Benchmark Dose Assessment for Coke Oven Emissions-Induced Mitochondrial DNA Copy Number Damage Effects

Objective The study aimed to estimate the benchmark dose(BMD)of coke oven emissions(COEs)exposure based on mitochondrial damage with the mitochondrial DNA copy number(mtDNAcn)as a biomarker.Methods A total of 782 subjects were recruited,including 238 controls and 544 exposed workers.The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction.Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95%confidence lower limit(BMDL).Results The mtDNAcn of the exposure group was lower than that of the control group(0.60±0.29 vs.1.03±0.31;P<0.001).A dose-response relationship was shown between the mtDNAcn damage and COEs.Using the Benchmark Dose Software,the occupational exposure limits(OELs)for COEs exposure in males was 0.00190 mg/m^(3).The OELs for COEs exposure using the BBMD were 0.00170 mg/m^(3)for the total population,0.00158 mg/m^(3)for males,and 0.00174 mg/m^(3)for females.In possible risk obtained from animal studies(PROAST),the OELs of the total population,males,and females were 0.00184,0.00178,and 0.00192 mg/m^(3),respectively.Conclusion Based on our conservative estimate,the BMDL of mitochondrial damage caused by COEs is0.002 mg/m^(3).This value will provide a benchmark for determining possible OELs.

Number matters:control of mammalian mitochondrial DNA copy number

Regulation of mitochondrial biogenesis is essential for proper cellular functioning. Mitochondrial DNA （mtDNA） depletion and the resulting mitochondrial malfunction have been implicated in cancer, neurodegeneration, diabetes, aging, and many other human diseases. Although it is known that the dynamics of the mammalian mitochondrial genome are not linked with that of the nuclear genome, very little is known about the mechanism of mtDNA propagation. Nevertheless, our understanding of the mode of mtDNA replication has ad- vanced in recent years, though not without some controversies. This review summarizes our current knowledge of mtDNA copy number control in mammalian cells, while focusing on both mtDNA replication and turnover. Although mtDNA copy number is seemingly in excess, we reason that mtDNA copy number control is an important aspect of mitochondrial genetics and biogenesis and is essential for normal cellular function.

Relationships between blood leukocyte mitochondrial DNA copy number and inflammatory cytokines in knee osteoarthritis

Osteoarthritis(OA)is a degenerative articular disorder manifested by cartilage destruction,subchondral sclerosis,osteophytes,and synovitis,resulting in chronic joint pain and physical disability in the elderly.The purpose of this study was to investigate mitochondrial DNA copy number(mtDNACN)and inflammatory cytokines in primary knee OA patients and healthy volunteers.A total of 204 knee OA patients and 169 age-matched healthy volunteers were recruited.Their relative blood leukocyte mtDNACN was assessed by quantitative real-time polymerase chain reaction(qRT-PCR),and ten inflammatory cytokines in their plasma were detected by multiplex immunoassay.Blood leukocyte mtDNACN in the OA group was significantly lower than that in the control group.Leukocyte mtDNACN in the control group was negatively correlated with their age(r=−0.380,P<0.0001),whereas mtDNACN in the OA group was positively correlated with their age(r=0.198,P<0.001).Plasma interleukin-4(IL-4)and IL-6 were significantly higher in the knee OA group than in the control group.The plasma IL-6 level was positively correlated with blood leukocyte mtDNACN in the OA group(r=0.547,P=0.0014).IL-5 showed as a major factor(coefficient 0.69)in the second dimension of principle components analysis(PCA)-transformed data and was significantly higher in the OA group(P<0.001)as well as negatively correlated with mtDNACN(r=−0.577,P<0.001).These findings suggest that elevation of plasma IL-4 and IL-6 and a relative reduction in mtDNACN might be effective biomarkers for knee OA.IL-5 is a plausible factor responsible for decreasing blood leukocyte mtDNACN in knee OA patients.

Health risks of rare earth elements exposure:Impact on mitochondrial DNA copy number and micronucleus frequency

Toxic effects in terms of mitochondria and hereditary substances have been characterized in vitro for individual rare earth elements,while,the joint effects of mixed elements exposure in the population remain ambiguous.Based on the Occupational Chromate Exposure Dynamic Cohort of China,this study investigated the relationship between 15 blood rare earth elements(cerium,dysprosium,erbium,europium,gadolinium,holmium,lanthanum,lutetium,neodymium,praseodymium,samarium,terbium,thulium,yttrium,and ytterbium)and mitochondrial DNA copy number(MtDNACN)as well as peripheral blood lymphocyte micronucleus frequency(MNF).The elastic net was used to select elements highly correlated with effect indicators,whose dose-response relationships were further illustrated by restricted cubic splines.Bayesian kernel regressionwas employed to explore the combined effects of elements and the contributions of single element.The results showed that most rare earth elementswere positively correlatedwith effect indicators,with yttrium showing the strongest association(β(95%CI):0.139(0.1089–0.189)for MtDNACN,0.937(0.345–1.684)for MNF).In the mixed exposure model,with the exposure level fixed at the 50th percentile as the reference,the effect estimates on MtDNACN and MNF increased by 0.228 and 0.598 units,respectively,at the 75th percentile.The single effect analysis implied that yttrium,lanthanum and terbium contributed the most to the elevation of MtDNACN,while yttrium posed the highest risk for genetic damage,accordingly,we provided recommendations to prioritize these elements of concern.In addition,we observed a chief mediating effect of MtDNACN on the elevation of MNF caused by lanthanum,whereas further mechanistic exploration is required to confirm this finding.

Somatic CDKN2A copy number variations are associated with the prognosis of esophageal squamous cell dysplasia

Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma.However,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is unknown.This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)ESCdys.Methods:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to 2019.Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy number.The cumulative regression and progression rates of ESCdys were evaluated using competing risk models.Results:A total of 205 patients with baseline m/M ESCdys were enrolled.The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion.CDKN2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable analysis.Conclusion:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

Clinical assessment and genomic landscape of a consanguineous family with three Kallmann syndrome descendants

Although some genes that cause Kallmann syndrome （KS） have been identified by traditional linkage analysis and candidate gene techniques, the syndrome＇s molecular etiology in the majority of patients remains poorly understood. In this paper, we present the clinical assessments of a consanguineous Hart Chinese family with three KS descendants. To understand the molecular etiology of KS from a genome-wide perspective, we investigated the genome-wide profile of structural variation in this family using the Affymetrix Genome-Wide Human SNP Array 6.0 platform. The results revealed that the three affected individuals had common copy number variants （microdeletions） on chromosomes lp21.1, 2q32.2, 8q21.13, 14q21.2 and Xp22.31. Moreover, the copy number variants on Xp22.31 were located in the intron of KAL 1, which causes X-linked KS. Two PCR assays were performed on these regions to validate the results obtained using the chips. In addition, genomic microdeletions in this region were verified in one of 29 Han Chinese sporadic KS cases and one of four other family cases, but not in 26 Han Chinese sporadic normosmic idiopathic hypogonadotropic hypogonadism cases and 100 unrelated Han Chinese normal controls. Our results provide a novel insight into the relative contributions of certain copy number variants to KS＇s molecular etiology and generate a list of interesting candidate regions for further studies.