The effect of ambient ozone exposure on three types of diabetes: a meta-analysis.

BACKGROUND: Ozone as an air pollutant is gradually becoming a threat to people's health. However, the effect of ozone exposure on risk of developing diabetes, a fast-growing global metabolic disease, remains controversial. OBJECTIVE: To evaluate the impact of ambient ozone exposure on the incidence rate of type 1, type 2 and gestational diabetes mellitus. METHOD: We systematically searched PubMed, Web of Science, and Cochrane Library databases before July 9, 2022, to determine relevant literature. Data were extracted after quality evaluation according to the Newcastle Ottawa Scale (NOS) and the agency for healthcare research and quality (AHRQ) standards, and a meta-analysis was used to evaluate the correlation between ozone exposure and type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2D), and gestational diabetes mellitus (GDM). The heterogeneity test, sensitivity analysis, and publication bias were performed using Stata 16.0. RESULTS: Our search identified 667 studies from three databases, 19 of which were included in our analysis after removing duplicate and ineligible studies. Among the remaining studies, three were on T1D, five were on T2D, and eleven were on GDM. The result showed that ozone exposure was positively correlated with T2D [effect size (ES) = 1.06, 95% CI: 1.02, 1.11] and GDM [pooled odds ratio (OR) = 1.01, 95% CI: 1.00, 1.03]. Subgroup analysis demonstrated that ozone exposure in the first trimester of pregnancy might raise the risk of GDM. However, no significant association was observed between ozone exposure and T1D. CONCLUSION: Long-term exposure to ozone may increase the risk of T2D, and daily ozone exposure during pregnancy was a hazard factor for developing GDM. Decreasing ambient ozone pollution may reduce the burden of both diseases.

Policy-relevant differences between secondhand and thirdhand smoke: strengthening protections from involuntary exposure to tobacco smoke pollutants.

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.

Thirdhand Exposures to Tobacco-Specific Nitrosamines through Inhalation, Dust Ingestion, Dermal Uptake, and Epidermal Chemistry.

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.

ViaChip for Size-based Enrichment of Viable Cells.

Live cells acquire different fates including apoptosis, necrosis, and senescence in response to stress and stimuli. Rapid and label-free enrichment of live cells from a mixture of cells adopting various cell fates remains a challenge. We developed a ViaChip for high-throughput enrichment of Viable cells via size-based separation on a multi-stage microfluidic Chip. Our chip takes advantage of the characteristic increase in cell size during cellular senescence and decreases during apoptosis and necrosis, in comparison to their viable and healthy counterparts. The core component of our ViaChip is a slanted and tunable 3D filter array in the vertical direction (z-gap) for rapid and continuous cell sieving. The shape of the 3D filter array is optimized for target cells to prevent clogging during continuous separation. We demonstrated enrichment of live human and mouse mesenchymal stem cells in culture and from live animals, as well as the removal of senescent and necrotic MSCs, respectively, achieving an enrichment efficiency of ~67% with the continuous flow at 1.5 mL/hour. With further improvements in throughput and separation efficiency, our ViaChip could find applications in cell-based drug screening for anti-cancer and anti-aging cell therapies.

Human X chromosome exome sequencing identifies BCORL1 as contributor to spermatogenesis.

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.

Chemical mixture exposure patterns and obesity among U.S. adults in NHANES 2005-2012.

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.

In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.

Host genetics and gut microbiota cooperatively contribute to azoxymethane-induced acute toxicity in Collaborative Cross mice.

Azoxymethane (AOM) is a widely used carcinogen to study chemical-induced colorectal carcinogenesis and is an agent for studying fulminant hepatic failure. The inter-strain susceptibility to acute toxicity by AOM has been reported, but its association with host genetics or gut microbiota remains largely unexplored. Here a cohort of genetically diverse Collaborative Cross (CC) mice was used to assess the contribution of host genetics and the gut microbiome to AOM-induced acute toxicity. We observed variation in AOM-induced acute liver failure across CC strains. Quantitative trait loci (QTL) analysis revealed three chromosome regions significantly associated with AOM toxicity. Genes located within these QTL, including peroxisome proliferator-activated receptor alpha (Ppara), were enriched for enzyme activator and nucleoside-triphosphatase regulator activity. We further demonstrated that the protein level of PPARα in liver tissues from sensitive strains was remarkably lower compared to levels in resistant strains, consistent with protective role of PPAR family in liver injury. We discovered that the abundance levels of gut microbial families Anaeroplasmataceae, Ruminococcaceae, Lactobacillaceae, Akkermansiaceae and Clostridiaceae were significantly higher in the sensitive strains compared to the resistant strains. Using a random forest classifier method, we determined that the relative abundance levels of these microbial families predicted AOM toxicity with the area under the receiver-operating curve (AUC) of 0.75. Combining the three genetic loci and five microbial families increased the predictive accuracy of AOM toxicity (AUC of 0.99). Moreover, we found that Ruminococcaceae and Lactobacillaceae acted as mediators between host genetics and AOM toxicity. In conclusion, this study shows that host genetics and specific microbiome members play a critical role in AOM-induced acute toxicity, which provides a framework for analysis of the health effects from environmental toxicants.

Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis.

OBJECTIVE: The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. DESIGN: We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. RESULTS: CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. CONCLUSIONS: CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

No difference in 4-nitroquinoline induced tumorigenesis between germ-free and colonized mice.

Variations in oral bacterial communities have been linked to oral cancer suggesting that the oral microbiome is an etiological factor that can influence oral cancer development. The 4-nitroquinoline 1-oxide (4-NQO)-induced murine oral and esophageal cancer model is frequently used to assess the effects of preventive and/or therapeutic agents. We used this model to assess the impact of the microbiome on tumorigenesis using axenic (germ-free) and conventionally housed mice. Increased toxicity was observed in germ-free mice, however, no difference in tumor incidence, multiplicity, and size was observed. Transcriptional profiling of liver tissue from germ-free and conventionally housed mice identified 254 differentially expressed genes including ten cytochrome p450 enzymes, the largest family of phase-1 drug metabolizing enzymes in the liver. Gene ontology revealed that differentially expressed genes were enriched for liver steatosis, inflammation, and oxidative stress in livers of germ-free mice. Our observations emphasize the importance of the microbiome in mediating chemical toxicity at least in part by altering host gene expression. Studies on the role of the microbiome in chemical-induced cancer using germ-free animal models should consider the potential difference in dose due to the microbiome-mediated changes in host metabolizing capacity, which might influence the ability to draw conclusions especially for tumor induction models that are dose dependent.

Genetic Susceptibility to Thirdhand-Smoke-Induced Lung Cancer Development.

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.

Short-term early exposure to thirdhand cigarette smoke increases lung cancer incidence in mice.

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.

Adverse Health Effects of Thirdhand Smoke: From Cell to Animal Models.

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.

Residential energy transition and chronic respiratory diseases.

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.

Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients.

BACKGROUND: The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM. AIM: To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. METHODS: A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. RESULTS: Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. CONCLUSION: This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.

Genetic and microbial determinants of azoxymethane-induced colorectal tumor susceptibility in Collaborative Cross mice and their implication in human cancer.

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.

A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice.

BACKGROUND: Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis. METHODS: 732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice. FINDINGS: Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment. INTERPRETATION: Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC. FUNDING: The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the "European Union Next Generation EU/PRTR," the Regional Government of Castile and León (CSI144P20), European Union.

Long-term, non-invasive FTIR detection of low-dose ionizing radiation exposure.

Non-invasive methods of detecting radiation exposure show promise to improve upon current approaches to biological dosimetry in ease, speed, and accuracy. Here we developed a pipeline that employs Fourier transform infrared (FTIR) spectroscopy in the mid-infrared spectrum to identify a signature of low dose ionizing radiation exposure in mouse ear pinnae over time. Mice exposed to 0.1 to 2 Gy total body irradiation were repeatedly measured by FTIR at the stratum corneum of the ear pinnae. We found significant discriminative power for all doses and time-points out to 90 days after exposure. Classification accuracy was maximized when testing 14 days after exposure (specificity > 0.9 with a sensitivity threshold of 0.9) and dropped by roughly 30% sensitivity at 90 days. Infrared frequencies point towards biological changes in DNA conformation, lipid oxidation and accumulation and shifts in protein secondary structure. Since only hundreds of samples were used to learn the highly discriminative signature, developing human-relevant diagnostic capabilities is likely feasible and this non-invasive procedure points toward rapid, non-invasive, and reagent-free biodosimetry applications at population scales.

Effect of Husbandry Practices on the Fecal Microbiota of C57BL/6J Breeding Colonies Housed in 2 Different Barrier Facilities in the Same Institution.

Evidence showing a relationship between the mouse gut microbiome and properties such as phenotype and reaction to therapeutic agents and other treatments has increased significantly over the past 20 to 30 y. Recent concerns regarding the reproducibility of animal experiments have underscored the importance of understanding this relationship and how differences in husbandry practices can affect the gut microbiome. The current study focuses on effects of different barrier practices in 2 barrier facilities at the same institution on the fecal microbiome of breeding C57Bl/6J mice. Ten female and 10 male C57Bl/6J mice were obtained in one shipment from Jackson Laboratories and were housed under different barrier conditions upon arrival. Fecal samples were collected on arrival and periodically thereafter and were sent to TransnetYX for microbiome analysis. Mice used for collection of feces were housed as breeding pairs, with a total of 5 breeding pairs per barrier. An additional fecal sample was collected from these mice at 8 wk after arrival. One F1 female and one F1 male from each breeding cage were housed as brother-sister breeding pairs and a fecal sample was collected from them at 8 wk of age. Brother-sister breeding colonies were continued through F3, with fecal samples for microbiome analysis were collected from each generation at 8 wk of age. Breeding colonies in the 2 barriers showed differences in relative abundance, α -diversity, and ß -diversity. Our data indicate that differences in barrier husbandry practices, including the use of autoclaved cages, the degree of restricted access, feed treatment practices, and water provision practices, can affect fecal microbiome divergence in both the parental and filial generations of different breeding colonies. To our knowledge, this is the first study to examine the effect of barrier husbandry practices on the microbiome of breeding colonies through the F3 generation.

Maternal exposure to pesticides and autism or attention-deficit/hyperactivity disorders in offspring: A meta-analysis.

OBJECTIVE: To analyze the association between maternal pesticide exposure and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorders (ADHD) in offspring. METHOD: Five databases including PubMed, Embase, Web of Science, Medline, as well as PsycINFO were systematically retrieved for the records related to pesticide exposure during pregnancy and ASD and ADHD in offspring before August 30, 2022. The pesticide category, maternal age and window of exposure as the main subgroups were presented. RESULTS: 949 studies were initially identified, and 19 studies were eventually included. Eleven were on ASD, seven were on ADHD, and one was on both disorders. Maternal pesticide exposure was positively related to ASD (pooled OR = 1.19 (95%CI: 1.04 to 1.36)) and ADHD (pooled OR = 1.20 (95%CI: 1.04 to 1.38)) in offspring. In the subgroup analysis, organophosphorus pesticides (OPs) (pooled OR = 1.14 (95%CI: 1.04 to 1.24)), pyrethroid (pooled OR = 1.40 (95%CI: 1.09 to 1.80)), and maternal age ≥30 years old (pooled OR = 1.24 (95%CI: 1.10 to 1.40)) increased the risk of ASD in offspring. Maternal organochlorine pesticides (OCPs) exposure was a risk factor for ADHD in offspring (pooled OR = 1.22 (95%CI: 1.03 to 1.45)). CONCLUSION: Maternal pesticide exposure increased the risk of ASD and ADHD in offspring. Moreover, OPs, pyrethroid, and maternal age ≥30 years old were found to be risk factors affecting children's ASD. Maternal exposure to OCPs increased the risk of ADHD in offspring. Our findings contribute to our understanding of health risks related to maternal pesticide exposure and indicate that the in utero developmental period is a vulnerable window-of-susceptibility for ASD and ADHD risk in offspring. These findings should guide policies that limit maternal exposure to pesticides, especially for pregnant women living in agricultural areas.