renal pelvic cancer and ureteral cancer. Method To elucidate the significance of DNA adducts in carcinogenesis in the urothelial system, we investigated 53 DNA adducts in the non-tumoral renal parenchyma and non-tumoral renal pelvis of patients with renal cell carcinoma, upper urinary tract urothelial carcinoma, and other diseases using liquid chromatography coupled with tandem mass spectrometry. A comparative analysis of tissue types, the status of malignancy, and clinical characteristics, including lifestyle factors, was performed. Results C5-Methyl-2′-deoxycytidine, C5-hydroxymethyl-2′-deoxycytidine (5hmdC), C5-formyl-2′-deoxycytidine, 2′-deoxyinosine, C8-oxo-2′-deoxyadenosine, and C8-oxo-2′-deoxyguanosine (8-OHdG) were detected in the renal parenchyma and renal pelvis. 8-OHdG was more frequently detected in the renal pelvis than in the renal cortex and medulla (p = 0.048 and p = 0.038, respectively). 5hmdC levels were significantly lower in the renal pelvis of urothelial carcinoma patients (n = 10) than in the urothelium of patients without urothelial carcinoma (n = 15) (p = 0.010). Regarding 5hmdC levels in the renal cortex and medulla, Spearman’s rank correlation test revealed a negative correlation between age and 5hmdC levels (r = − 0.46, p = 0.018 and r = − 0.45, p = 0.042, respectively). Conclusions The present results revealed a reduction of 5hmdC levels in the non-tumoral urinary tract mucosa of patients with upper urinary tract urothelial carcinoma. Therefore, the urothelial cell epithelia of patients with upper urinary tract cancer, even in non-cancerous areas, may be predisposed to urothelial cancer.

Effect of dietary selenium intake on gut microbiota in older population in Enshi region

Background The microbial ecosystem in the human gut varies between individuals with differences in diet. Selenium is one of most common trace elements in everyday diet, and selenium intake affects the human gut microbiota. We studied the effect of selenium intake on the gut microbiota in regions of Enshi with different distributions of selenium. Methods One hundred elderly subjects (>65 years) were recruited from high-selenium and low-selenium areas in Enshi and blood, nail, and fecal specimens were obtained. The selenium contents in these samples were determined in triplicate by hydride generation atomic fluorescence spectrometry. DNA was extracted from fecal specimens and the microbial diversity was analyzed by 16 S RNA. Results The selenium contents in the blood and nails were significantly different between the high- and low-selenium areas, and the composition of the intestinal microbiota, including abundance and extent of intestinal flora, was altered. The function and metabolic pathways of the gut microbiota showed clear differences. Conclusions As a trace element in human diet, selenium intake is an important factor that affects the intestinal microbiota and is likely involved in many human diseases. This study provides new clues and ideas for studying the correlation between selenium and human health.

PIG-A gene mutation as a genotoxicity biomaker in polycyclic aromatic hydrocarbon-exposed barbecue workers

Background The PIG-A gene mutation assay is a valuable tool for measuring in vivo gene mutations in blood cells. The human PIG-A assay, used as a potential genotoxicity biomarker, is minimally invasive, sensitive, and cost-efficient; however, the relationship between carcinogen exposure and PIG-A mutations is not well understood. Methods We investigated the genotoxic effect of red blood cells using PIG-A assay and lymphocyte cytokinesis-block micronucleus test in barbecue restaurant workers (N = 70) exposed to polycyclic aromatic hydrocarbons (PAHs) and self-identified healthy control subjects (N = 56). Urinary PAH metabolites were measured to evaluate internal exposure levels. Results Multivariate Poisson regression showed that the PAH-exposed workers exhibited significantly higher PIG-A mutant frequency (MF) (8.04 ± 6.81 × 10− 6) than did the controls (5.56 ± 5.26 × 10− 6) (RR = 0.707, 95% CI: 0.615–0.812, P < 0.001). These results indicate that PAH exposure is a risk factor for elevated PIG-A MF. The frequencies of micronuclei (MN) and nuclear buds (NBUD) in the PAH-exposed workers (MN: 3.06 ± 2.07 ‰, NBUD: 1.38 ± 1.02 ‰) were also significantly higher than in the controls (MN: 1.46 ± 0.64 ‰, P < 0.001; NBUD: 0.70 ± 0.60 ‰, P < 0.001). Additionally, PIG-A MFs showed better associations with several urinary hydroxylated PAH metabolites (P2-OH-Flu = 0.032, r2-OH-Flu = 0. 268; P2-OH-Phe = 0.022, r2-OH-Phe = 0.286; P3-OH-Phe = 0.0312, r3-OH-Phe = 0.270; P4-OH-Phe = 0.018, r4-OH-Phe = 0.296), while the increase in MN, NPB, and NBUD frequencies was not associated with any OH-PAH metabolites; and high-PAH-exposed workers showed the highest PIG-A MFs. Furthermore, there was a significant association between PIG-A MF and PAH exposure levels (Chi-square test for trend, P = 0.006). Conclusions Our results indicate that an increase in PIG-A MF in barbecue workers could reflect the response to PAH exposure, providing evidence of its potential as a genotoxicity biomarker in human risk assessment.

Telomere length in peripheral leukocytes is a sensitive marker for assessing genetic damage among workers exposed to isopropanol, lead and noise: the case of an electronics manufacturer

Background Workers in electronics manufacturers may be exposed to various occupational hazards such as isopropanol, lead, and noise. Telomeres are special segments of cap-like DNA protein complex at end of liner chromosomes in eukaryotic cells. Telomere length is a potential marker of genetic damage. The aim of this study is to evaluate the effect of occupational hazards on the relative telomere length (rTL) of peripheral blood cells of workers in an electronics manufacturer, and to explore whether relative telomere length could be a biomarker for assessing genetic damage in the electronics manufacturing industry. Methods We investigated a large-scale electronics manufacturer in the Pearl River Delta Region. We ultimately collected 699 qualified workers (248 with isopropanol exposure, 182 with lead exposure, 157 with noise exposure, and 112 controls). During physical examination of the workers, we gave them questionnaires to understand their health statuses and living habits. We also collected peripheral blood samples from these workers to test exposure levels and rTL in the leucocytes. Results The concentrations of air isopropanol in all monitored workshops was 25.3 mg/m3 and air lead smoke was 0.020 mg/m3. The maximum equivalent continuous A sound level noise exposure position was 82.2dB (A). All were lower than those in the Occupational Exposure Limits in Workplaces in China. Urinary acetone in the isopropanol exposed group was 1.04 (0, 1.50) mg/L, and cumulative urinary acetone was 1.48 (0, 5.09) mg-years/L. Blood lead levels (BLLs) were 28.57 (22.77, 37.06) µg/dL, and cumulative blood lead levels (CBLLs) were 92.75 (55.47, 165.13) µg-years/dL. rTL was different between occupational exposed workers and controls: rTL was 0.140 units (95 % CI: 0.022, 0.259) shorter in lead exposed workers and 0.467 units (95 % CI: 0.276–0.658) shorter in noise exposed workers compared to the controls. There is no statistical difference in rTL between isopropanol exposure workers and the controls. In order to elucidate the relationship between rTL and occupational hazards exposure, we divided the isopropanol exposure workers into three groups (0, ~1.43 mg/L, and >1.43 mg/L). None of the rTL difference was statistically significant among exposed workers at different uroacetone levels (P>0.05). The groups with ≥100 µg/dL blood lead had shorter rTL than the group with blood lead below 100 µg/dL (F=4.422, P=0.013). We incorporated age, gender, birthplace, race, education level, smoking, and alcohol consumption into the linear regression equation. Only blood lead concentration (X) was entered into the regression equation, yielding a multivariate linear regression equation of Y=0.397-0.124X (F=8.091, P=0.005). Workers with different hearing loss also had statistically significant differences in rTL (F=5.731, P=0.004). rTL was a protective factor for the occurrence of noise-induced hearing loss (NIHL). The longer the rTL, the lower the risk of NIHL [OR=0.64 (0.42, 0.98)]. Conclusions rTL was shorter in lead exposed workers and noise exposed workers, and it was a protective factor for the occurrence of the noise-induced hearing loss. Thus, rTL of peripheral blood may be a sensitive marker of genetic damage among workers in environments with lead and noise exposure.

Glycoprotein 2 in health and disease: lifting the veil

In 2020, we discovered glycoprotein 2 (GP2) variants associated with pancreatic cancer susceptibility in a genome-wide association study involving the Japanese population. Individuals carrying a missense coding variant (rs78193826) in the GP2 gene resulting in a p.V432M substitution had an approximately 1.5-fold higher risk of developing pancreatic cancer than those without this variant. GP2 is expressed on the inner surface of zymogen granules in pancreatic acinar cells, which are responsible for the sorting, storage and secretion of digestive enzymes. Upon neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of zymogen granules and then secreted into the pancreatic duct and intestinal lumen. While the functions of GP2 remain poorly understood, emerging evidence suggests that it plays an antibacterial role in the gastrointestinal tract after being secreted from pancreatic acinar cells. Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa. In this review article, we summarize the role of GP2 in health and disease, emphasizing its functions in the gastrointestinal tract, as well as genetic variations in the GP2 gene and their associations with disease susceptibility. We hope that its robust genetic associations with pancreatic cancer, coupled with its emerging role in gastrointestinal mucosal immunity, will spur renewed research interest in GP2, which has been understudied over the past 30 years compared with its paralog uromodulin (UMOD).

Epigenetics in neurodegenerative disorders induced by pesticides

Neurodegenerative diseases are becoming major socio-economic burdens. However, most of them still have no effective treatment. Growing evidence indicates excess exposure to pesticides are involved in the development of various forms of neurodegenerative and neurological diseases through trigger epigenetic changes and inducing disruption of the epigenome. This review summaries studies on epigenetics alterations in nervous systems in relation to different kinds of pesticides, highlighting potential mechanism in the etiology, precision prevention and target therapy of various neurodegenerative diseases. In addition, the current gaps in research and future areas for study were also discussed.

Thorium and fetal neural tube defects: an epidemiological evidence from large case-control study

Background Thorium is ubiquitous in the environment and its relationship with birth defects is still under discussion. This study aimed to investigate the associations of maternal exposure to thorium with risk of neural tube defects (NTDs) by using a case–control study, as well as the relationship between thorium exposure and the indoor air pollution from coal combustion. Methods This study was conducted in 11 local healthcare hospitals during 2003–2007 in Shanxi and Hebei provinces, China. A total of 774 mothers were included as participants who delivering 263 fetuses with NTDs including 123 with anencephaly, 115 with spina bifida, 18 with encephalocele, and 7 other NTD subtypes (cases), and 511 health fetuses without NTDs (controls). Their hair samples were collected as close as to the occipital posterior scalp, of which those grew from 3 months before to 3 months after conception was cut to measure the thorium concentration by inductively coupled plasma-mass spectrometry. Results We found a higher hair thorium concentration in the total NTD cases with 0.901 (0.588–1.382) ng/g hair [median (inter-quartile range)] than that in the controls with a value of 0.621 (0.334–1.058) ng/g hair. Similar results were found for the three concerned NTD subtypes. Maternal hair thorium concentration above its median of the controls was associated with an increased risk of the total NTDs with an adjusted odds ratio of 1.80 [95% confidence interval (CI), 1.23–2.63)] by adjusting for all confounders. There was obvious dose-response relationship between maternal hair thorium concentration and the risk of total NTDs, as well as their two subtypes (i.e. anencephaly and spina bifida). Maternal hair thorium concentration was positive associated with their exposure level to indoor air pollution from coal combustion during cooking. Conclusions Overall, our findings revealed that maternal periconceptional thorium exposure was associated with the risk of NTDs in North China. Reducing the coal usage in the household cooking activities may decrease maternal thorium exposure level. Graphical abstract