Co-exposure Effects Research Articles

A review of cardiovascular effects and underlying mechanisms of legacy and emerging per- and polyfluoroalkyl substances (PFAS).

Cardiovascular disease (CVD) poses the leading threats to human health and life, and their occurrence and severity are associated with exposure to environmental pollutants. Per- and polyfluoroalkyl substances (PFAS), a group of widely used industrial chemicals, are characterized by persistence, long-distance migration, bioaccumulation, and toxicity. Some PFAS, particularly perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexanesulfonic acid (PFHxS), have been banned, leaving only legacy exposure to the environment and human body, while a number of novel PFAS alternatives have emerged and raised concerns, such as polyfluoroalkyl ether sulfonic and carboxylic acid (PFESA and PFECA) and sodium p-perfluorous nonenoxybenzene sulfonate (OBS). Overall, this review systematically elucidated the adverse cardiovascular (CV) effects of legacy and emerging PFAS, emphasized the dose/concentration-dependent, time-dependent, carbon chain length-dependent, sex-specific, and coexposure effects, and discussed the underlying mechanisms and possible prevention and treatment. Extensive epidemiological and laboratory evidence suggests that accumulated serum levels of legacy PFAS possibly contribute to an increased risk of CVD and its subclinical course, such as cardiac toxicity, vascular disorder, hypertension, and dyslipidemia. The underlying biological mechanisms may include oxidative stress, signaling pathway disturbance, lipid metabolism disturbance, and so on. Various emerging alternatives to PFAS also play increasingly prominent toxic roles in CV outcomes that are milder, similar to, or more severe than legacy PFAS. Future research is recommended to conduct more in-depth CV toxicity assessments of legacy and emerging PFAS and explore more effective surveillance, prevention, and treatment strategies, accordingly.

Intraperitoneal hepato-renal toxicity of zinc oxide and nickel oxide nanoparticles in male rats: biochemical, hematological and histopathological studies.

In recent years, zinc oxide (ZnO) and nickel oxide (NiO) nanoparticles (NPs) have become more prevalent in commercial and industrial products. However, questions have been raised regarding their potential harm to human health. Limited studies have been conducted on their intraperitoneal toxicity in rats, and their co-exposure effects remain uncertain. Therefore, this study aimed to investigate some biological responses induced by a single intraperitoneal injection of ZnO-NPs (200 mg/kg) and/or NiO-NPs (50 mg/kg) in rats over time intervals. Blood and organ samples were collected from 36 male rats for hematological, biochemical, oxidative stress, and histological analysis. Results showed that the administration of NPs reduced the body and organ weights as well as red blood cell (RBC) indices and altered white blood cell (WBC) and platelet (PLT) counts. The experimental groups exhibited elevated levels of aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine (CREA), urea, lipid profile, glucose (GLU), total protein (TP), albumin (ALB) and malondialdehyde (MDA), and decreased uric acid (UA), superoxide dismutase (SOD), and glutathione (GSH). Histological observations also revealed architectural damages in liver and kidneys. These alterations were time-dependent and varied in their degree of toxicity. Co-exposure of NPs initially lessened the damage but increased it afterwards compared to individual exposure. In conclusion, intraperitoneal injection of ZnO-NPs and/or NiO-NPs alters biological processes and induces oxidative stress in rats' liver and kidneys in a time-dependent manner, with NiO-NPs being more potent than ZnO-NPs. Furthermore, co-exposed NPs initially appeared to be antagonistic to one another while further aiming toward synergism.

Co-exposure health risk of benzo[a]pyrene with aromatic VOCs: Monoaromatic hydrocarbons inhibit the glucuronidation of benzo[a]pyrene

Occupational workers and residents near petrochemical industry facilities are exposed to multiple contaminants on a daily basis. However, little is known about the co-exposure effects of different pollutants based on biotransformation. The study examined benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon related to the petrochemical industry, to investigate changes in toxicity and co-exposure mechanism associated with different monoaromatic hydrocarbons (MAHs). A central composite design method was used to simulate site co-exposure scenarios to reveal biotransformation of BaP when co-exposed with benzene, toluene, chlorobenzene, or nitrobenzene in microsome systems. BaP metabolism depended on MAH concentration, and association of MAH with microsome concentration/incubation time. Particularly, MAH co-exposure negatively affected BaP glucuronidation, an important phase Ⅱ detoxification process. BaP metabolite intensities decreased to 43%–80% for OH–BaP-G, and 32%–71% for diOH-BaP-G in co-exposure system with MAHs, compared with control group. Furthermore, glucuronidation was affected by competitive and time-dependent inhibition. Co-exposure significantly decreased gene expression of UGT 1A10 and BCRP/ABCG2 in HepG2 cells, which are involved in BaP detoxification through metabolism and transmembrane transportation. Therefore, human co-exposure to multiple contaminants may deteriorate toxic effects of these chemicals by disturbing metabolic pathways. This study provides a reference for assessing toxic effects and co-exposure risks of pollutants.

Associations of co-exposure to polycyclic aromatic hydrocarbons and metals with hyperuricemia risk in Chinese coke oven workers: Mediating roles of oxidative damage

Ubiquitous polycyclic aromatic hydrocarbons (PAHs) and metals could induce hyperuricemia and oxidative damage individually, while their co-exposure effects on hyperuricemia risk and the potential roles of oxidative damage in these health outcomes remain poorly understood. We conducted a cross-sectional study in 1379 coke oven workers. We evaluated the levels of PAH-metal exposure and oxidative damage by urinary monohydroxy-PAHs, plasma benzo [a]pyrene-7,8-diol-9,10-epoxide-albumin (BPDE-Alb) adducts, urinary metals, urinary 8-iso-prostaglandin-F2α, and urinary 8-hydroxydeoxyguanosine (8-OH-dG). The subjects were classified into cases of hyperuricemia and controls by the levels of blood uric acid. We found that the sum of multiple hydroxyphenanthrene (ΣOH-Phe) was robustly associated with the increase in hyperuricemia risk, while rubidium and strontium had robust protective associations with hyperuricemia risk (Ptrend<0.05). The risk association of ΣOH-Phe was weaker in workers with high levels of rubidium and strontium [P for modifying effect (PME) < 0.030]. The protective association of strontium was more pronounced in workers with higher ΣOH-Phe (PME = 0.014). We also found that 8-OH-dG was a risk factor for hyperuricemia (Ptrend = 0.006) and mediated 10.13% of the elevated hyperuricemia risk associated with ΣOH-Phe. Our findings suggested that individual PAHs and metals, as well as their co-exposure, may influence hyperuricemia risk among coke oven workers, with oxidative DNA damage playing a potential mediating role in their associations.

PM2.5 elemental composition in indoor residential environments and co-exposure effects on respiratory health in an industrial area

This study aimed to identify and characterise indoor sources of particulate matter (PM) in domestic environments. 74 inhabited apartments located in the urban area of Gela (Sicily, Italy), close to a refinery, and in three villages of the hinterland were evaluated, in real-world conditions, for the elemental composition of PM2.5. The samples were collected simultaneously inside and outside each apartment for 48 h. In addition, two of the apartments were simultaneously studied for four weeks.The elemental composition of PM2.5 was determined by applying a chemical fractionation procedure followed by inductively-coupled plasma spectrometry analysis, with both optical emission and mass detection. The extractable, more bio-accessible fraction (ext), and the mineralised residual fraction (res) of each element were determined, thus increasing the selectivity of elements as source tracers.Indoor air in the considered apartments was affected by both outdoor pollution and specific indoor emission sources. The behaviour of each source was studied in detail, identifying a reliable tracer: Tires for soil, Asext for industrial sources, Vext for heavy oil combustion, Ce for cigarette smoking and Mo for the use of vacuum dust cleaners. Asext and Vext showed an excellent infiltration capacity, while the concentration of Tires was affected by a low infiltration capacity and by the contribution of particles re-suspension caused by the residents' movements. In the case of Ce and Mo, indoor concentrations were much higher than outdoor with a high variability among the apartments, due to the inhabitants’ habits concerning cigarette smoke and use of electric appliances. To test the overall effect of the concomitant exposure to the identified sources on Wh12 M and on DDA, a WQS analysis was conducted. Cigarette smoking and heavily oil combustion driven the Wh12 M odds increase, while the DDA odds increase was mainly driven by heavily oil combustion and the use of vacuum dust cleaners.

Accumulation of microplastics and Tcep pollutants in agricultural soil: Exploring the links between metabolites and gut microbiota in earthworm homeostasis

Agricultural soil contamination with plastic film has become a critical global environmental problem, requiring greater research on the possible occurrence and biological risk of microplastics (MPs) and their additives in soil ecosystems. The presence of MPs and tris (2-chloroethyl) phosphate (Tcep) in agricultural soil was investigated at nine sites in the present study. Polyethylene MPs (PE-MPs) and Tcep were found at all nine sites. To study co-exposure effects on soil microbiota and earthworms, and to mimic a realistic exposure scenario, 0.05 % (w/w) PE-MPs with three particle size ranges were combined with Tcep (1.0 mg/kg). After 28 days of exposure, there was no indication that added PE-MPs and/or Tcep significantly affected the soil microbial community structure. In earthworms, size-selective intake, digestion and egestion of PE-MPs may occur, with Tcep co-exposure affecting the residual Tcep concentration in earthworm intestines (3.52–9.31 μg/g dw). Long-term earthworm PE-MPs intake caused intestinal damage, and Tcep co-exposure increased oxidative stress, thereby influencing their feeding behavior and growth, resulting in weight loss (3.42 %–14.96 %), especially for the most common PE-MPs sizes (0–300 μm). High performance liquid chromatography-mass spectrometry (LC-MS) was used for metabolomic analysis, revealing the significant up-regulation of citrate (p < 0.001) and down-regulation of l-glutamate (p < 0.05) in co-exposure groups. Co-exposure resulted in the alteration of most metabolic pathways, thereby impairing nervous, digestive and excretory systems in the earthworm, with an associated decrease in amino acid metabolism and changes in tricarboxylic acid (TCA) cycle intermediates. Gut microbiota, such as Proteobacteria (Verminephrobacter and Bradyrhizobium) and Firmicutes (Bacillus), are critically important in maintaining earthworm metabolic homeostasis, particularly for the TCA cycle and amino acid metabolism. Overall, MPs and Tcep co-exposure in agricultural soil enhanced their toxicity to earthworms and may potentially endanger the development of agricultural sustainability.

Associations between co-exposure to multiple metals and renal function: a cross-sectional study in Guangxi, China.

The association between co-exposure to multiple metals and renal function is poorly understood. We aimed to evaluate the individual and joint effects of metal exposure on renal function in this study. We performed a cross-sectional study including 5828 participants in Guangxi, China, in 2019. Urine concentrations of 17 metals were detected by inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression model and restricted cubic spline (RCS) were applied to investigate the association of individual metal exposure with renal dysfunction. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the co-exposure effects of the metals. Participants with the highest quartile of urinary Cu were at 1.84-fold (95% confidence interval (CI): 1.20-2.87) increased risk of renal dysfunction compared with the lowest quartile. The highest quartiles of urinary Sr, Cs, V, Ba, and Se were associated with 0.27-fold (95% CI: 0.17-0.43), 0.33 (95% CI: 0.19-0.53), 0.41 (95% CI: 0.25-0.65), 0.58 (95% CI: 0.36-0.90), and 0.33 (95% CI: 0.19-0.56) decreased risk of renal dysfunction compared with their lowest quartile, respectively. Furthermore, urinary Ba and Cu were non-linearly correlated with renal dysfunction. The WQS analysis showed that mixed metal exposure was inversely associated with renal dysfunction (OR = 0.47, 95% CI: 0.35-0.62), and Sr accounted for the largest weight (52.2%), followed by Cs (32.3%) in the association. Moreover, we observed a potential interaction between Cu, Cs, and Ba for renal dysfunction in BKMR model. Exposure to Se, Sr, Cs, V, and Ba is associated with decreased risk of renal dysfunction, whereas an increased risk is associated with Cu exposure. Co-exposure to these metals is negatively associated with renal dysfunction, and Sr and Cs are the main contributors to the associations.

WITHDRAWN: Co-exposure effects of arsenic and fluoride on intelligence and oxidative stress in school-aged children: A cohort study

This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause.

Co-exposure of serum calcium, selenium and vanadium is nonlinearly associated with increased risk of type 2 diabetes mellitus in a Chinese population

BackgroundMetals play an important role in type 2 diabetes mellitus (T2DM). This study aimed to explore the association of T2DM risk with single metal exposure and multi-metal co-exposure. MethodsA case-control study with 223 T2DM patients and 302 controls was conducted. Serum concentrations of 19 metals were determined by inductively coupled plasma mass spectrometry (ICP-MS). Those metals with greater effects were screened out and co-exposure effects of metals were assessed by least absolute shrinkage and selection operator (LASSO) regression. ResultsSerum calcium (Ca), selenium (Se) and vanadium (V) were found with greater effects. Higher levels of Ca and Se were associated with increased T2DM risk (OR = 2.23, 95%CI: 1.38–3.62, Ptrend = 0.002; OR = 3.16, 95%CI: 1.82–5.50, Ptrend < 0.001), but higher V level was associated with decreased T2DM risk (OR = 0.58, 95%CI: 0.34–0.97, Ptrend < 0.001). Serum Ca and V concentrations were nonlinearly associated with T2DM risk (Poverall < 0.001, Pnonliearity < 0.001); however, Se concentration was linearly associated with T2DM risk (Poverall < 0.001, Pnonliearity = 0.389). High co-exposure score of serum Ca, Se and V was associated with increased T2DM risk (OR = 3.50, 95%CI: 2.08–5.89, Ptrend < 0.001) as a non-linear relationship (Poverall < 0.001, Pnonliearity = 0.003). ConclusionsThis study suggest that higher levels of serum Ca and Se were associated with increased T2DM risk, but higher serum V level was associated with decreased T2DM risk. Moreover, co-exposure of serum Ca, Se and V was nonlinearly associated with T2DM risk, and high co-exposure score was positively associated with T2DM risk.

Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses

BackgroundExposure to vinylcyclohexene (VCH) and methylmercury (MeHg+) can induce oxidative stress and gene modulation. Several studies have been evaluating the effects of VCH and MeHg+, but little is known about interactive effects between them. This work aimed to assess the exposure and co-exposure effects of MeHg+ and VCH on oxidative stress and gene modulation in Drosophila melanogaster.MethodsReactive species production, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated after exposure and co-exposure to VCH (1 mM) and MeHg+ (0.2 mM) for one or three days in the head and body (thorax and abdomen) of flies. The expression of genes related to redox state and inflammatory response was evaluated after exposure and co-exposure to VCH and MeHg+ for three days.ResultsSurvival decreased only in flies co-exposed to VCH and MeHg+ for three days. All treatments increased total reactive species production after one day of exposure. However, no significant changes were observed in the head after three days of exposure. One day of exposure to VCH caused an increase in the head GST activity, whereas MeHg+ induced an increase after three days of exposure. Regarding the body, all treatments increased GST activity after one day of exposure, but only the flies exposed to MeHg+ presented an increase in GST activity after three days of exposure. Treatments did not alter AChE activity in the head. As for gene expression, there was a significant increase in the Relish transcription factor gene in the flies’ body, but Nrf2, Keap1, Jafrac1, TrxR1, and NF-κβ were not altered.ConclusionThe results suggest that exposure to VCH and MeHg+ induce oxidative stress and activation of an inflammatory response in fruit flies.

Co-Exposure to SiO2 Nanoparticles and Arsenic Induced Augmentation of Oxidative Stress and Mitochondria-Dependent Apoptosis in Human Cells.

Widespread application of silica nanoparticles (nSiO2) and ubiquitous metalloid arsenic (As) may increase their chances of co-exposure to human beings in daily life. Nonetheless, studies on combined effects of nSiO2 and As in human cells are lacking. We investigated the co-exposure effects of nSiO2 and As in human liver (HepG2) and human fibroblast (HT1080) cells. Results showed that nSiO2 did not cause cytotoxicity. However, exposure of As caused oxidative stress and apoptosis in both types of cells. Interesting results were that co-exposure of a non-cytotoxic concentration of nSiO2 significantly augmented the As induced toxicity in both cells. Intracellular level of As was higher in the co-exposure group (nSiO2 + As) than the As group alone, suggesting that nSiO2 facilitates the cellular uptake of As. Co-exposure of nSiO2 and As potentiated oxidative stress indicated by pro-oxidants generation (reactive oxygen species, hydrogen peroxide and lipid peroxidation) and antioxidants depletion (glutathione level, and glutathione reductase, superoxide dismutase and catalase activities). In addition, co-exposure of nSiO2 and As also potentiated mitochondria-mediated apoptosis suggested by increased expression of p53, bax, caspase-3 and caspase-9 genes (pro-apoptotic) and decreased expression of bcl-2 gene (anti-apoptotic) along with depleted mitochondrial membrane potential. To the best of our knowledge, this is the first study showing that co-exposure of nSiO2 and As induced augmentation of oxidative stress and mitochondria-mediated apoptosis in HepG2 and HT1080 cells. Hence, careful attention is required for human health assessment following combined exposure to nSiO2 and As.

Co-exposure to polycyclic aromatic hydrocarbons and metals, four common polymorphisms in microRNA genes, and their gene-environment interactions: Influences on oxidative damage levels in Chinese coke oven workers

BackgroundHuman are often simultaneously exposed to polycyclic aromatic hydrocarbons (PAHs) and metals, yet relatively little is known regarding their co-exposure effects on oxidative damage. Genetic factors and the gene-environment interactions can also determine the severity of oxidative damage. Four polymorphisms in microRNA (miRNA) genes (rs11614913, rs2292832, rs2910164, and rs3746444) have been well-studied to be associated with oxidative damage-related diseases. ObjectiveTo investigate the influences of PAH-metal co-exposure, four polymorphisms, and their interactions on oxidative damage levels. MethodsWe conducted a cross-sectional study in 1385 coke oven workers. We quantified exposure levels of PAHs and metals by urinary monohydroxy-PAHs, plasma benzo[a]pyrene-7,8-diol-9,10-epoxide-albumin adducts, and urinary metals, respectively, and measured oxidative damage levels by 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine. We also genotyped four polymorphisms. ResultsIn multiple-pollutant models, 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were associated with multiple PAH exposure biomarkers, as well as with multiple metals (ptrend < 0.05). Metabolites of phenanthrene and pyrene interacted synergistically with lead and zinc to influence 8-iso-prostaglandin-F2α (βinteraction > 7.75%, false discovery rate-adjusted pinteraction ≤ 2.25 × 10−5). Significantly higher 8-hydroxydeoxyguanosine was observed in carriers of rs11614913 CC variant homozygote than TC carriers (p = 0.037). Associations of the number of rs11614913 C allele with increased 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were significant (βstd > 0, ptrend < 0.05) and more pronounced in workers with lower metals [p for modifying effect (pME) < 0.040]. Positive associations of some PAHs and metals with 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were weaker in carriers of rs11614913 CC genotype or C allele (pME < 0.05). ConclusionPAH-metal co-exposure, rs11614913, and their interactions may affect oxidative damage levels in Chinese population in a complex manner that are worthy of further investigation.

Preventive effect of TiO2 nanoparticles on heavy metal Pb-induced toxicity in human lung epithelial (A549) cells

Wide application of TiO2 nanoparticles (nTiO2) and ubiquitous lead (Pb) pollution in natural environment enhance the chance of co-exposure of humans to Pb and nTiO2. We investigated the effects of nTiO2 on Pb-induced toxicity in human lung epithelial (A549) cells. Results showed that nTiO2 was not toxic to A549 cells. Conversely, Pb-induced cytotoxicity and oxidative stress in A549 cells were evidenced by cell viability reduction, cell membrane damage, reactive oxygen species generation and depletion of antioxidants. The Pb was also found to alter the regulation of apoptotic genes and cell cycle. Interestingly, in co-exposure group (nTiO2 + Pb), nTiO2 effectively attenuated the cytotoxicity, oxidative stress and apoptotic responses of Pb in A549 cells. Cellular uptake experiments demonstrated that nTiO2 increased the bioaccumulation of Pb in cells. However, due to strong adsorption of Pb on nTiO2, free Pb ions were not available even inside the cells. Hence, nTiO2 significantly prevented the bioavailability and toxicity of Pb in A549 cells. This is the first report providing insight into understanding the mechanism of nTiO2 mediated prevention against Pb-induced toxicity in human cells. This study warranted further research on co-exposure effects of nTiO2 and Pb at in vivo mammalian models.

Parental transfer of perfluorooctane sulfonate and ZnO nanoparticles chronic co-exposure and inhibition of growth in F1 offspring

Perfluorooctane sulfonate (PFOS) and ZnO nanoparticles (Nano-ZnO) are two kinds of environmental contaminants that have been frequently detected in natural waters. The potential joint toxicity of PFOS and nano-ZnO remains to be fully elucidated. The objective of this study was to evaluate co-exposure effects of PFOS and nano-ZnO on growth in initial generation (F0) zebrafish after chronic exposure and to examine possible parental transfer of PFOS and nano-ZnO transgenerational effects on the growth of first generation (F1) larvae. When zebrafish (2 h after incubation) were exposed to single- and co-exposure groups for 120 days, bioconcentration resulted in significantly less growth as measured by body length and body weight, higher mortality, and less spawning in the F0 generation. These effects were possibly due to the down-regulation of the expression of Vtg1 genes along with a sex hormone (T/E2) involved in the hypothalamus-pituitary-gonad (HPG) axis. Furthermore, after long-term exposure, less fertilization, less hatching, greater mortality and more malformation were found in the F1 generation. The down-regulation of genes and hormones might be responsible for transgenerational toxicity. This study suggested that chronic exposure to PFOS and nano-ZnO adversely impacts development, reproduction in the F0 generation, and offspring embryonic growth.

Prenatal exposure to tobacco and cannabis: Effects on autonomic and emotion regulation

Tobacco and cannabis are often used together in pregnancy and both have effects on children's regulatory system. Yet, little is known about the impact of co-use on the development of emotion regulation at the developmentally salient age of 2 years. One pathway linking co-exposure to tobacco and cannabis to toddler regulation may be via poor autonomic regulation in infancy. In addition, substance using mothers may be more dysregulated themselves, which may have direct effects on toddler regulation, but may also affect parenting, particularly maternal sensitivity during mother-child interactions. Thus, a second pathway linking exposure to toddler regulation may be via maternal dysregulation and low maternal sensitivity. We examined a conceptual model linking prenatal exposure to toddler regulation via these two pathways in a prospective sample (N = 247) of mother-child dyads recruited in the first trimester of pregnancy. Results indicated significant effects of co-exposure on poor autonomic regulation in infancy, which in turn predicted poor toddler emotion regulation. Mothers who used both tobacco and cannabis displayed lower sensitivity during play interactions with their infants. Maternal sensitivity was modestly stable from infant to toddler period and was predictive of higher toddler emotion regulation. Continued postnatal exposure to tobacco was also a significant, unique predictor of lower toddler emotion regulation. Results highlight the importance of examining co-exposure effects and suggest that this common pattern of use may be associated with higher infant/toddler risks.

Involvement of two uptake mechanisms of gold and iron oxide nanoparticles in a co-exposure scenario using mouse macrophages.

Little is known about the simultaneous uptake of different engineered nanoparticle types, as it can be expected in our daily life. In order to test such co-exposure effects, murine macrophages (J774A.1 cell line) were incubated with gold (AuNPs) and iron oxide nanoparticles (FeOxNPs) either alone or combined. Environmental scanning electron microscopy revealed that single NPs of both types bound within minutes on the cell surface but with a distinctive difference between FeOxNPs and AuNPs. Uptake analysis studies based on laser scanning microscopy, transmission electron microscopy, and inductively coupled plasma optical emission spectrometry revealed intracellular appearance of both NP types in all exposure scenarios and a time-dependent increase. This increase was higher for both AuNPs and FeOxNPs during co-exposure. Cells treated with endocytotic inhibitors recovered after co-exposure, which additionally hinted that two uptake mechanisms are involved. Cross-talk between uptake pathways is relevant for toxicological studies: Co-exposure acts as an uptake accelerant. If the goal is to maximize the cellular uptake, e.g., for the delivery of pharmaceutical agents, this can be beneficial. However, co-exposure should also be taken into account in the case of risk assessment of occupational settings. The demonstration of co-exposure-invoked pathway interactions reveals that synergetic nanoparticle effects, either positive or negative, must be considered for nanotechnology and nanomedicine in particular to develop to its full potential.

Effects of fusariotoxin co-exposure on THP-1 human immune cells.

Deoxynivalenol (DON), nivalenol (NIV), T-2 toxin (T2), fumonisin B1 (FB1), zearalenone (ZEA), and moniliformin (MON) mycotoxins are common food and feed contaminants produced by Fusarium spp. However, while they are usually found to co-occur in a large range of commodities, only few data are available on mycotoxin co-exposure effects and cellular response mechanisms. In this study, the individual and combined toxic effects of these fusariotoxins were evaluated on the THP-1 human immune cell line as major fusariotoxins are mostly potent immunomodulators. In particular, four relevant fusariotoxin mixtures, namely DON-MON, DON-FB1, DON-ZEA, and NIV-T2, were studied using several parameters including cell viability as well as the expression of cell surface markers and the main mitogen-activated protein kinases (MAPKs). After 48h exposure, a reduction of cell viability in a dose-dependent manner was observed for T2, the most cytotoxic mycotoxin, followed by NIV, DON, MON, FB1, and ZEA. Regarding mycotoxin mixtures, they mainly showed antagonism on cell viability reduction. Interestingly, at concentrations inhibiting 50% of cell viability, most viable cells exhibited surface marker loss and thus became potentially non-functional. In addition, during the first 18h of exposure, the effects of mycotoxin mixtures on early cell apoptosis and necrosis were found to be different from those induced by the toxins alone. At the molecular level, after 1h exposure of individual and combined mycotoxins, the three main MAPK signaling pathways (p38, SAPK/JNK, and ERK1/2) were activated, highlighting a fast reaction of the exposed cells even at low cytotoxicity levels.

Co-Exposure Effects of LPS with Various Aflatoxin B1 Doses in Isolated Perfused Rat Liver Model

Co-Exposure Effects of LPS with Various Aflatoxin B1 Doses in Isolated Perfused Rat Liver Model

The effects of phthalate and nonylphenol exposure on body size and secondary sexual characteristics during puberty

Some phthalic acid esters (PAEs) and nonylphenol (NP) are endocrine-disrupting chemicals (EDCs) that are widely used in consumer products. Consequently, the general population is exposed simultaneously to both groups of chemicals. To investigate the single- and co-exposure effects of PAEs (DMP, DEP, DnBP, DiBP, BBzP, and DEHP) and NP on obesity and pubertal maturity to compare the body sizes of general adolescents with the complainants of the phthalate-tainted foods scandal that occurred in Taiwan. This study included 270 general adolescents aged 6.5-15.0 years and 38 complainants aged 6.5-8.5 years. Nine metabolites of the five PAEs and of NP were measured in urine. We used a questionnaire to evaluate pubertal maturity, measured anthropometric indices (APs) to assess body size, and collected urine samples to measure the two groups of chemicals. We found that urinary PAE metabolite concentrations (specifically, metabolites of DEP, DnBP, DiBP, and DEHP) were positively associated with the APs for abdominal obesity (including skinfold thickness, waist circumference, waist-to-height ratio, and waist-to-hip) and indicated a dose-response relationship. Mono-methyl phthalate (MMP) exposure was inversely associated with pubarche among boys. The daily intake of DEHP in general adolescents exceeded the reference doses (RfD-20 μg/kgbw/day) and tolerable daily intake (TDI-50 μg/kgbw/day) by 3.4% and 0.4%, respectively. No associations were observed between NP exposure or co-exposure and the APs or pubertal maturity. No significant differences were observed between general adolescents and the complainants with regard to weight, height, or BMI. The study suggests that PAE (specifically, DEP, DnBP, DiBP, and DEHP) exposure is associated with abdominal obesity in adolescents and that the APs for abdominal obesity are more sensitive than BMI for measuring obesity among adolescents. We suggest that the RfD and TDI for PAEs should be revised to provide sufficient protection.

An assessment of the potential for co-exposure to allergenic pollen and air pollution in Copenhagen, Denmark

Co-exposure to air pollutants and pollen allergens can aggravate the allergic reaction and reduce the threshold at which susceptible individuals are affected. Here we assessed which air pollutants may be of particular relevance when investigating co-exposure with pollen. We examined the yearly variation and diurnal patterns of pollen and air pollution on days with peak pollen concentrations and non-peak days separately. The analysis was performed for measurements of grass and birch pollen, sulfur dioxide, ozone, nitrogen dioxide and particulate matter. Results indicated that high ozone concentrations coincide both seasonally and diurnally with high pollen concentrations, and that ozone concentrations were higher on peak pollen days, potentially leading to clinically relevant simultaneous co-exposure. For nitrogen dioxide and sulfur dioxide no periods with peaks simultaneously with peaks in pollen loads was identified, and concentrations were below potential thresholds for adjuvant effects to the allergic reaction. For particulate matter no simultaneous peaks in diurnal or seasonal concentrations were identified, however concentrations were higher on peak pollen days compared with non-peak days. When considering co-exposure effects from pollen and pollutants, ozone appears to be the most relevant pollutant to further examine for effects of simultaneous co-exposures.