ABSTRACT
BACKGROUND: Advances of spatial transcriptomics technologies enabled simultaneously profiling gene expression and spatial locations of cells from the same tissue. Computational tools and approaches for integration of transcriptomics data and spatial context information are urgently needed to comprehensively explore the underlying structure patterns. In this manuscript, we propose HyperGCN for the integrative analysis of gene expression and spatial information profiled from the same tissue. HyperGCN enables data visualization and clustering, and facilitates downstream analysis, including domain segmentation, the characterization of marker genes for the specific domain structure and GO enrichment analysis. RESULTS: Extensive experiments are implemented on four real datasets from different tissues (including human dorsolateral prefrontal cortex, human positive breast tumors, mouse brain, mouse olfactory bulb tissue and Zabrafish melanoma) and technologies (including 10X visium, osmFISH, seqFISH+, 10X Xenium and Stereo-seq) with different spatial resolutions. The results show that HyperGCN achieves superior clustering performance and produces good domain segmentation effects while identifies biologically meaningful spatial expression patterns. This study provides a flexible framework to analyze spatial transcriptomics data with high geometric complexity. CONCLUSIONS: HyperGCN is an unsupervised method based on hypergraph induced graph convolutional network, where it assumes that there existed disjoint tissues with high geometric complexity, and models the semantic relationship of cells through hypergraph, which better tackles the high-order interactions of cells and levels of noise in spatial transcriptomics data.
Subject(s)
Gene Expression Profiling , Humans , Animals , Mice , Gene Expression Profiling/methods , Transcriptome , Deep Learning , Cluster Analysis , Computational Biology/methods , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Olfactory Bulb/metabolismABSTRACT
Starting in the 1970s, individuals, businesses and the public have increasingly benefited from policies prohibiting smoking indoors, saving thousands of lives and billions of dollars in healthcare expenditures. Smokefree policies to protect against secondhand smoke exposure, however, do not fully protect the public from the persistent and toxic chemical residues from tobacco smoke (also known as thirdhand smoke) that linger in indoor environments for years after smoking stops. Nor do these policies address the economic costs that individuals, businesses and the public bear in their attempts to remediate this toxic residue. We discuss policy-relevant differences between secondhand smoke and thirdhand smoke exposure: persistent pollutant reservoirs, pollutant transport, routes of exposure, the time gap between initial cause and effect, and remediation and disposal. We examine four policy considerations to better protect the public from involuntary exposure to tobacco smoke pollutants from all sources. We call for (a) redefining smokefree as free of tobacco smoke pollutants from secondhand and thirdhand smoke; (b) eliminating exemptions to comprehensive smoking bans; (c) identifying indoor environments with significant thirdhand smoke reservoirs; and (d) remediating thirdhand smoke. We use the case of California as an example of how secondhand smoke-protective laws may be strengthened to encompass thirdhand smoke protections. The health risks and economic costs of thirdhand smoke require that smokefree policies, environmental protections, real estate and rental disclosure policies, tenant protections, and consumer protection laws be strengthened to ensure that the public is fully protected from and informed about the risks of thirdhand smoke exposure.
ABSTRACT
Tobacco-specific nitrosamines (TSNAs) are emitted during smoking and form indoors by nitrosation of nicotine. Two of them, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are human carcinogens with No Significant Risk Levels (NSRLs) of 500 and 14 ng day-1, respectively. Another TSNA, 4-(methylnitrosamino)-4-(3-pyridyl) butanal (NNA), shows genotoxic and mutagenic activity in vitro. Here, we present additional evidence of genotoxicity of NNA, an assessment of TSNA dermal uptake, and predicted exposure risks through different pathways. Dermal uptake was investigated by evaluating the penetration of NNK and nicotine through mice skin. Comparable mouse urine metabolite profiles suggested that both compounds were absorbed and metabolized via similar mechanisms. We then investigated the effects of skin constituents on the reaction of adsorbed nicotine with nitrous acid (epidermal chemistry). Higher TSNA concentrations were formed on cellulose and cotton substrates that were precoated with human skin oils and sweat compared to clean substrates. These results were combined with reported air, dust, and surface concentrations to assess NNK intake. Five different exposure pathways exceeded the NSRL under realistic scenarios, including inhalation, dust ingestion, direct dermal contact, gas-to-skin deposition, and epidermal nitrosation of nicotine. These results illustrate potential long-term health risks for nonsmokers in homes contaminated with thirdhand tobacco smoke.
Subject(s)
Nicotiana , Nitrosamines , Animals , Carcinogens/toxicity , Dust , Eating , Humans , Mice , Nicotine/chemistry , Nitrosamines/chemistry , Nicotiana/chemistry , Nicotiana/metabolismABSTRACT
BACKGROUND: Infertility affects approximately 15% of couples worldwide with male infertility being responsible for approximately 50% of cases. Although accumulating evidence demonstrates the critical role of the X chromosome in spermatogenesis during the last few decades, the expression patterns and potential impact of the X chromosome, together with X linked genes, on male infertility are less well understood. METHODS: We performed X chromosome exome sequencing followed by a two-stage independent population validation in 1333 non-obstructive azoospermia cases and 1141 healthy controls to identify variant classes with high likelihood of pathogenicity. To explore the functions of these candidate genes in spermatogenesis, we first knocked down these candidate genes individually in mouse spermatogonial stem cells (SSCs) using short interfering RNA oligonucleotides and then generated candidate genes knockout mice by CRISPR-Cas9 system. RESULTS: Four low-frequency variants were identified in four genes (BCORL1, MAP7D3, ARMCX4 and H2BFWT) associated with male infertility. Functional studies of the mouse SSCs revealed that knocking down Bcorl1 or Mtap7d3 could inhibit SSCs self-renewal and knocking down Armcx4 could repress SSCs differentiation in vitro. Using CRISPR-Cas9 system, Bcorl1 and Mtap7d3 knockout mice were generated. Excitingly, Bcorl1 knockout mice were infertile with impaired spermatogenesis. Moreover, Bcorl1 knockout mice exhibited impaired sperm motility and sperm cells displayed abnormal mitochondrial structure. CONCLUSION: Our data indicate that the X-linked genes are associated with male infertility and involved in regulating SSCs, which provides a new insight into the role of X-linked genes in spermatogenesis.
Subject(s)
Chromosomes, Human, X/genetics , Repressor Proteins/genetics , Spermatogenesis/genetics , Testis/growth & development , Animals , CRISPR-Cas Systems/genetics , Exome/genetics , Humans , Male , Mice , Mice, Knockout , Sperm Motility/genetics , Spermatogonia/metabolism , Spermatogonia/pathology , Testis/pathology , Exome SequencingABSTRACT
BACKGROUND: The effect of chemical exposure on obesity has raised great concerns. Real-world chemical exposure always imposes mixture impacts, however their exposure patterns and the corresponding associations with obesity have not been fully evaluated. OBJECTIVES: To discover obesity-related mixed chemical exposure patterns in the general U.S. METHODS: Sparse Decompositional Regression (SDR), a model adapted from sparse representation learning technique, was developed to identify exposure patterns of chemical mixtures with exclusion (non-targeted model) and inclusion (targeted model) of health outcomes. We assessed the relationships between the identified chemical mixture patterns and obesity-related indexes. We also conducted a comprehensive evaluation of this SDR model by comparing to the existing models, including generalized linear regression model (GLM), principal component analysis (PCA), and Bayesian kernel machine regression (BKMR). RESULTS: Eight core exposure patterns were identified using the non-targeted SDR model. Patterns of high levels of MEP, high levels of naphthalene metabolites (ΣOH-Nap), and a pattern of high exposure levels of MCOP, MCNP, and MCPP were positively associated with obesity. Patterns of high levels of BP3, and a pattern of higher mixed levels of MPB, PPB, and MEP were found to have negative associations. Associations were strengthened using the targeted SDR model. In the single chemical analysis by GLM, BP3, MBP, PPB, MCOP, and MCNP showed significant associations with obesity or body indexes. The SDR model exceeded the performance of PCA in pattern identification. Both SDR and BKMR identified a positive contribution of ΣOH-Nap and MCOP, as well as a negative contribution of BP3 and PPB to obesity. CONCLUSION: Our study identified five core exposure patterns of chemical mixtures significantly associated with obesity using the newly developed SDR model. The SDR model could open a new avenue for assessing health effects of environmental mixture contaminants.
Subject(s)
Obesity , Adult , Humans , Nutrition Surveys , Bayes Theorem , Obesity/chemically induced , Obesity/epidemiology , Principal Component Analysis , Chromatography, GasABSTRACT
BACKGROUND: Pregnant women are exposed to a number of pesticides which are widely used in China. Their potential risks on reproduction and infants are still unknown. OBJECTIVE: We aimed to investigate whether infant's birth weight and length of gestation were associated with levels of various pesticides in maternal blood based on Nanjing Medical University (NMU) affiliated hospitals data and meta-analysis, and also to explore the possible intermediate metabolomics pathways. METHODS: Eligible subjects (n = 102) were included in this study from the affiliated hospitals of NMU. Gas chromatography tandem mass spectrometry (GC/MS) and Q-Exactive mass spectrometer (QE) were used to detect 37 pesticides (9 organophosphorus pesticides, 7 organochlorine pesticides, 5 carbamate pesticides, and 16 others) and 161 metabolites (53 in animo acid metabolism 47 in lipid metabolism, 18 in carbohydrate metabolism, 14 in nucleotide metabolism and 29 in other metabolisms) in maternal blood, respectively. Multi-linear regression and Bayesian kernel machine regression (BKMR) were performed to identify the association of single/mixed pesticide exposure in maternal blood with birth weight and length of gestation. Moreover, we conducted a meta-analysis including additional 2497 subjects to evaluate whether exposure to key pesticide, ß-hexachlorocyclohexane (ß-HCH) was associated with decreased birth weight globally. Mediation analysis was used to explore the metabolic alteration mediating the association between key pesticide exposure and birth outcomes. RESULTS: We found that decreased birth weight was significantly associated with increasing levels of mecarbam and ß-HCH. We did not find any association between length of gestation and these pesticides. Among pesticides with detection rate more than 50%, BKMR analysis found an overall negative association of mixed pesticides exposure with birth weight, and verified that ß-HCH was the key pesticide for such effect. Meta-analysis revealed a significantly negative association between exposure to ß-HCH and birth weight. Metabolomics identified three metabolites and five metabolites as significant mediators for the effect of mecarbam and ß-HCH, respectively, among which glyceraldehyde and its related glycerolipid metabolism and thyroxine and its related thyroid hormone metabolism were found to be the mostly enriched mediating metabolic pathway. CONCLUSIONS: Based on the comprehensive pesticide exposome and metabolome wide associational study combined with meta-analysis, we found that prenatal exposure to ß-HCH and mecarbam decreased birth weight via disrupting thyroid hormone metabolism and glyceraldehyde metabolism, providing new insights into the toxic effects of exposure to pesticides on birth outcomes.
Subject(s)
Birth Weight , Exposome , Maternal Exposure , Metabolomics , Pesticides , Pregnancy Outcome , Bayes Theorem , China , Female , Gas Chromatography-Mass Spectrometry , Humans , Pesticides/toxicity , Pregnancy , Thyroid Hormones/metabolismABSTRACT
Recently, potential health concerns have been raised about thirdhand smoke (THS), a much less well-understood type of smoke exposure defined as residual tobacco smoke sorbed onto indoor surfaces after active smoking has ceased. THS exposure is derived from the involuntary inhalation, ingestion, or dermal uptake of indoor pollutants. The timescale for exposure to THS pollution is generally much longer than secondhand smoke, and could stretch to days, months, or years (long-term, low-level exposure). Recent studies showed that exposure to THS at early age in mice can affect body weight, immunity, and lung cancer development. However, adverse health effects of THS in human populations remain poorly understood and many questions remain unanswered. One major question is how genetic factors influence susceptibility to THS-induced health effects, especially tumor development and whether there is an age-specific window of susceptibility for these effects. By addressing these questions, we will provide a better understanding of the effects of THS on human health and disease. This information would address critical knowledge gaps that are required for the formulation of policies related to indoor air quality. IMPLICATIONS: THS, the residual tobacco smoke remaining in the environment after tobacco has been smoked, represents an underestimated public health hazard. Evidence supports its widespread presence in indoor environments. Vulnerable populations are believed to include infants and children living in a smoking household exposed to THS and/or secondhand smoke, and exposure has been identified as a risk factor for lung cancer later in life. These and future studies will provide novel and important evidence of how early-life exposure to THS affects cancer development and other diseases, which should be useful for framing and enforcing new policies against passive smoking in the world.
Subject(s)
Genetic Predisposition to Disease/genetics , Lung Neoplasms/chemically induced , Lung Neoplasms/genetics , Smoking/adverse effects , Smoking/genetics , Tobacco Smoke Pollution/adverse effects , Air Pollution, Indoor/analysis , Animals , Family Characteristics , Genetic Predisposition to Disease/epidemiology , Humans , Lung Neoplasms/epidemiology , Risk Factors , Vulnerable PopulationsABSTRACT
Exposure to thirdhand smoke (THS) is a recently described health concern that arises in many indoor environments. However, the carcinogenic potential of THS, a critical consideration in risk assessment, remains untested. Here we investigated the effects of short-term early exposure to THS on lung carcinogenesis in A/J mice. Forty weeks after THS exposure from 4 to 7 weeks of age, the mice had increased incidence of lung adenocarcinoma, tumor size and, multiplicity, compared with controls. In vitro studies using cultured human lung cancer cells showed that THS exposure induced DNA double-strand breaks and increased cell proliferation and colony formation. RNA sequencing analysis revealed that THS exposure induced endoplasmic reticulum stress and activated p53 signaling. Activation of the p53 pathway was confirmed by an increase in its targets p21 and BAX. These data indicate that early exposure to THS is associated with increased lung cancer risk.
Subject(s)
Lung Neoplasms/chemically induced , Smoking/adverse effects , Time Factors , Tobacco Smoke Pollution/adverse effects , Animals , Cell Proliferation/physiology , Disease Models, Animal , Incidence , Mice , Nicotiana/adverse effectsABSTRACT
Hirschsprung disease (HSCR) is a genetic disorder of neural crest development. It is also believed that epigenetic changes plays a role in the progression of this disease. Here we show that the MIR143 host gene (MIR143HG), the precursor of miR-143 and miR-145, decreased cell proliferation and migration and forms a negative feedback loop with RBM24 in HSCR. As RBM24 mRNA is a target of miR-143, upregulation of RBM24 upon an increase in the level of MIR143HG could be attributed to sequestration of miR-143 by MIR143HG (sponge effect). The RBM24 protein was shown to bind to MIR143HG, and subsequently, accelerated its degradation by destabilizing its transcript and facilitating its interaction with Ago2, thus forming a negative feedback between MIR143HG and RBM24. In addition, experiments using siRNA against DROSHA indicated that RBM24 could promote the biogenesis of miR-143. This feedback loop we describe here represents a novel mode of autoregulation, with implications in HSCR pathogenesis.
ABSTRACT
Thirdhand smoke (THS) is the contamination that persists after secondhand tobacco smoke has been emitted into air. It refers to the tobacco-related gases and particles that become embedded in materials, such as the carpet, walls, furniture, blankets, and toys. THS is not strictly smoke, but chemicals that adhere to surfaces from which they can be released back into the air, undergo chemical transformations and/or accumulate. Currently, the hazards of THS are not as well documented as the hazards of secondhand smoke (SHS). In this Perspective, we describe the distribution and chemical changes that occur as SHS is transformed into THS, studies of environmental contamination by THS, human exposure studies, toxicology studies using animal models and in vitro systems, possible approaches for avoiding exposure, remediation of THS contamination, and priorities for further research.
Subject(s)
Air Pollution, Indoor/analysis , Nicotiana , Smoke , Animals , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Humans , Particulate Matter/analysis , Particulate Matter/toxicityABSTRACT
The newly identified smoke hazard, thirdhand smoke (THS), has gained public attention in recent years but its health impact and biological effects are largely unknown. THS may be defined by "the four Rs": tobacco chemicals that remain, react, re-emit, and/or are resuspended long after active smoking has ceased. This review summarizes recent research progress in the effects of THS on genotoxicity, metabolism and early life development using cellular and animal models. We first reported that THS generated in laboratory systems caused significant DNA damage in human cell lines. Our finding that THS significantly induces oxidative base lesions has been confirmed in skin wounds of mice models exposed to THS. THS also induced metabolomic changes in human reproductive cell lines. Furthermore, we demonstrated that early exposure to THS not only negatively impacts body weight in both male and female mice, but also induces persistent changes to immunological parameters in peripheral blood in these mice. These results indicate that THS is genotoxic at realistic experimental doses and that there may be a window of susceptibility for some forms of cellular damage induced by THS.
Subject(s)
Tobacco Smoke Pollution , Air Pollutants/toxicity , Animals , Apoptosis/drug effects , DNA Adducts/chemistry , DNA Adducts/metabolism , DNA Damage/drug effects , Humans , Immune System/drug effects , Immune System/metabolism , Models, Animal , Reproduction/drug effectsABSTRACT
Hirschsprung disease (HSCR) is a congenital disorder caused by the defective function of the embryonic enteric neural crest. The impaired migration of embryonic enteric neural crest plays an important role in the pathogenesis of this disease. Recent studies showed that the ARP2/3 complex and RAC isoforms had effects on actin cytoskeleton remodelling, which contributes to migration. Moreover, some regulatory relationships were identified between ARP2/3 complex and RAC isoforms. Although microRNAs (miRNAs) have been known to modulate target gene expression on the post-transcriptional level, little is known about the regulation among miRNAs, ARP2/3 complex and RAC isoforms. Here, we report that down-regulation of ARP2 and ARP3, two main subunits of ARP2/3 complex, suppressed migration and proliferation in 293T and SH-SY5Y cell lines via the inhibition of RAC1 and RAC2. Meanwhile, as the target genes, ARP2 and ARP3 are reduced by increased miR-24-1* and let-7a*, respectively, in 70 HSCR samples as compared with 74 normal controls. Co-immunoprecipitation showed that aberrant reduction in ARP2 and ARP3 could weaken the function of ARP2/3 complex. Our study demonstrates that the miR-24-1*/let-7a*-ARP2/3 complex-RAC isoforms pathway may represent a novel pathogenic mechanism for HSCR.
Subject(s)
Actin-Related Protein 2-3 Complex/metabolism , Cell Movement , Hirschsprung Disease/genetics , Hirschsprung Disease/pathology , MicroRNAs/metabolism , rac GTP-Binding Proteins/metabolism , rac1 GTP-Binding Protein/metabolism , Actin-Related Protein 2-3 Complex/genetics , Base Sequence , Cell Line, Tumor , Cell Proliferation , Demography , Down-Regulation/genetics , Female , Humans , Immunoprecipitation , Infant , Male , MicroRNAs/genetics , Models, Biological , Protein Isoforms/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Up-Regulation/genetics , RAC2 GTP-Binding ProteinABSTRACT
Third hand smoke (THS) is the accumulation of second hand smoke (SHS) toxins on surfaces in homes, cars, clothing and hair of smokers. It is known that 88M US nonsmokers ≥3 years old living in homes of smokers are exposed to THS toxicants and show blood cotinine levels of ≥0.05 ng/ml, indicating that the toxins are circulating in their circulatory systems. The goal of the present study is to investigate the mechanisms by which THS causes impaired wound healing. We show that mice living under conditions that mimic THS exposure in humans display delayed wound closure, impaired collagen deposition, altered inflammatory response, decreased angiogenesis, microvessels with fibrin cuffs and a highly proteolytic wound environment. Moreover, THS-exposed mouse wounds have high levels of oxidative stress and significantly lower levels of antioxidant activity leading to molecular damage, including protein nitration, lipid peroxidation and DNA damage that contribute to tissue dysfunction. Furthermore, we show that elastase is elevated, suggesting that elastin is degraded and the plasticity of the wound tissue is decreased. Taken together, our results lead us to conclude that THS toxicants delay and impair wound healing by disrupting the sequential processes that lead to normal healing. In addition, the lack of elastin results in loss of wound plasticity, which may be responsible for reopening of wounds.
Subject(s)
Nicotiana/adverse effects , Tobacco Smoke Pollution/adverse effects , Wound Healing , Animals , Capillary Permeability , Chemokines/biosynthesis , Collagen/metabolism , Mice , Mice, Inbred C57BL , Neovascularization, Physiologic , Oxidative Stress , Tissue Inhibitor of Metalloproteinase-1/analysisABSTRACT
Thirdhand smoke (THS) is defined as residual tobacco components that remain on indoor surfaces after tobacco has been smoked, such as walls furniture, and dust particles, which are re-emitted into the air. THS also includes secondary pollutants generated from the reaction of surface residual smoke compounds with reactive indoor air pollutants. THS is a new hidden health hazard, with infants and children being most at risk of higher exposure. This article summarized the aging process of secondhand smoke and the mechanism of generation of THS; reviewed the current status of research on THS regarding its chemical constituents, physical and chemical properties, biological toxicity, as well as degree of pollution in China and other countries; and finally provided the perspectives on the future study of THS.
Subject(s)
Air Pollution, Indoor , Environmental Exposure , Tobacco Smoke Pollution , Adolescent , Child , Child, Preschool , China , Dust , Humans , Infant , Infant, Newborn , Research , SmokeABSTRACT
OBJECTIVE: To investigate thirdhand smoke (THS) pollution in certain places of Nanjing, as well as to analyze its distribution characteristics. METHODS: From March to May, 2014, we selected 3 types of places (residencies, public places and transportation vehicles) that were close to people's living in Jianye,Yuhua,Jiangning,Xuanwu,Gulou and Pukou districts of Nanjing city.For each of the above 3 types of places, 2-3 smoking and non-smoking (smoking ban) locations were investigated, totally 51 locations, 9-10 samples were collected each location, totally 477 samples. The surface wipe sampling method in conjunction with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized to quantify the levels of nicotine that served as the tracer of THS pollution.One-way ANOVA and t-tests were employed to compare the levels of nicotine collected at different places and locations. RESULTS: Totally 477 samples were collected in this study, of which 27.0% was from residencies (129/477), 61.0% (291/477) from public places and 11.9% (57/477) from transportations. The levels of indoor surface nicotine in smoking residences, public places and transportations were (214 ± 55),(1 408 ± 177) and (1 511 ± 785) µg/m(2), respectively, which were all higher than those in the corresponding non-smoking places ((23 ± 9),(62 ± 11), and (46 ± 15) µg/m(2); t values were 13.79, 13.15, 3.45, respectively. P values were <0.001, <0.001 and 0.006, respectively).In the smoking places, the levels of surface nicotine on walls, desks, sofas, cabinets, door backsides and air conditioning openings were (171 ± 62),(232 ± 38),(373 ± 151),(903 ± 239), (978 ± 212), (1 721 ± 517) µg/m(2) (F = 7.06, P = 0.009).In the smoking condition, the levels of surface nicotine collected from public places were higher (F = 9.25, P = 0.024), while under non-smoking (smoking ban) conditions, the levels of surface nicotine collected from residences were lower (F = 7.88, P < 0.001). CONCLUSION: THS pollution was widespread in public places, residences and transportations in Nanjing city, which was more serious in the smoking environments than non-smoking (smoking ban) environments; the contamination was less serious in non-smoking (smoking ban) private residences; in the smoking condition, the levels of surface nicotine were relatively high at locations close to air conditioning openings, door backsides and cabinets.
Subject(s)
Housing , Public Facilities , Tobacco Smoke Pollution , Air Conditioning , China , Humans , Nicotine , Smoking , Tandem Mass Spectrometry , TransportationABSTRACT
STUDY QUESTION: Do genetic variants in known canonical pathways that have been widely suggested to affect spermatogenesis confer susceptibility to non-obstructive azoospermia (NOA)? SUMMARY ANSWER: Rs1406714 in CHD2, rs2126986 in GNAO1 and rs7226979 in BCL2 were associated with NOA in Han Chinese men at a significant level after multiple testing corrections. WHAT IS KNOWN ALREADY: Previous genome-wide association studies (GWASs) have identified three loci for NOA, whereas less attention has been given to those markers that did not exceed the genome-wide significance threshold. STUDY DESIGN, SIZE, DURATION: We conducted a two-stage association study containing 1653 NOA cases and 2329 controls to investigate the susceptibility markers for NOA. PARTICIPANTS/MATERIALS, SETTING, METHODS: Imputation and pathway-based approaches can be applied to identify additional causal makers with small effects on NOA. We performed a candidate pathway-based association study using imputed-genotyping data for 24 238 single nucleotide polymorphisms estimated from NOA GWAS. Remarkably, 40 markers were associated with NOA in both imputation analysis and NOA GWAS (Stage 1) after linkage disequilibrium analysis and selected for validation (Stage 2) in another population. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the literature, genes from 11 biological pathways known or hypothesized to be important in spermatogenesis were selected. Combined analysis using directly genotyped data for Stages 1 and 2 revealed that rs1406714 in CHD2 was associated with decreased risk of NOA [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68-0.89, Pmeta = 1.7E-04], whereas rs2126986 in GNAO1 and rs7226979 in BCL2 were both risk makers for NOA (rs2126986: OR = 1.28, 95% CI = 1.15-1.41, Pmeta = 2.3E-06; rs7226979: OR = 1.21, 95% CI = 1.11-1.33, Pmeta = 4.5E-05). LIMITATIONS, REASONS FOR CAUTION: Our analysis of genes in the pathways studied was not exhaustive. WIDER IMPLICATIONS OF THE FINDINGS: Our study opens new avenues for the identification of other novel causal markers that are related to NOA. It will also provide a new paradigm for understanding the etiology of male infertility and contribute to the development of targeted therapies.
Subject(s)
Azoospermia/genetics , DNA-Binding Proteins/genetics , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Genome-Wide Association Study , Genotype , Humans , Male , Polymorphism, Single NucleotideABSTRACT
Phytoestrogens are plant-derived compounds that may interact with estrogen receptors and mimic estrogenic effects. It remains unclear whether the individual variability in metabolizing phytoestrogens contributes to phytoestrogens-induced beneficial or detrimental effects. Our aim was to determine whether there is any interaction between metabolic rates (MR) of phytoestrogens and genetic polymorphisms in related xenobiotic metabolizing enzyme genes. MR was used to assess phytoestrogen exposure and individual metabolic ability. The amount of phytoestrogens in urine was measured by ultra-high performance liquid chromatography-tandem mass spectrometry in 600 idiopathic infertile male patients and 401 controls. Polymorphisms were genotyped using the SNPstream platform combined with the Taqman method. Prototypes and metabolites of secoisolariciresinol (SEC) have inverse effects on male reproduction. It was found that low MR of SEC increased the risk of male infertility (OR 2.49, 95 % CI 1.78, 3.48, P trend = 8.00 × 10(-8)). Novel interactions were also observed between the MR of SEC and rs1042389 in CYP2B6, rs1048943 in CYP1A1, and rs1799931 in NAT2 on male infertility (P inter = 1.06 × 10(-4), 1.14 × 10(-3), 3.55 × 10(-3), respectively). By analyzing the relationships between urinary phytoestrogen concentrations, their metabolites and male infertility, we found that individual variability in metabolizing SEC contributed to the interpersonal differences in SEC's effects on male reproduction.
Subject(s)
Arylamine N-Acetyltransferase/genetics , Butylene Glycols/urine , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP2B6/genetics , Infertility, Male/metabolism , Lignans/urine , Phytoestrogens/urine , Polymorphism, Single Nucleotide , Adult , Asian People/genetics , Biotransformation , Butylene Glycols/adverse effects , Butylene Glycols/metabolism , Case-Control Studies , Humans , Infertility, Male/chemically induced , Infertility, Male/enzymology , Infertility, Male/urine , Lignans/adverse effects , Lignans/metabolism , Male , Phytoestrogens/adverse effects , Phytoestrogens/metabolism , Young AdultABSTRACT
Solid fuels are widely used in China and increase the concentrations of indoor air pollutants. Nevertheless, there is limited longitudinal evidence linking solid fuel use and Gastrointestinal (GI) and liver diseases. This study aimed to prospectively investigate the association between household solid fuel use and the risk of GI and liver diseases in middle aged and elderly adults. This work was based on the China Health and Retirement Longitudinal Study (CHARLS). Longitudinal data incorporate with cross-sectional data were analyzed. Compared with individuals using clean fuel for cooking, solid fuel users were observed to have higher risk of GI diseases (OR in 2011, 2013, 2015, 2018 wave separately: 1.37, 95 % CI: 1.24-1.50, P < 0.001; 1.24, 95 % CI: 1.11-1.39, P < 0.001; 1.18, 95 % CI: 1.06-1.33, P < 0.001; 1.23, 95 % CI: 1.04-1.45, P < 0.05). The associations between solid fuel use and liver diseases were not significant in most of the groups. Participants transforming from solid to clean cooking fuels had lower risk of GI and liver diseases than persistent solid fuel users. Moreover, biomass cooking fuel users were at a significant higher risk of both liver and GI diseases compared with clean fuel users. Overall, household solid fuel use, especially for cooking, was related to higher risk of GI and liver diseases, while switching from solid to clean fuels could reduce this risk. Using biomass for cooking was identified to be more associated with the increasing risk of GI and liver diseases than cooking with coal.
Subject(s)
Air Pollution, Indoor , Cooking , Gastrointestinal Diseases , Liver Diseases , Humans , Air Pollution, Indoor/statistics & numerical data , Air Pollution, Indoor/analysis , Middle Aged , Aged , Male , Female , China/epidemiology , Liver Diseases/epidemiology , Gastrointestinal Diseases/epidemiology , Longitudinal Studies , Cross-Sectional Studies , Coal , Air Pollutants/analysisABSTRACT
Obtaining clean energy is of prime importance for planetary health and sustainable development. We aimed to assess the association between residential energy transition and the risk of chronic respiratory diseases. Using data from the Global Health Observatory and Global Burden of Diseases, Injuries, and Risk Factors Study, we delineated the spatial distribution and temporal trends of the population using clean fuels for cooking at a global scale. In the China Health and Retirement Longitudinal Study, we performed rigorous and well-structured multistage analyses incorporating both cross-sectional and prospective data analyses to examine the associations between solid fuel use, residential energy transition, duration of solid fuel use, and the risk of chronic respiratory diseases. Despite great progress, huge disparities in access to clean energy persist globally. Residential energy transition was associated with a lower risk of chronic respiratory diseases. In the period of 2011-2013, compared with persistent solid fuel users, both participants who switched from solid to clean fuels (adjusted risk ratio [RR] 0.78, 95% confidence interval [CI] 0.62-0.98) and persistent clean fuel users (adjusted RR 0.71, 95% CI 0.57-0.89) had significantly lower risk of chronic respiratory diseases (p < 0.001 for trend). Consistent associations were observed in the period of 2011-2015 and 2011-2018. Household energy transition from solid to clean fuels could reduce the risk of chronic respiratory diseases. This is a valuable lesson for policy-makers and the general public to accelerate energy switching to alleviate the burden of chronic respiratory diseases and achieve health benefits, particularly in low- and middle-income countries.
ABSTRACT
Background: Intervertebral disc degeneration (IVDD) is the main cause of low back pain (LBP), but the specific regulatory factors, pathways and specific molecular mechanisms remain unclear. Methods: We identified and quantitatively analyzed Pfirrmann Grade II (n=3) and Pfirrmann Grade IV (n=3) pulposus samples via MRI. The differential abundance of proteins in the samples was determined and quantitatively analyzed by relative and absolute quantitative analysis of the isotope marker levels combined with the liquid chromatography-tandem mass spectrometry (LCâMSMS/MS). Results: A total of 70 proteins (30 significantly increased proteins (> 1.2-fold change) and 40 significantly decreased proteins (< 0.8-fold change)) showed different levels among the groups. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO) enrichment analyses and Western blot analysis showed that CYCS, RAC1, and PSMD14 may play important roles in IVDD and that EpsteinâBarr virus infection, viral myocarditis, colorectal cancer, nonalcoholic fatty liver disease (NAFLD) and amyotrophic lateral sclerosis (ALS) are the main pathways involved in IVDD. Conclusion: CYCS, RAC1 and PSMD14 may play important roles in IVDD, and EpsteinâBarr virus infection, viral myocarditis, colorectal cancer, NAFLD and ALS may be the main pathways involved in IVDD.