peer reviewed | Metconazole (MEZ), a chiral triazole fungicide, produces enantioselective adverse effects in non-target organisms. Among MEZ's isomers, cis-MEZ displays robust antimicrobial properties. Evaluating MEZ and cis-MEZ's toxicity may mitigate fungicide usage and safeguard non-target organisms. Our study evaluated the toxicity of MEZ and its cis-isomers at concentrations of 0.02, 0.2, 2, and 4 mg L−1. We report stereoselectivity and severe cardiovascular defects in zebrafish, including pericardial oedema, decreased heart rate, increased sinus venous and bulbous arteries distances, intersegmental vessel defects, and altered cardiovascular development genes (hand2, gata4, nkx2.5, tbx5, vmhc, amhc, dll4, vegfaa, and vegfc). Further, MEZ significantly increased oxidative stress and apoptosis in zebrafish, primarily in the cardiac region. Isoquercetin, an antioxidant found in plants, partially mitigates MEZ-induced cardiac defects. Furthermore, MEZ upregulated the Wnt/β-catenin pathway genes (wnt3, β-catenin, axin2, and gsk-3β) and β-catenin protein expression. Inhibitor of Wnt Response-1 (IWR-1) rescued MEZ-induced cardiotoxicity. Our findings highlight oxidative stress, altered cardiovascular development genes, and upregulated Wnt/β-catenin signaling as contributors to cardiovascular toxicity in response to MEZ and cis-MEZ treatments. Importantly, 1R,5S-MEZ exhibited greater cardiotoxicity than 1S,5R-MEZ. Thus, our study provides a comprehensive understanding of cis-MEZ's cardiovascular toxicity in aquatic life. © 2024 Elsevier Ltd

An increasing number of epidemiological studies have examined the association between ultrafine particles (UFP) and imbalanced autonomic control of the heart, a potential mechanism linking particulate matter air pollution to cardiovascular disease. This study systematically reviews and meta-analyzes studies on short-term effects of UFP on autonomic function, as assessed by heart rate variability (HRV). We searched PubMed and Web of Science for articles published until June 30, 2022. We extracted quantitative measures of UFP effects on HRV with a maximum lag of 15 days from single-pollutant models. We assessed the risk of bias in the included studies regarding confounding, selection bias, exposure assessment, outcome measurement, missing data, and selective reporting. Random-effects models were applied to synthesize effect estimates on HRV of various time courses. Twelve studies with altogether 1,337 subjects were included in the meta-analysis. For an increase of 10,000 particles/cm³ in UFP assessed by central outdoor measurements, our meta-analysis showed immediate decreases in the standard deviation of the normal-to-normal intervals (SDNN) by 4.0% [95% confidence interval (CI): 7.1%, −0.9%] and root mean square of successive R-R interval differences (RMSSD) by 4.7% (95% CI: 9.1%, 0.0%) within 6 h after exposure. The immediate decreases in SDNN and RMSSD associated with UFP assessed by personal measurements were smaller and borderline significant. Elevated UFP were also associated with decreases in SDNN, low-frequency power, and the ratio of low-frequency to high-frequency power when pooling estimates of lags across hours to days. We did not find associations between HRV and concurrent-day UFP exposure (daily average of at least 18 h) or exposure at lags ≥ one day. Our study indicates that short-term exposure to ambient UFP is associated with decreased HRV, predominantly as an immediate response within hours. This finding highlights that UFP may contribute to the onset of cardiovascular events through autonomic dysregulation.

Once in the aquatic ecosystems, nanoplastics (NPls) can interact with other contaminants acting as vectors of transport and altering their toxicological effects towards organisms. Thus, the present study aims to investigate how polystyrene NPls (44 nm) interact with the herbicide phenmedipham (PHE) and affect its toxicity to zebrafish embryos. Single exposures to 0, 0.015, 0.15, 1.5, 15 and 150 mg/L NPls and 0.02, 0.2, 2 and 20 mg/L PHE were performed. Embryos were also exposed to the binominal combinations: 0.015 mg/L NPls + 2 mg/L PHE, 0.015 mg/L NPls + 20 mg/L PHE, 1.5 mg/L NPls + 2 mg/L PHE and 1.5 mg/L NPls + 20 mg/L PHE. Due to the low solubility of PHE in water, a solvent control was performed (0.01% acetone). PHE was quantified. Mortality, heartbeat and hatching rate, malformations appearance, locomotor behavior and biomarkers related to oxidative stress, neurotransmission and energy budgets were analyzed. During 96 h, NPls and PHE single and combined exposures did not affect embryos development. After 120 h, NPls induced hyperactivity and PHE induced hypoactivity. After 96 h, NPls increased catalase activity and PHE increased glutathione S-transferases activity. On the combination 0.015 mg/L NPls + 20 mg/L PHE, hyperactivity behavior was found, similar to 0.015 mg/L NPls, and cholinesterase activity was inhibited. Additionally, the combination 1.5 mg/L NPls + 20 mg/L PHE increased both catalase and glutathione S-transferases activities. The combination NPls with PHE affected more biochemical endpoints than the single exposures, showing the higher effect of the binominal combinations. Dissimilar interactions effects – no interaction, synergism and antagonism – between NPls and PHE were found. The current study shows that the effects of NPls on bioavailability and toxicity of other contaminants (e.g. PHE) cannot be ignored during the assessment of NPls environmental behavior and risks.

Microplastics are sometimes considered not harmful at environmentally relevant concentrations. Yet, such studies were conducted under standard thermal conditions and thereby ignored the impacts of higher mean temperatures (MT), and especially daily temperature fluctuations (DTF) under global warming. Moreover, an evolutionary perspective may further benefit the future risk assessment of microplastics under global warming. Here, we investigated the effects of two generations of exposure to an environmentally relevant concentration of polystyrene microplastics (5 μg L⁻¹) under six thermal conditions (2 MT × 3 DTF) on the life history, physiology, and behaviour of Daphnia magna. To assess the impact of thermal evolution we thereby compared Daphnia populations from high and low latitudes. At the standard ecotoxic thermal conditions (constant 20 °C) microplastics almost had no effect except for a slight reduction of the heartbeat rate. Yet, at the challenging thermal conditions (higher MT and/or DTF), microplastics affected each tested variable and caused an earlier maturation, a higher fecundity and intrinsic growth rate, a decreased heartbeat rate, and an increased swimming speed. These effects may be partly explained by hormesis and/or an adaptive response to stress in Daphnia. Moreover, exposure to microplastics at the higher mean temperature increased the fecundity and intrinsic growth rate of cold-adapted high-latitude Daphnia, but not of the warm-adapted low-latitude Daphnia, suggesting that thermal evolution in high-latitude Daphnia may buffer the effects of microplastics under future warming. Our results highlight the critical importance of DTF and thermal evolution for a more realistic risk assessment of microplastics under global warming.

Exposure to fine particulate matter (PM₂.₅) was associated with altered heart rate variability (HRV). However, whether blood pressure (BP) control and angiotensin II receptor blocker (ARB) treatment modifies the associations was seldom addressed. Therefore, we conducted a 3-phase panel study among 282 hypertensive subjects aged 35–74 years in four cities of China to address this issue. Real-time personal PM₂.₅ sampling and 24-h ambulatory electrocardiogram monitoring were performed repeatedly in 3 different seasons. Linear mixed-effects models were fitted overall and by control status of BP and ARB treatment to assess the associations between short-term PM₂.₅ exposure and HRV. The average hourly PM₂.₅ concentrations (Mean ± SD) ranged from 19.3 ± 18.2 μg/m³ to 99.4 ± 76.9 μg/m³ across study phases and cities. Generally, PM₂.₅ exposure was associated with decreased hourly and 24-h HRV. However, these adverse impacts were attenuated among patients with controlled BP (<140/90 mmHg). For each 10 μg/m³ increment in moving average of previous 2 days' (MA2d) PM₂.₅ exposure, 24-h SDNN (standard deviation of NN intervals) and rMSSD (root mean square of successive RR interval differences) decreased by 0.89% (95% CI: 0.19%–1.59%) and 2.98% (95% CI: 1.04%–4.89%) among patients with uncontrolled BP (≥140/90 mmHg), whereas no obvious declines were observed among those with controlled BP (Pdᵢffₑᵣₑₙcₑ = 0.007 and 0.022, respectively). Furthermore, ARB treatment alleviated or eliminated PM₂.₅-associated declines in hourly and 24-h HRV among those with uncontrolled BP. For instance, 24-h SDNN decreased by 1.31% (95% CI: 0.54%–2.07%) with a 10 μg/m³ increment in lag 2 days’ PM₂.₅ exposure in ARB nonusers, whereas no obvious changes were observed in ARB users (Pdᵢffₑᵣₑₙcₑ = 0.021). In conclusion, although PM₂.₅ exposure would decrease HRV, better BP control and ARB treatment could attenuate these adverse impacts, which provides supporting evidence for alleviating autonomic dysfunction of hypertension patients living in areas with high-level PM₂.₅.

Exposure to traffic-related air pollution (TRAP) may enhance the risk of cardiovascular disease. However, the short-term effects of TRAP components on the cardiovascular system are not well understood. We conducted a randomized, double-blinded, crossover intervention study in which 39 healthy university students spent 2 h next to a busy road. Participants wore a powered air-purifying respirator (PAPR) or an N95 mask. PAPRs were equipped with a filter for particulate matter (PM), a PM and volatile organic compounds (VOCs) filter or a sham filter. Participants were blinded to PAPR filter type and underwent randomized exposures four times, once for each intervention mode. Blood pressure (BP), heart rate (HR) and heart rate variability (HRV) were measured before, during and for 6 h after the roadside exposure. Linear mixed-effect models were used to evaluate the effects of the interventions relative to baseline controlling for other covariates. All HRV measures increased during and following exposure for all intervention modes. Some HRV measures (SDNN and rMSSD during exposure and SDNN after exposure) were marginally affected by PM filtration. Wearing the N95 mask affected VLF power and rMSSD responses to traffic exposure differently than the PAPR interventions. Both systolic and diastolic BP increased slightly during exposure, but then were generally lower than baseline after exposure for the sham and filter interventions. HR, which fell during exposure and mostly remained lower than baseline after exposure, was lower yet with all filter interventions compared to the sham mode following exposure. Therefore, short-term exposure to traffic acutely affects HRV, BP and HR, but N95 mask and PAPR interventions generally show little efficacy in reducing these effects. Removing the PM component of TRAP has some limited effects on HRV responses to exposure but exaggerates the traffic-related decrease in HR. HRV findings from N95 mask interventions need to be interpreted cautiously.

Polycyclic aromatic hydrocarbons (PAHs) exposure is associated with heart rate variability (HRV) reduction, a widely used marker of cardiovascular autonomic dysfunction. The role of DNA methylation in the relationship between PAHs exposure and decreased HRV is largely unknown. This study aims to explore epigenome-wide DNA methylation changes associated with PAHs exposure and further evaluate their associations with HRV alternations among non-current smokers. We measured 10 mono-hydroxylated PAHs (OH-PAHs) in urine and DNA methylation levels in blood leukocytes among participants from three panels of Chinese non-current smokers (152 in WHZH, 99 in SY, and 53 in COW). We conducted linear regression analyses between DNA methylation and OH-PAHs metabolites with adjustment for age, gender, body mass index, drinking, blood cell counts, and surrogate variables in each panel separately, and combined the results by using inverse-variance weighted fixed-effect meta-analysis to obtain estimates of effect size. The median value of total OH-PAHs ranged from 0.92 × 10⁻² in SY panel (62.6% men) to 13.82 × 10⁻² μmol/mmol creatinine in COW panel (43.4% men). The results showed that methylation levels of cg18223625 (COL20A1) and cg07805771 (SLC16A1) were significantly or marginally significantly associated with urinary 2-hydroxynaphthalene [β(SE) = 0.431(0.074) and 0.354(0.068), FDR = 0.016 and 0.056, respectively], while methylation level of cg09235308 (PLEC1) was positively associated with urinary total OH-PAHs [β(SE) = 0.478(0.079), FDR = 0.004]. Hypermethylations of cg18223625, cg07805771, and cg09235308 were inversely associated with HRV indices among the WHZH and COW non-current smokers. However, we did not observe significant epigenome-wide associations for the other 9 urinary OH-PAHs. These findings provide new evidence that PAHs exposure is linked to differential DNA methylation, which may help better understand the influences of PAHs exposure on HRV alternations.

Systemic toxicity, particularly, developmental defects of humidifier disinfectant chemicals that have caused lung injuries in Korean children, remains to be elucidated. This study evaluated the mechanisms of the adverse effects of 5-chloro-2-methyl-4-isothiazoline-3-one/2methyl-4-isothiazolin-3-one (CMIT/MIT), one of the main biocides of the Korean tragedy, and identify the most susceptible developmental stage when exposed in early life. To this end, the study was designed to analyze several endpoints (morphology, heart rate, behavior, global DNA methylation, gene expressions of DNA methyl-transferases (dnmts) and protein profiling) in exposed zebrafish (Danio rerio) embryos at various developmental stages. The results showed that CMIT/MIT exposure causes bent tail, pericardial edema, altered heart rates, global DNA hypermethylation and significant alterations in the locomotion behavior. Consistent with the morphological and physiological endpoints, proteomics profiling with bioinformatics analysis suggested that the suppression of cardiac muscle contractions and energy metabolism (oxidative phosphorylation) were possible pivotal underlying mechanisms of the CMIT/MIT mediated adverse effects. Briefly, multi-level endpoint analysis indicated the most susceptible window of exposure to be ≤ 6 hpf followed by ≤ 48 hpf for CMIT/MIT. These results could potentially be translated to a risk assessment of the developmental exposure effects to the humidifier disinfectants.

Penconazole is a widely used chiral triazole bactericide that may adversely affect the environment. It contains two corresponding enantiomers and there may be differences in toxicity between the isomers. Therefore, in this study, we exposed zebrafish embryos to different concentrations of the penconazole enantiomer to study the developmental toxicity and neurotoxicity of penconazole on zebrafish and the difference in toxicity between enantiomers. The results showed that penconazole exposure caused adverse effects on zebrafish embryos, such as autonomous motor abnormalities, heart rate slowing, and increased deformity, resulting in significant developmental toxicity. Meanwhile, also caused the zebrafish larvae to slow movement, the neurotransmitter content and nervous system related gene expression significantly changed, which proved that penconazole also caused neurotoxicity to zebrafish. Interestingly, our results also clearly show that (+)-penconazole is significantly more toxic to zebrafish than (−)-penconazole at the same concentration, whether it is developmental toxicity or neurotoxicity, which suggests that we should focus on (+)-penconazole more when conducting toxicological studies on penconazole.