Human Epidemiological Studies Research Articles

The potential carcinogenicity of orthopaedic implants – a scoping review

BackgroundEvery year, hundreds of thousands of patients receive an orthopaedic or dental implant containing metals such as cobalt, chromium and titanium. Since the European Chemicals Agency (2020) classified pure cobalt metal as a Category 1B carcinogen, manufacturers of products containing ≥ 0.1% of this metal must perform a risk assessment and justify that there are no viable alternatives. The up-classification of cobalt metal to a carcinogen without good evidence that its use in implants is carcinogenic may cause unnecessary concern to the many patients who have, or may require such implants. Although in vitro and animal studies have shown such metals to be carcinogenic, human epidemiological studies have not been definitive. In addition, although many advances have been made in the past few decades with regard to the materials used in implant metals, no recent review of their carcinogenic effects have been published.MethodsThis scoping review aims to summarise epidemiological studies conducted in recent years (from 2010 to present) to outline the carcinogenic effects of orthopaedic metal implants that have been published. This encompasses implants of different materials and surfaces, including metal, polyethylene and ceramic orthopaedic implants, cemented and cementless joint replacement surgeries, and surgical techniques such as resurfacing and total joint replacements that are currently in use and the potential carcinogenicity related to their use. Research papers with various study designs published in the English language were included. Studies were excluded if participants had a prior history of cancer before receiving orthopaedic implants and if they focused solely on the carcinogenicity of metals or materials not related to orthopaedic implants.ResultsA total of 16 studies, encompassing over 700,000 implant patients, were identified through PubMed and have been included in this review. In long term follow-up of up to 17.9 years, no increased risk of all-site cancer was seen in these patients. However, an increase in site-specific cancers, namely prostate, melanoma and haematological cancers have been identified. Specifically, an increase in prostate cancer was identified in three studies.ConclusionBased on the summarised evidence, there is no consistent evidence to show that patients with any type of orthopaedic implant has an increased risk of cancer, although slight (non-statistically significant) increases in prostate cancer was observed and this, in particular, deserves longer-term surveillance.

Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles.

Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and neurodevelopmental disorders. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams chronically to vehicle or low-dose deltamethrin (3 mg/kg/3 days) with or without high-dose folate supplementation (methylfolate, 5 mg/kg/3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to neurodevelopmental disorders (including the social domain); increased plasma folate concentrations; and increased neural expression of SHMT1, a folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotypes (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two folate-related proteins. We conclude that DPE causes neurodevelopmental disorder-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.

Occupational Benzene Exposure and Lung Cancer in Human Studies: A Systematic Review and Meta-Analysis.

Benzene is classified as carcinogenic to humans based on evidence that benzene causes acute myeloid leukemia. However, there is limited evidence that benzene causes lung cancer. We performed a systematic review, quality assessment, and meta-analysis of published cohort and case-control studies on the association between occupational benzene exposure and lung cancer risk. We reviewed the relevant human epidemiological studies from PubMed and Embase databases to 19 August 2024. Data extraction included study characteristics, effect estimates, and exposure assessment details. Two investigators independently evaluated study quality using the Newcastle-Ottawa scale (NOS) framework and exposure assessment quality based on a priori criteria. Six risk of bias (ROB) domains were constructed from the NOS criteria to identify and quantify possible biases and their impacts on parameter estimates. Meta-analysis relative risk (pooled RR) and associated confidence intervals were calculated using random-effects models, and a flexible exposure-response meta-regression was fitted to assess the shape of the association. Subgroup analyses were conducted to explore the consistency of results. Of 252 articles identified, 13 studies covering 366,975 participants (17,030 lung cancer cases) were included in our analysis. The meta-analysis of ever occupational benzene exposure showed an elevated risk of lung cancer (pooled ; 95% CI: 1.03, 1.27; ). Subgroup analyses revealed that larger pooled RRs in studies based on highly exposed groups had higher overall quality and better exposure assessments and included both males and females (as opposed to only males). A positive linear trend was observed in the exposure-response meta-analysis. Our meta-analysis supports an association between occupational benzene exposure and an increased risk of lung cancer. https://doi.org/10.1289/EHP15086.

Pancreatic ductal adenocarcinoma, β-blockers and antihistamines: A clinical trial is needed.

Survival in pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) at just 5 months is the worst of all cancers. It is predicted to become the second highest cause of cancer deaths worldwide this decade and unlike most cancers, there has been little progress in improving survival in PDAC. Numerous studies including molecular and mechanistic studies, cancer biology studies and retrospective human epidemiological studies suggest that two well-known, approved drug classes - β-blockers and H1-antihistamines - may be beneficial and thus may potentially prolong life in patients with PDAC. In our opinion, the body of evidence has reached a point where the potential gains outweigh the very low risks involved in a clinical study in PDAC. We thus believe that it is now time for a clinical trial involving these two agents in PDAC patients. As a repurposing of generic drugs, this is not likely to be appealing to pharmaceutical companies and therefore is likely to require governmental, philanthropic and /or charitable organisational input. In this article, we opine and propose that an urgent clinical trial is needed to determine if repurposing these two orally administered, inexpensive, largely safe drug classes, either alone or in combination, could prolong survival in PDAC and thus improve the outcome for the 10,000 people worldwide who die from PDAC each week.

Quantifying residents' exposure to agricultural pesticides using new geospatial approaches

A better understanding of environmental exposure to agricultural pesticides is crucial for public health, regulatory and management purposes. Residents in close vicinity to agricultural fields are likely to be more exposed to pesticides. In that context, an innovative geospatial approach for mapping estimates of agricultural pesticide exposure was developed in this study.Data on pesticide application rates, high-resolution annual datasets of the geographic distribution of crops, and the 100x100m grid population dataset were utilized to complete this analysis in Wallonia (Belgium) over the period 2015-2019. Pesticide exposure metrics were estimated using a buffer-based exposure model by conducting neighborhood analysis within a 1000m buffer radius. Subsequently, a population weighted method was used to ‘up-scale’ the exposure data to administrative levels. In a limited validation effort, model estimates were compared with pesticide measurements in air collected at 12 stations during the period 2015-2016.The results present the first modeling map of environmental exposure to agricultural pesticides for the whole of the Walloon region. The northern part of the Sambre-Meuse axis demonstrates more intensive agriculture and the highest pesticide weighted exposure indices. The majority of the population resides near agricultural areas, with only 4% living in regions that lack crops within a 1000m radius, primarily in the central areas of large cities. A positive trend association between pesticide measures in air and the index was observed at the different stations, nevertheless further validation efforts are needed to accurately compare the same active ingredients.This work gives a valuable basis for research and environmental health actions in Belgium. Maps highlight areas where human biomonitoring and epidemiological studies should be implemented to investigate the impact of potential environmental exposure to pesticides. This information helps policy-makers to take measures to control and reduce the load of agricultural pesticides in the environment.

First evidence of microplastic inhalation among free-ranging small cetaceans.

Plastic is a ubiquitous environmental contaminant, resulting in widespread exposure across terrestrial and marine spaces. In the environment, plastics can degrade into microparticles where exposure has been documented in a variety of fauna at all trophic levels. Human epidemiological studies have found relationships between inhaled microplastics and oxidative stress and inflammation. Previous studies of bottlenose dolphins (Tursiops truncatus) have reported prevalent exposure to plasticizing chemicals (e.g., phthalates) as well as particle loads in gastrointestinal tracts, but exposure from inhalation has not yet been studied. The objective of this study was to determine if inhalation is a viable route of microplastic exposure for free-ranging dolphins. Exhalation samples were opportunistically collected from dolphins residing in Sarasota Bay, Florida (n = 5) and Barataria Bay, Louisiana (n = 6) during catch-and-release health assessments to screen for microplastic particles. All dolphin samples contained at least one suspected microplastic particle, and polymer composition was determined for 100% of a subset (n = 17) of samples. Additional studies are warranted to better understand the extent of inhaled microplastics, as well as to explore impacts, given potential risks to lung function and health.

Natural products‐based antiangiogenic agents: New frontiers in cancer therapy

AbstractAngiogenesis, vital for tumor growth and metastasis, is a promising target in cancer therapy. Natural compounds offer potential as antiangiogenic agents with reduced toxicity. This review provides a comprehensive overview of natural product‐based antiangiogenic therapies, focusing on molecular mechanisms and therapeutic potential. A systematic search identified relevant articles from 2019 to 2023. Various natural compounds, including polyphenols, terpenes, alkaloids, cannabinoids, omega‐3 fatty acids, polysaccharides, proteins, and carotenoids, were investigated for their antiangiogenic properties. Challenges such as dose standardization, routes of administration, and potential side effects remain. Further studies, including in‐depth animal models and human epidemiological studies, must elucidate clinical efficacy and safety. Synergistic effects with current antiangiogenic therapies, such as bevacizumab and tyrosine kinase inhibitors, should be explored. Additionally, the potential hormone‐dependent effects of compounds like genistein highlight the need for safety evaluation. In conclusion, natural products hold promise as adjunctive therapies to conventional antineoplastic drugs in modulating angiogenesis in cancer. However, robust clinical trials are needed to validate preclinical findings and ensure safety and efficacy.

Confirmation of Di(2-ethylhexyl) phthalate-induced micronuclei by repeated dose liver micronucleus assay: focus on evaluation of liver micronucleus assay in young rats

BackgroundDi(2-ethylhexyl) phthalate (DEHP) is a plasticizer commonly used in a wide variety of products, including medical devices. It is rapidly metabolized in the liver into various metabolites upon absorption through oral ingestion, dermal absorption, and inhalation. DEHP is classified as a non-genotoxic hepatocarcinogen in rodents, as its chronic exposure has been associated with the development of liver cancer in these animals, but most genotoxicity studies have been negative. Epidemiologic studies in humans suggest that long-term high intakes of DEHP may be a risk factor for liver dysfunction.The repeated-dose liver micronucleus (RDLMN) assay is a well-established method for assessing chromosomal changes caused by hepatic genotoxins and/or carcinogens. It is particularly valuable for detecting substances that undergo metabolic activation, especially when the metabolite has a short half-life or does not reach the bone marrow effectively. Therefore, we investigated whether the RDLMN assay could detect DEHP-induced micronucleus formation in the liver following a 14 or 28-day treatment.ResultsWe report that the RDLMN assay demonstrated an increased frequency of hepatic micronuclei in rats exposed to DEHP for 14 or 28 days. The increases in micronuclei correlated with hepatomegaly, an established response to phthalates in the liver. Conversely, no such increases were observed in the micronucleus assay using bone marrow from these rats.ConclusionThe detection of DEHP-induced micronuclei by the RDLMN assay suggests that this assay could detect the potential genotoxicity and hepatocarcinogenicity of DEHP. It also demonstrated the utility of the RDLMN assay in identifying metabolically activated hepatic carcinogens.

O-075 Particulate matter (PM2.5 and PM10) exposure prior to oocyte collection is associated with decreased live birth rates in subsequent frozen embryo transfers

Abstract Study question Does exposure to particulate matter air pollution prior to oocyte collection (OPU) or frozen embryo transfer (FET) impact FET live birth rates? Summary answer Increasing PM10 and PM2.5 exposure prior to OPU is associated with decreased odds of live birth in subsequent FET, independent of the conditions at FET. What is known already Ambient air pollution is increasing, and exposure is associated with adverse reproductive health outcomes, including infertility, miscarriage, preterm birth and low birth weight. Animal studies have shown that air pollutants can impair spermatogenesis, oogenesis, ovarian reserve and embryogenesis. These findings are corroborated by human epidemiological studies. The impact of ambient air pollution on IVF outcomes is uncertain. Additionally, whether pollutants exert a greater impact during oocyte development or early pregnancy is uncertain. Therefore, studies of FETs offer an opportunity to delineate different phases of reproduction that may be adversely affected by pollution. Study design, size, duration A retrospective analysis of 3,657 FETs in a single Australian centre from January 2013 – December 2021. All FETs during the study period were included; data were collected from the clinic database. Air pollutant concentrations for each day during the study were obtained from the Governmental monitoring body, including SO2, CO, O3, NO2, PM10 and PM2.5. Evaluation of FETs allowed separation of environmental effects during oocyte development and during early pregnancy. Participants/materials, setting, methods Quartiles were created for pollutants averaged over 24 hours, 2 weeks, 4 weeks and 3 months prior to OPU and prior to FET. Multi-pollutant models were created to account for co-exposures and were adjusted for variables at the time of OPU and FET. Bonferroni correction was made to account for the 4 timepoints tested on each outcome. Linear trends were assessed for each model, and pairwise comparisons against the first quartile were performed. Main results and the role of chance Overall, air quality was excellent, with pollutant levels within published safe limits on > 99% of days during the study period. Increasing PM10 exposure in the 2 weeks prior to OPU was associated with decreased odds of livebirth (linear trend p = 0.009); the odds of livebirth decreased by 38% when PM10 concentrations were in the highest quartile compared with the lowest (OR 0.62, p = 0.010). Increasing PM2.5 exposure in the 3 months prior to OPU was also associated with decreased odds of livebirth (linear trend p = 0.011). No significant linear trends were observed between livebirths and other pollutants. The summer seasonal association with livebirth that we have previously demonstrated consistently held in the multi-pollutant models. No significant linear trends were observed between air pollutants and biochemical pregnancy, clinical pregnancy, miscarriage, gestation at birth or embryological outcomes. Limitations, reasons for caution The retrospective design is a limitation. Whilst corrections were made for multiple pollutant co-exposures, other environmental conditions, patient factors and repeated cycles, we were unable to account for all potential covariates. To reduce the risk of type 1 error due to the multiple timeframes, we utilised a Bonferroni correction. Wider implications of the findings Even when PM2.5 and PM10 exposures are within so-called “safe” ranges, increasing exposure in the weeks and months prior to OPU are associated with decreasing livebirth rates, independent of the conditions at the time of FET. Trial registration number 2022/ET000980

Scientific Committee guidance on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments.

EFSA requested its Scientific Committee to prepare a guidance document on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments. The guidance document provides an introduction to epidemiological studies and illustrates the typical biases, which may be present in different epidemiological study designs. It then describes key epidemiological concepts relevant for evidence appraisal. This includes brief explanations for measures of association, exposure assessment, statistical inference, systematic error and effect modification. The guidance then describes the concept of external validity and the principles of appraising epidemiological studies. The customisation of the study appraisal process is explained including tailoring of tools for assessing the risk of bias (RoB). Several examples of appraising experimental and observational studies using a RoB tool are annexed to the document to illustrate the application of the approach. The latter part of this guidance focuses on different steps of evidence integration, first within and then across different streams of evidence. With respect to risk characterisation, the guidance considers how evidence from human epidemiological studies can be used in dose-response modelling with several different options being presented. Finally, the guidance addresses the application of uncertainty factors in risk characterisation when using evidence from human epidemiological studies.

Development of a tool for rapid assessment of the evidence of human observational epidemiological studies with focus on risk of bias in the context of public health and risk assessment

Development of a tool for rapid assessment of the evidence of human observational epidemiological studies with focus on risk of bias in the context of public health and risk assessment

Better Together: Tandem Mass Spectrometry Achieves up to 50 Times Lower Quantification of 62 Disinfection Byproducts in Drinking Water.

Disinfection byproducts (DBPs) are ubiquitous contaminants present in nearly all drinking water and are associated with adverse health effects in human epidemiologic studies. The most toxic DBPs are unregulated and often occur at concentrations well below regulated DBPs; thus, quantification at low parts-per-trillion (ng/L) levels is critical in assessing exposure. We developed a new liquid-liquid extraction-gas chromatography-tandem mass spectrometry (LLE-GC-MS/MS) method with the first analysis by tandem gas chromatography-mass spectrometry of 23 priority unregulated DBPs including 13 haloacetamides, 3 haloacetic acids, 2 haloacetonitriles, 1 haloacetaldehyde, 2 haloketones, and 2 halonitromethanes. When combined with our previous GC-MS/MS method for haloacetic acids and previously reported MS/MS transitions that we optimized for this method, the analysis of 62 regulated and priority unregulated DBPs at lower quantification limits is achieved. Limits of quantification for most DBPs were between 5 and 30 ng/L with r2 > 0.99 and an average of 9 times lower limits of quantification (LOQs) compared to LLE-GC-MS using selected ion monitoring (SIM). Relative standard deviations ranged from 0.7 to 30% for 61 DBPs in spiked samples. This new method was validated using tap waters from four US cities, where individual DBP concentrations ranged from 5 to 126,882 ng/L. This project provides the most comprehensive GC-MS/MS method for DBP analysis to date and is capable of analyzing volatile and semivolatile DBPs across nine different compound classes, including a class not previously analyzed by GC-MS/MS.

#1141 Chronic kidney disease in inflammatory bowel disease: systematic review and meta-analysis

Abstract Background and Aims Chronic kidney disease (CKD) is defined by a reduction in kidney function (estimated glomerular filtration rate < 60 mL/min/1.73 m2) and/or damage markers that are present for at least three months, regardless of the underlying aetiology. Case reports and cohort studies suggest that inflammatory bowel disease (IBD is associated with CKD. The extent and magnitude of a potential association between IBD and CKD is currently unknown. Method A comprehensive search was conducted in EMBASE, MEDLINE, Web of Science, the Cochrane database, and SCOPUS. Two separate reviewers were involved in the process of article selection and evaluation. In studies where a comparison between an IBD population and a non-IBD control population was available, odds ratios were calculated to quantify the association. To derive an overall estimate of the effect, the Mantel–Haenszel test was employed, utilising a random effect model. This systematic was registered with Prospero. Results Fifty-four articles were included in the review (Table 1). Eight articles compared an IBD population with a healthy control population and were included in the meta-analysis, although with high heterogeneity (I2 88%). An increased risk of CKD in the IBD population was observed, with an overall odds ratio of 1.59 (95% CI 1.31-1.93) (Fig. 1). Importantly, this effect was independent of 5-aminosalicylic acid use. Data on other therapies was sparse, except for known nephrotoxic medication like tacrolimus and cyclosporine. Interestingly, several studies reported a decreasing relative risk with increasing age, potentially reflecting an increased baseline risk in this ageing population. Conclusion The existing evidence on CKD in IBD was systematically reviewed, including all human epidemiological studies. An increased CKD prevalence in IBD was found; independent of medication. Hence, we suggest regular measurements of kidney function for all patients with IBD, irrespective of the therapeutic regimen. Measurements should include determination of the baseline creatinine, albumin/creatinine ratio and urinary sediment. For patients having a normal baseline function, we would recommend annual follow-up. A more systematic research approach regarding CKD and IBD is warranted

Prenatal Vitamin B12 and Children's Brain Development and Cognitive, Language and Motor Outcomes: A Scoping Review.

Adequate maternal nutrient intake of vitamin B12 is critical to fetal brain development and subsequent neurodevelopmental outcomes. We conducted a scoping review to map the current state of knowledge from human epidemiological studies on the associations between maternal vitamin B12 during pregnancy and children's brain, cognitive, language, and motor development to identify gaps in the literature and suggest directions for future research. PubMed and OVID MEDLINE were searched. Search terms were vitamin B12, prenatal or maternal, neurodevelopment or cognitive development or brain. Animal studies were excluded. In total, 148 publications were identified, of which 19 met our inclusion criteria: (1) maternal vitamin B12 assessed via a measure of status, dietary intake, supplementation, or deficiency; and (2) an outcome related to brain development or cognitive, language, or motor development in children less than 18 years of age was assessed. This scoping review suggests that evidence supporting a relationship between maternal vitamin B12 during pregnancy and children's neurodevelopmental outcomes is inconclusive. Further longitudinal research is needed to clarify the effects of maternal vitamin B12 supplementation, status, and intake on children's brain development and neurodevelopmental outcomes.

Placental programming mediates the vicious cycle between maternal gestational diabetes and offspring type 2 diabetes in a novel mouse model

Accumulating evidence from human epidemiological studies indicates that there is a vicious cycle between maternal gestational diabetes (GDM) and offspring type 2 diabetes (T2D). However, the underlying mechanisms remain unclear. A handful of studies found that mitochondrial defects occur in the GDM placenta, including excess accumulation of destroyed mitochondria, reduced ATP and enhanced ROS production, which indicates that mitophagy, a specific process to remove destroyed mitochondria, may be impaired in the GDM placenta. Our recent study suggested that BNIP3 plays a critical role in maintaining mitochondria homeostasis in human trophoblast cells. Therefore, in this study, we hypothesized that conditional knockout of BNIP3 specifically in mouse trophoblast cells will recapitulate the typical symptoms of GDM in maternal pregnancy and T2D in offspring. First, we made male mice with double homozygous Cre and LoxP by breeding Cyp19-Cre and Bnip3-LoxP mice, which was used to mate females with homozygous LoxP, forming a cKO group. On the other hand, wild-type female mice were bred by males with homozygous Cre, forming a control group (CT). Second, offspring from cKO and CT mothers were allowed to grow up. On Day 18 of pregnancy, glucose tolerance test was conducted in pregnant cKO or CT mice. The placental tissues were collected and mRNA and protein levels of BNIP3 were measured by qPCR and Western blotting, respectively. In male offspring at the age of eight months, glucose tolerance test was conducted, and metabolic rate was measured by CaloBox Indirect Calorimetry. All numerical parameters between the cKO and CT pregnant mice, and between their male offspring were analyzed by ANOVA (n=5). The main findings include: 1) On Day 18 of pregnancy, BNIP3 mRNA and protein levels in the placental tissue were reduced by 47% and by 40% in cKO compared to CT mice (p<0.05), respectively (p<0.05); 2) Pregnant cKO mice demonstrated enhanced glucose intolerance compared to those control mice; 3) At the age of 8 months, the body weight of male offspring from cKO mothers was increased by 1.16-fold (p<0.05) compared to those from CT mothers; 4) Male offspring from cKO mothers demonstrated enhanced glucose intolerance compared to those from CT mothers; 5) The metabolic rates was lower in male offspring from cKO mothers compared to those from CT mothers, with decreased oxygen consumption and carbon dioxide production by 1.18- and 1.19-fold, respectively (p<0.05). These results suggest that placental programming possibly via the disrupted functions of BNIP3 in trophoblast cells mediates the occurrence of maternal GDM and offspring T2D, therefore, placental BNIP3 may play a critical role in the vicious cycle of maternal GDM and offspring T2D and thus, being a potential target in treatment of GDM and prevention of T2D. NIH research grants R03HD095417, U54MD007597. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The use of effect biomarkers in chemical mixtures risk assessment – Are they still important?

Human epidemiological studies with biomarkers of effect play an invaluable role in identifying health effects with chemical exposures and in disease prevention. Effect biomarkers that measure genetic damage are potent tools to address the carcinogenic and/or mutagenic potential of chemical exposures, increasing confidence in regulatory risk assessment decision-making processes. The micronucleus (MN) test is recognized as one of the most successful and reliable assays to assess genotoxic events, which are associated with exposures that may cause cancer. To move towards the next generation risk assessment is crucial to establish bridges between standard approaches, new approach methodologies (NAMs) and tools for increase the mechanistically-based biological plausibility in human studies, such as the adverse outcome pathways (AOPs) framework. This paper aims to highlight the still active role of MN as biomarker of effect in the evolution and applicability of new methods and approaches in human risk assessment, with the positive consequence, that the new methods provide a deeper knowledge of the mechanistically-based biology of these endpoints.

Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review).

The etiopathogenesis of type 1 diabetes mellitus (T1DM) is a complex multifactorial process that involves an intricate network of genetic, epigenetic, immunological, and environmental factors. Despite the advances in recent years, some aspects of the mechanisms involved in triggering the disease are still unclear. Infections with certain viruses have been suggested as possible environmental triggers for the autoimmune process that leads to selective and progressive destruction of pancreatic β-cells and insufficiency of insulin production, which is its hallmark. In this review, advances in knowledge and evidence that suggest the participation of certain viruses in the mechanisms of disease initiation and progression are described. It has been accepted that environmental factors, including viruses, can initiate and possibly sustain, accelerate, or slow down the autoimmune process and consequently damage insulin-producing pancreatic β-cells. Although the role of these agents, especially human enteroviruses, has been exhaustively studied as the most likely triggers of the activation of autoimmunity that destroys pancreatic islets and leads to T1DM, certain doubts remain. Clinical epidemiological and experimental studies in humans and animals provide consistent and increasing evidence that persistent viral infections, especially with human enteroviruses and rotavirus infections, are associated with an increased risk of the disease in individuals genetically predisposed to autoimmunity.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

Pathologists’ perspective on the study design, analysis, and interpretation of proliferative lesions in a lifetime rodent carcinogenicity bioassay of sucralose

Sucralose, a sugar substitute first approved for use in 1991, is a non-caloric sweetener regulated globally as a food additive. Based on numerous experimental animal studies (dating to the 1980s) and human epidemiology studies, international health agencies have determined that sucralose is safe when consumed as intended. A single lifetime rodent carcinogenicity bioassay conducted by the Ramazzini Institute (RI) reported that mice fed diets containing sucralose develop hematopoietic neoplasia, but controversy continues regarding the validity and relevance of these data for predicting health effects in humans. The present paper addresses the controversy by providing the perspective of experienced pathologists on sucralose-related animal toxicity and carcinogenicity data generally, and the RI carcinogenicity bioassay findings specifically, using results from publicly available papers and international regulatory authority decisions. In the authors’ view, flaws in the design, methodology, data evaluation, and reporting of the RI carcinogenicity bioassay for sucralose diminish the value of the data as evidence that this agent represents a carcinogenic hazard to humans. This limitation will remain until the RI bioassay is repeated under Good Laboratory Practices and the design, data, and accuracy of the pathology diagnoses and interpretations are reviewed by qualified pathologists with experience in evaluating potential chemically-induced carcinogenic hazards.

A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1

The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.