Low-level Exposure Research Articles

The Link Between Paraquat and Demyelination: A Review of Current Evidence

Paraquat (1,1′-dimethyl-4,4′-bipyridilium dichloride), a widely used bipyridinium herbicide, is known for inducing oxidative stress, leading to extensive cellular toxicity, particularly in the lungs, liver, kidneys, and central nervous system (CNS), and is implicated in fatal poisonings. Due to its biochemical similarities with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), paraquat has been used as a Parkinson’s disease model, although its broader neurotoxic effects suggest the participation of multiple mechanisms. Demyelinating diseases are conditions characterized by damage to the myelin sheath of neurons. They affect the CNS and peripheral nervous system (PNS), resulting in diverse clinical manifestations. In recent years, growing concerns have emerged about the impact of chronic, low-level exposure to herbicides on human health, particularly due to agricultural runoff contaminating drinking water sources and their presence in food. Studies indicate that paraquat may significantly impact myelinating cells, myelin-related gene expression, myelin structure, and cause neuroinflammation, potentially contributing to demyelination. Therefore, demyelination may represent another mechanism of neurotoxicity associated with paraquat, which requires further investigation. This manuscript reviews the potential association between paraquat and demyelination. Understanding this link is crucial for enhancing strategies to minimize exposure and preserve public health.

Interplay and long-lasting effects of maternal low-level Pb, Hg, and Cd exposures on offspring cognition

Lead (Pb), mercury (Hg), and cadmium (Cd) are prevalent and persistent environmental contaminants, causing detrimental effects on millions of individuals worldwide. Our previous research demonstrated that early-life exposure to low-level Pb, Hg, and Cd mixtures may lead to cognitive impairments. However, the association and interaction among low levels of Pb, Hg, or Cd exposure remains unclear. In this study, a two-level full factorial design (5.481, 0.036, and 2.132 mg/L for Pb, Hg, and Cd respectively) was conducted to assess the interplay among maternal Pb, Hg, and Cd exposure on offspring cognition. Following exposure during pregnancy and lactation, a competitive absorption among Pb, Hg, and Cd was observed. Maternal exposure to each metal alone resulted in higher blood and brain concentrations of Pb, Hg, and Cd in offspring compared to co-exposure at equivalent levels. However, behavioral experiments conducted in the Morris water maze and novel object recognition test revealed maternal Pb, Hg, and Cd exposure synergistically impaired offspring's spatial cognition and recognition memory. Importantly, this dysfunction persisted into middle age even without exposure after adulthood. Moreover, the open field test and elevated plus maze indicated maternal low-level Pb, Hg, and Cd co-exposure triggered risk-taking behavior in weaning offspring, with a significant main effect for Pb exposure. No long-lasting effect on risk-taking behavior was detected in middle-aged offspring. Further investigation into molecular mechanisms showed that the dysregulation of corticosterone reaction and immune response might be the potential mechanism underlying Pb, Hg, and Cd co-exposure-induced cognitive impairments. Our study highlights the synergistic and long-lasting effects of multiple heavy metal exposures,underscoring the urgency to prevent exposure to metal mixtures among children and women of childbearing age.

Functional brain network organization and multidomain resilience to neighborhood disadvantage in youth.

Though youth living in disadvantaged neighborhoods experience greater risk for poor behavioral and mental health outcomes, many go on to show resilience in the face of adversity. A few recent studies have identified neural markers of resilience in cognitive and affective brain networks, yet the broader network organization supporting resilience in youth remains unknown, particularly in relation to neighborhood disadvantage. Moreover, most studies have defined resilience as the absence of psychopathology, which does not consider growing evidence that resilience also includes positive outcomes across multiple domains (e.g., social, academic). We examined associations between brain network organization and multiple resilience domains in a sample of 708 twins (7-19 years old) recruited from neighborhoods with above-average poverty levels. Graph analysis on functional connectivity data from resting-state and task-based functional magnetic resonance imaging was used to characterize features of intrinsic whole-brain and network-level organization, from which we explored associations with resilience in three domains: psychological, social, and academic. Fewer connections between a brain network involved in self-referential processing (i.e., default mode network) and the subcortical system were associated with greater social resilience. Further, greater whole-brain functional integration (i.e., efficiency) was associated with better psychological resilience among youth with relatively lower levels of cumulative adversity exposure. Alternatively, lower whole-brain efficiency and higher whole-brain robustness to disruption (i.e., assortativity) were associated with greater psychological and social resilience among youth with relatively higher levels of cumulative adversity. These findings advance support for multidimensional resilience models and reveal distinct neural mechanisms supporting resilience to neighborhood disadvantage across specific domains in youth. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

You make me feel like dancing: the effects of dance exposure on children’s cultural interests and social-emotional development

Stratification by race and socioeconomic status generates disparities in cultural exposure and consumption. Though public education can serve as a mechanism for addressing social inequalities, schools with high concentrations of low-income and minority students often lack the resources to provide enriching cultural experiences. Efforts to make cultural exposure and consumption more equitable remain stymied by school and neighborhood stratification, as well as by lingering questions about the value of cultural consumption for students. Employing a randomized research design, we analyze the effects of elementary students in under-resourced school participating in a collaborative dance program provided by a major ballet company. We find that participation increases students’ enthusiasm for dance and sense of self-efficacy. Students with prior lower levels of arts and culture exposure demonstrate the largest gains in self-efficacy and experience an increase in their sense of school connectedness. Male students, who were less enthusiastic about dance prior to the program, show the largest increase in dance enthusiasm. These findings demonstrate that targeted efforts by schools and arts organizations can play a meaningful role in students’ cultural capital acquisition, which in turn leads to higher student self-efficacy and sense of belonging, particularly for students with lower levels of arts and cultural learning experience.

Association between residential greenness exposure and semen quality: A retrospective study in China

BackgroundThe association between greenness exposure and semen quality and the underlying mechanism are unclear. ObjectivesTo assess the association between greenness exposure and semen quality and whether the association is mediated by air pollutant exposure. MethodsWe collected data from 10,273 men in Zhejiang, China, whose wives received assisted reproductive technology from 2015 to 2021. The mean exposure concentrations of air pollutants and greenness indices (normalized difference vegetation index (NDVI) and the soil-adjusted vegetation index (SAVI)) in the 300 m, 400 m, 800 m, and 1000 m buffer zones were assessed from 0–90 days prior to semen testing on the basis of the patient’s residential address. A multivariate linear mixed-effects model was used to evaluate the associations, and mediation analysis was used to investigate the influences of air pollutant exposure and body mass index (BMI) on the associations. ResultsThe average (standard deviation) age of the participants was 33.1 (5.2) years. After adjusting for confounders, progressive motility was positively associated with the NDVI400m (β (95 % CI): 1.744 (0.834, 2.655)) and SAVI400m (β (95 % CI): 1.484 (0.591, 2.377)). Furthermore, we found that NO2 and CO exposure significantly mediated part of the association between greenness exposure and progressive motility. Similar results are observed in the sensitivity analysis. ConclusionsOur results suggest that greater greenness exposure is associated with higher semen quality and can be partially mediated by lower NO2 and CO exposure levels.

DNA Methylation Biomarkers for Cumulative Lead Exposures and Cognitive Impairment

BackgroundRecent evidence suggests that cumulative low-level lead exposure has adverse effects on cognitive function in the elderly. To date, the few studies that have measured bone lead exposure relied on K-X-ray fluorescence (KXRF), methods that are mostly unavailable in large community-based studies. Here, we employ a methylation-based estimation method for bone and blood lead in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. MethodsTibia, patella, and blood lead levels were estimated using blood DNA methylation (DNAm) biomarkers in 625 participants from the ADNI cohort. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Longitudinal analyses were conducted using linear mixed-effect regression models. Participants had different years of baseline (2010-2014) and follow-up visits (2014-2015). ResultsDNAm derived tibia and patella lead levels were negatively associated with MoCA scores throughout follow-up, while DNAm derived blood lead level was not associated with MoCA scores. On average, we observed lower MoCA scores with increasing DNAm tibia lead (per interquartile range (IQR): β=-0.23; 95%CI: -0.44, -0.03) and DNAm patella lead, albeit the latter was weaker (per IQR: β=-0.19; 95%CI: -0.41, 0.04). When stratifying by gender, women showed a stronger decrease in cognitive function with increasing DNAm tibia lead (per IQR β=-0.34; 95%CI: -0.65, -0.04) than men (per IQR β=-0.15; 95%CI: -0.42, 0.13). The estimated decrease in MoCA scores per DNAm tibia lead IQR increase was stronger among participants with one or two APOE4 alleles (per IQR β=-0.37; 95%CI: -0.74, -0.01) than those with zero alleles (per IQR β=-0.14; 95%CI: -0.38, 0.10). ConclusionThese findings strengthen the evidence that cumulative long-term lead exposures levels are associated with decreased cognitive function in the elderly, especially among women and carriers of one or two APOE4 alleles. These findings based on whole blood methylation data corroborate previous epidemiologic studies that used KXRF for measuring bone lead.

Health Risk Assessment of Ambient Air Benzene Among Primary School Children in Urban and Rural Areas in Johor, Malaysia

Introduction: It is a fact that children are vulnerable, and are at risk from benzene, a volatile, carcinogenic organic compound. The aim of our study is to determine the levels of ambient air benzene and examine the non-carcinogenic and carcinogenic risks involved Methods: A cross-sectional study was conducted in two urban and two rural primary schools in Johor, Malaysia. Benzene concentrations were measured using BUCK Libra L-4 pumps and analyzed in the gas chromatography-mass spectrometry (GC-MS). Data were collected from 334 10-12 year old children, to calculate the exposure levels based on their body weights and heights. The hazard quotient (HQ) served to evaluate the non-carcinogenic risks, whereas the lifetime cancer risk (LCR) was determined with the aid of the United States Environmental Protection Agency (USEPA). Results and Discussion: Benzene concentrations were higher in rural than urban areas, surpassing the European Union (EU) standard of 5 μg/m³. It was also established that the highest average levels recorded were 6.89 ± 6.68 μg/m³. The HQ values, nonetheless, had indicated no immediate non-carcinogenic risk, while LCR estimates were found to be within a tolerable range across all sites. Findings showed that although the immediate risk from benzene exposure is low, long-term exposure still poses a significant cancer risk to children; even low levels of chronic exposure can heighten the likelihood of children to develop cancers. Conclusion: This study has produced a revelation that there are elevated benzene levels in rural areas in Johor. Despite the low, immediate non-carcinogenic risks, further investigation on the potential for long-term cancer risks is warranted. These risks can be addressed by conducting stricter air quality monitoring, enhancing vehicle emission standards, and introducing educational programs that can raise awareness about benzene exposure.

Exposure to air pollutants and subclinical carotid atherosclerosis measured by magnetic resonance imaging: A cross-sectional analysis.

Long-term exposure to air pollution has been associated with higher risk of cardiovascular mortality. Less is known about the association of air pollution with initial development of cardiovascular disease. Herein, the association between low-level exposure to air pollutants and subclinical carotid atherosclerosis in adults without known clinical cardiovascular disease was investigated. Cross-sectional analysis within a prospective cohort study. The Canadian Alliance for Healthy Hearts and Minds Cohort Study; a pan-Canadian cohort of cohorts. Canadian adults (n = 6645) recruited between 2014-2018 from the provinces of British Columbia, Alberta, Ontario, Quebec, and Nova Scotia, were studied, for whom averages of exposures to nitrogen dioxide (NO2), ozone (O3), and fine particulate matter (PM2.5) were estimated for the years 2008-2012. Carotid vessel wall volume (CWV) measured by magnetic resonance imaging (MRI). In adjusted linear mixed models, PM2.5 was not consistently associated with CWV (per 5 μg/m3 PM2.5; adjusted estimate = -8.4 mm3; 95% Confidence Intervals (CI) -23.3 to 6.48; p = 0.27). A 5 ppb higher NO2 concentration was associated with 11.8 mm3 lower CWV (95% CI -16.2 to -7.31; p<0.0001). A 3 ppb increase in O3 was associated with 9.34 mm3 higher CWV (95% CI 4.75 to 13.92; p<0.0001). However, the coarse/insufficient O3 resolution (10 km) is a limitation. In a cohort of healthy Canadian adults there was no consistent association between PM2.5 or NO2 and increased CWV as a measure of subclinical atherosclerosis by MRI. The reasons for these inconsistent associations warrant further study.

Environmental burden of disease related to pyrethroid-insecticide exposure and neurodevelopmental toxicity in Europe based on human biomonitoring

Abstract As indicated by human biomonitoring (HBM) studies, exposure to pyrethroids is widespread in Europe with significantly higher exposure observed in children compared to adults. Epidemiological, toxicological, and mechanistic studies raise concerns about potential health effects in humans and, particularly, behavioral disorders such as attention deficit hyperactivity disorder (ADHD) in children at low levels of exposure. Based on an exposure-response function from a single European study and on available quality-assured and harmonized HBM data collected in France, Germany, Iceland, Switzerland, and Israel, an initial estimate of the environmental burden of disease for ADHD associated with pyrethroid exposure (measured by the metabolite 3-phenoxybenzoic acid) was made for individuals aged 0-19 years. The estimated yearly number of prevalence-based disability-adjusted life years (DALYs) per million inhabitants due to ADHD were 34 DALYs for Israel, 26 DALYs for France, 14 DALYs for both Switzerland and Iceland, and 4 DALYs for Germany. Additionally, a substantial number of ADHD cases, averaging 18%, were associated with pyrethroid exposure. Yet, these figures should be interpreted with caution given the uncertainty of some input parameter. In addition to burden of disease estimates due to ADHD, the associated burden of autism-spectrum disorder (ASD) due to pyrethroid exposure and the health economic costs attributable to ADHD and ASD will also be investigated further. To ensure adequate follow-up of policy measures and more robust disease burden estimates, more HBM studies are recommended, along with increased efforts to harmonize the design of epidemiological studies to ensure more meaningful meta-analyses of exposure-response functions. This is particularly important for pyrethroids as more evidence on potential adverse health effects is continuously emerging.

Missed opportunities of method information index plus (MII+) counseling among current modern contraceptive users. multi-level analysis from the Ethiopian PMA 2021 data set

IntroductionIn Ethiopia, there is a decrease in percentage of women who receive method information index counseling service from 39% (95%CI: 33%, 44%) in 2015 to 12% in 2019 (95% CI: 10%, 14%) nationally, and less than 40% of these services provided are high quality. Therefore, the aim of this study was to identify modern contraceptive users-related factors at individual level and community level associated with missed opportunities of method information index plus counseling.MethodsThis study used the datasets from the 2019 Performance Monitoring for Action Ethiopia Survey, which comprised a total of 8,365 households (98.9%) and 7,988 women (98.8%). The data analysis was done with Stata version 14. Using multilevel mixed effect logistics regression, both individual and community-level factors were found to be associated with missed opportunities of method information index plus counseling. a P-value of less than 0.05 was used to declare statistical significance. The association was presented using an adjusted odds ratio with a 95% confidence interval.ResultsThe study shows that the prevalence of missed opportunity MII + family planning counseling among current modern contraceptive users was 81% (79.15, 82.66) and factors significantly associated with missed opportunities of method information index plus counselling are educational status, low level of media exposure, religion, receiving the service in health centers and health posts, never heard of any other methods, number of children at first contraceptive use and region.ConclusionsIn Ethiopia 81% of women had a missed opportunities of MII + counseling service. In order to address this, we recommend policy makers to focus on training of health care workers and pharmacists about MII + counseling, and establishing ways to improve access to media exposure.

Occupational exposure to nickel or hexavalent chromium and the risk of lung cancer (SYNERGY)

Abstract Background Hexavalent chromium (Cr(VI)) and nickel (Ni) are known occupational carcinogens, with frequent exposures, for example, in welding-related activities. However, limited evidence exists on the exposure-response relationship of Cr(VI) or Ni with lung-cancer risk. We estimated lung-cancer risks based on quantitative indices of occupational exposure to each metal, and their interaction with smoking habits. Methods Fourteen case-control studies from Europe and Canada (16,901 cases, 20,965 control subjects) were pooled. A measurement-based job-exposure matrix was used to estimate year- and region-specific exposure levels for Cr(VI) and Ni, which were linked to the study subjects’ occupational histories. Odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for study, age group, smoking, and exposure to other occupational lung carcinogens. Results The OR for the highest quartile (&amp;gt;99.5 μg/m3-years) of cumulative exposure to Cr(VI) in men was 1.32 (95% CI 1.19-1.47) and for nickel (highest quartile &amp;gt;78.1 μg/m3-years) OR = 1.29 (95% CI 1.15-1.45). Corresponding effect estimates in women were slightly lower. The joint effects of Cr(VI) and nickel with smoking were generally greater than additive. Conclusions We observed positive exposure-response relationships in the low-dose range of Cr(VI) and Ni exposures, based on a large study population including detailed information on smoking habits and a measurement-based job-exposure matrix. Although, we cannot rule out a combined classical measurement and Berkson error structure that may have caused bias in our risk estimates, our results provide empirical evidence to further specify preventive measures at the workplace in order to protect workers from hazardous substances. Key messages • Relatively low cumulative levels of occupational exposure to Cr(VI) and Ni were associated with increased ORs for lung cancer, particularly in men. • Important empirical insights for the prevention of cancer at the workplace can be drawn from the results.

Blood pressure and renal function responses in workers exposed to lead for up to six years

Abstract Background Lead is a widespread environmental toxicant. However, there is currently no consensus whether low-level lead exposure raises blood pressure (BP) or induces kidney dysfunction. Purpose The Study for Promotion of Health in Recycling Lead (SPHERL) assessed the BP and renal function (RF) responses for up to six years in the workers without previous occupational lead exposure. Methods BP was the average of 5 consecutive readings and the estimated glomerular filtration rate was derived from serum creatinine (eGFRcrt) and cystatin C (eGFRcys). Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 mg/dL). The statistical methods included multivariable-adjusted mixed models and interval-censored Cox regression analysis. Results The 234 workers analyzed were on average 28.5 years old and included 91.9% men. The baseline BL concentration was 4.35 µg/dL and increased 3.17-fold over follow-up (median: 2.03 years; range: 0.92-6.45 years). The changes in BP and RF were not significantly correlated with the follow-up-to-baseline BL ratio (p≥0.51 and p≥0.18, respectively). The fully-adjusted changes in systolic/diastolic BP associated with a doubling of BL were -0.25/-0.12 mm Hg (CI: -0.94 to 0.44/-0.66 to 0.42 mm Hg). Accordingly, the incidence of stage-1 or -2 hypertension was not associated with the BL change (p≥0.063). Similarly, the changes in eGFRcrt and eGFRcys associated with a 3-fold BL increment were not significant, amounting to -0.70 mL/min/1.73 m2(CI: -1.70 to 0.30 mL/min/1.73 m2) and -1.06 ml/min/1.73 m2 (-2.16 to 0.03 mL/min/1.73 m2). Conclusion The BP and RF responses to an over 3-fold BL increment were small and not significant confirming the safety of modern lead-handing facilities operating under current safety rules.Figure 1Figure 2

A preliminary estimate of the environmental burden of disease associated with exposure to pyrethroid insecticides and ADHD in Europe based on human biomonitoring

Human biomonitoring (HBM) data indicate that exposure to pyrethroids is widespread in Europe, with significantly higher exposure observed in children compared to adults. Epidemiological, toxicological, and mechanistic studies raise concerns for potential human health effects, particularly, behavioral effects such as attention deficit hyperactivity disorder (ADHD) in children at low levels of exposure. Based on an exposure-response function from a single European study and on available quality-assured and harmonized HBM data collected in France, Germany, Iceland, Switzerland, and Israel, a preliminary estimate of the environmental burden of disease for ADHD associated with pyrethroid exposure was made for individuals aged 0–19 years. The estimated annual number of prevalence-based disability-adjusted life years (DALYs) per million inhabitants were 27 DALYs for Israel, 21 DALYs for France, 12 DALYs for both Switzerland and Iceland, and 3 DALYs for Germany; while the annual ADHD cases per million inhabitants attributable to pyrethroids were 2189 for Israel, 1710 for France, 969 for Iceland, 944 for Switzerland, and 209 for Germany. Direct health costs related to ADHD ranged between 0.3 and 2.5 million EUR yearly per million inhabitants for the five countries. Additionally, a substantial number of ADHD cases, on average 18%, were associated with pyrethroid exposure. Yet, these figures should be interpreted with caution given the uncertainty of the estimation. A sensitivity analysis showed that by applying a different exposure-response function from outside the EU, the population attributable fraction decreased from an average of 18 to 7%. To ensure more robust disease burden estimates and adequate follow-up of policy measures, more HBM studies are needed, along with increased efforts to harmonize the design of epidemiological studies upfront to guarantee meta-analysis of exposure-response functions. This is particularly important for pyrethroids as evidence of potential adverse health effects is continuously emerging.

MicroRNA Profile Changes in Brain, Cerebrospinal Fluid, and Blood Following Low-Level Repeated Blast Exposure in a Rat Model.

It is well documented that service members are exposed to repeated low-level blast overpressure during training with heavy weapons such as artillery, mortars and explosive breaching. Often, acute symptoms associated with these exposures are transient but cumulative effect of low-level repeated blast exposures (RBEs) can include persistent deficits in cognitive and behavioral health. Thus far, reliable diagnostic biomarkers which can guide countermeasure strategies have not been identified. In this study, rats were exposed to multiple field-relevant blast waves with 8.5 and 10 psi peak positive overpressures, applying one exposure per day for 14 consecutive days. micro-RNAs that can potentially be used as biomarkers for RBEs were assessed in blood, brain, and cerebrospinal fluid (CSF). RBE caused a differential pattern of changes in various miRNAs in blood, brain and CSF in an overpressure-dependent manner. Our key outcomes were decrease of mir-6215 and let-7 family miRNAs and increase of mir-6321 and mir-222-5p in brain, blood, and CSF. Expression pattern of these miRNAs is in concurrence with various neurological conditions such as upregulation of mir-6321 in focal ischemic injury and downregulation of mir-6215 in nerve injury model. Contrarily, Let-7 family miRNAs have neuroprotective role and their downregulation suggests progression of blast induced traumatic brain injury (bTBI) with RBE at 14× -8.5 psi. Repeated blast caused alterations in miRNAs that are likely involved in vascular integrity, inflammation, and cell death. These results indicate that miRNAs are differentially dysregulated in response to blast injuries and may represent better prognostic and diagnostic biomarkers than traditional molecules to identify blast-specific brain injury.

Compliance with the 2016 WHO’s antenatal care recommendation and its determinants among women in Sub-Saharan Africa: a multilevel-analysis of population survey data

BackgroundDespite the positive impact of adhering to the new antenatal care model on pregnancy outcomes and maternal health service uptake, women in resource-limited settings exhibit low levels of compliance with this recommendation. Previous studies on women’s adherence to the new antenatal care recommendation have been limited to individual countries, with no evidence available at Sub-Saharan Africa (SSA) level. Therefore, this study sought to investigate compliance with the 2016 WHO’s recommendation of at least eight antenatal care contacts among women in SSA countries and identify its determinants.MethodsThe study utilized a weighted sample of 101,983 women who had received antenatal care during their index pregnancy, drawn from recent DHS data of sixteen SSA countries. A multilevel mixed-effect analysis was conducted to identify factors that influence compliance with new antenatal care recommendations. Model comparison was performed using deviance and log-likelihood values, and statistical significance was determined at a P-value of less than 0.05.ResultsThe level of compliance with the recommended antenatal care contacts among women in SSA was 9.9% (95% CI: 9.7-10.1%), with the highest rate in Sierra Leone (26.1%) and lowest in Rwanda (< 1%). A multivariable logistic regression analysis showed that age, education, employment status, household wealth, healthcare decisions, the timing of antenatal contacts, consumption of nutritional supplements, residence, community-level women illiteracy, and media exposure were the significant determinants of compliance.ConclusionOnly one in ten pregnant women in SSA countries had attended the recommended number of antenatal contacts, with Sierra Leone having the highest compliance rate and Rwanda and Senegal having the lowest. Therefore, policymakers should focus on improving access to education, especially for women and their partners, and providing exempted services for pregnant women from low-income households. Interventions that target communities with low levels of literacy and media exposure could also be effective in improving the uptake of the services.

The Protective Effect of the Supplementation with an Extract from Aronia melanocarpa L. Berries against Cadmium-Induced Changes of Chosen Biomarkers of Neurotoxicity in the Brain-A Study in a Rat Model of Current Lifetime Human Exposure to This Toxic Heavy Metal.

Since even low-level environmental exposure to cadmium (Cd) can lead to numerous unfavourable health outcomes, including damage to the nervous system, it is important to recognize the risk of health damage by this xenobiotic, the mechanisms of its toxic influence, and to find an effective protective strategy. This study aimed to evaluate, in a female Wistar rat model of current human environmental exposure to Cd (1 and 5 mg/kg of diet for 3-24 months), if the low-to-moderate treatment with this element can harm the brain and whether the supplementation with a 0.1% Aronia melanocarpa L. (Michx.) Elliott berries (chokeberries) extract (AE) can protect against this effect. The exposure to Cd modified the values of various biomarkers of neurotoxicity, including enzymes (acetylcholinesterase (AChE), sodium-potassium adenosine triphosphatase (Na+/K+-ATPase), phospholipase A2 (PLA2), and nitric oxide synthase 1 (NOS1)) and non-enzymatic proteins (calmodulin (CAM), nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (KEAP1)) crucial for the functioning of the nervous system, as well as the concentrations of calcium (Ca) and magnesium (Mg) and some metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in the brain tissue. The co-administration of AE, partially or entirely, protected from most of the Cd-induced changes alleviating its neurotoxic influence. In conclusion, even low-level chronic exposure to Cd may adversely affect the nervous system, whereas the supplementation with A. melanocarpa berries products during the treatment seems a protective strategy.

Relationship between low-level arsenic exposure in drinking water and kidney cancer risk in Texas

Kidney cancer rates are increasing in the US and worldwide. Arsenic, a known human carcinogen, is a suspected contributor to this rise, particularly in areas with arsenic-rich groundwater. However, research on the connection between low-level arsenic in drinking water and kidney cancer is limited. In our ecological study, we assessed the association between county-level drinking water arsenic levels and kidney cancer incidences using data from 240 counties in Texas. The analysis included 28,896 cancer cases among adults aged ≥20 years and 101,776,294 person-years during the period 2016–2020. Spatial Poisson regression models estimated the risk ratio (RR) for incident kidney cancer based on drinking water arsenic levels, adjusting for demographic, socioeconomic, and other risk factors, as well as spatial factors. Population-weighted drinking water arsenic levels were calculated using data from water testing for both public water systems and private wells, adjusted for populations served from each source. After adjusting for spatial factors and covariates, we observed 6% and 22% higher incidence of cancer in the medium (1–5 ppb) (RR 1.06, 95% CI 1.01, 1.11) and high arsenic (>5 ppb) group counties (RR 1.22, 95% CI 1.12, 1.34) compared to the low arsenic level ones (<1 ppb), showing a dose-response relationship (p-trend <0.001). Additionally, when arsenic was treated as a continuous variable, the incidence increased by 4% for each doubling of drinking water arsenic level (RR 1.04, 95% CI 1.02, 1.07) when considering drinking water arsenic level as a continuous variable. Our study suggests that exposure to low-level drinking water arsenic may be associated with an increased risk of kidney cancer. Further prospective studies are required to confirm our findings.

Macrophage MAPK7/AhR/STAT3 Signaling Mediates Mitochondrial ROS Burst and Enterohepatic Inflammatory Responses Induced by Deoxynivalenol Relevant to Low-Dose Exposure in Children.

Deoxynivalenol (DON) can induce endoplasmic reticulum (ER) stress, mitochondrial ROS burst, and macrophage polarization. Here, we investigated the mechanism linking the above three aspects with the dose range relevant to low-level exposure in children. At 0.5 μg/kg bw/day, we found remarkable liver and gut inflammatory responses after 6-week exposure in mice age comparable to humans 7-12 years old. Through antioxidant intervention, we found that ROS played a driver role in macrophage polarization and inflammatory responses induced by DON in the liver and gut. Further bioinformatics analysis uncovered that ER stress-associated protein MAPK7 (ERK5) may bind with AhR to initiate a mitochondrial ROS burst and macrophage M1 polarization. The downstream cellular events of MAPK7-AhR interaction may be mediated by the AhR/STAT3/p-STAT(Ser727) pathway. This mechanism was further supported by DON toxicity mitigation using cyanidin-3-glucoside (C-3-G), which docks to MAPK7 oligomerization region 200-400 aa and disrupts MAPK7-AhR interaction. Overall, our study provides novel evidence and mechanism for DON-induced inflammatory responses in the liver and gut system. Our findings call attention to the health risks associated with low-level DON exposure in the prepuberty children population.

The association between patterns of exposure to adverse life events and the risk of chronic kidney disease: a prospective cohort study of 140,997 individuals

Exposure to adverse life events is linked to somatic disorders. The study aims to evaluate the association between adverse events at varying life stages and the risk of chronic kidney disease (CKD), a condition affecting about 10% population worldwide. This prospective cohort study included 140,997 participants from the UK Biobank. Using survey items related to childhood maltreatment, adulthood adversity and catastrophic trauma, we performed latent class analysis to summarize five distinct patterns of exposure to adverse life events, namely “low-level exposure”, “childhood exposure”, “adulthood exposure”, “sexual abuse” and “child-to-adulthood exposure”. We used Cox proportional hazard regression to evaluate the association of patterns of exposure to adverse life events with CKD, regression-based mediation analysis to decompose the total effect, and gene-environment-wide interaction study (GEWIS) to identify interactions between genetic loci and adverse life events. During a median follow-up of 5.98 years, 2734 cases of incident CKD were identified. Compared with the “low-level exposure” pattern, “child-to-adulthood exposure” was associated with increased risk of CKD (hazard ratio 1.37, 95% CI 1.14 to 1.65). BMI, smoking and hypertension mediated 11.45%, 9.79%, and 4.50% of this total effect, respectively. Other patterns did not show significant results. GEWIS and subsequent analyses indicated that the magnitude of the association between adverse life events and CKD differed according to genetic polymorphisms, and identified potential underlying pathways (e.g., interleukin 1 receptor activity). These findings underscore the importance of incorporating an individual’s psychological encounters and genetic profiles into the precision prevention of CKD.

Low level exposure to BDE-47 facilitates the development of prostate cancer through TOP2A/LDHA/lactylation positive feedback circuit

2,2′,4,4′-tetra brominated diphenyl ether (BDE-47) is one of the most widely distributed congeners of polybrominated diphenyl ethers. While the relationships between BDE-47 exposure and other hormone-dependent cancers (such as breast cancer) are well established, no previous study has examined whether BDE-47 exposure is related to the development of prostate cancer (PCa). Through bulk and single-cell RNA sequencing (scRNA-seq) analyses, as well as in vitro and in vivo experiments, this study aims to investigate the effect of BDE-47 exposure on PCa progression. Herein, we found that low dose BDE-47 promoted the growth of PCa cells (PC3 and LNCaP) in a dose-dependent manner in vitro and in vivo. Based on Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas (TCGA), we obtained 34 BDE-47-related and PCa-related genes through screening and overlapping. These genes were significantly enriched in fatty acid metabolism-related gene ontology (GO) terms, which were also enriched for genes targeting BDE-47 obtained from the UniProt. Through scRNA-seq data, certain cell type-specific expression was observed for CYP2E1, PIK3R1, FGF2, and TOP2A in PCa tissues from men. Molecular docking simulation showed that BDE-47 was tightly bound to the protein residues of AOX1, PIK3R1, FGF2, CAV2, CYP2E1 and TOP2A. Further screening in terms of patient overall survival, receiver operating characteristics curve (ROC) curve and Gleason score grading system narrowed the candidate genes down to TOP2A. Mechanistically, the growth-promoting effect of BDE-47 on PCa cells could be reversed by TOP2A inhibitor. RNA-seq followed by experimental verification demonstrated that TOP2A promoted PCa progression through upregulating LDHA and glycolysis. Furthermore, lactate upregulated TOP2A transcription through lactylation of H3K18la in PCa cells, which could be rescued by LDHA knockdown. Taken together, low dose BDE-47 triggered PCa progression through TOP2A/LDHA/lactylation positive feedback circuit, thus revealing epigenetic shifting and metabolic reprogramming underpinning BDE-47-induced carcinogenesis of the prostate.