Early-life exposure to mycotoxin zearalenone exacerbates aberrant immune response, oxidative stress, and mortality of Caenorhabditis elegans under pathogen Bacillus thuringiensis infection.

Zearalenone (ZEN) is a prevalent mycotoxin that severely impacts human and animal health. However, the possible interactions between ZEN exposure, pathogen infection, immune system, and reactive oxygen species (ROS) were rarely investigated. We studied the effects of early-life ZEN (50 µM) exposure on the immune response of Caenorhabditis elegans against Bacillus thuringiensis infection and the associated mechanisms. The transcriptomic responses of C. elegans after early-life ZEN exposure were investigated using RNA sequencing and followed by verification using quantitative PCR analysis. We also investigated the immune responses of the worms through B. thuringiensis killing assays and by measuring oxidative stress. The transcriptomics result showed that early-life exposure to ZEN resulted in 44 differentially expressed genes, 7 of which were protein-coding genes with unknown functions. The Gene Ontology analysis suggested that metabolic processes and immune response were among the most significantly enriched biological processes, and the KEGG analysis suggested that lysosomes and metabolic pathways were the most significantly enriched pathways. The ZEN-exposed worms exhibited significantly reduced survival after 24-h B. thuringiensis infection, reaching near 100% mortality compared to 60% of the controls. Using qRT-PCR assay, we found that ZEN further enhanced the expression of immunity genes lys-6, spp-1, and clec-60 after B. thuringiensis infection. A concurrently enhanced ROS accumulation was also observed for ZEN-exposed worms after B. thuringiensis infection, which was 1.2-fold compared with the controls. Moreover, ZEN exposure further enhanced mRNA expression of catalases (ctl-1 and ctl-2) and increased catalase protein activity after B. thuringiensis exposure compared with their non-exposed counterparts, suggesting an elevated oxidative stress. This study suggests that early-life exposure to mycotoxin zearalenone overstimulates immune responses involving spp-17, clec-52, and clec-56, resulting in excessive ROS production, enhanced oxidative stress as indicated by aggravated ctl expression and activity, and a decline in host resistance to pathogenic infection which ultimately leads to increased mortality under B. thuringiensis infection. Our findings provide evidence that could improve our understanding on the potential interactions between mycotoxin zearalenone and pathogens.

Tangeretin Supplementation Mitigates the Aging Toxicity Induced by Dietary Benzo[a]pyrene Exposure with Aberrant Proteostasis and Heat Shock Responses in Caenorhabditis elegans.

Benzo[a]pyrene (BaP) is a common food contaminant that can impair organismal aging. Tangeretin (TAN) may mitigate aging toxicities as a dietary supplement. This study used Caenorhabditis elegans to investigate the effects of chronic exposure to BaP on aging and to determine whether TAN supplementation could alleviate BaP-induced toxicity. Early life exposure to BaP (10 µM) significantly inhibited growth by 5%, and exposure to 0.1 to 10 µM BaP impaired C. elegans motility, resulting in a 3.4-6.5% reduction in motility. Chronic exposure to BaP (10 µM) age-dependently aggravated aberrant protein aggregation (7% increase) and shortened the median lifespan of the worms from 20 to 16 days. In addition, BaP worsened the age-dependent decline in motility and pharyngeal pumping, as well as the accumulation of reactive oxygen species. Furthermore, exposure to BaP resulted in significantly higher relative transcript levels of approximately 1.8-2.0-fold for the hsp-16.1, hsp-16.2, hsp-16.49, and hsp-70 genes. Stressed worms exposed to BaP exhibited significantly lower survival under heat stress. Dietary TAN supplementation alleviated the BaP-induced decline in motility, pumping, and poly-Q accumulation and restored heat shock proteins' transcript levels. Our findings suggest that chronic BaP exposure adversely affects aging and that TAN exposure mitigates the BaP-induced aging toxicity.

Co-contaminants of ethinylestradiol and sulfamethoxazole in groundwater exacerbate ecotoxicity and ecological risk and compromise the energy budget of C. elegans.

Ethinylestradiol (EE2) and sulfamethoxazole (SMX) are among pharmaceuticals and personal care products (PPCPs) and regarded as emerging contaminants in groundwater worldwide. However, the ecotoxicity and potential risk of these co-contaminants remain unknown. We investigated the effects of early-life long-term co-exposure to EE2 and SMX in groundwater on life-history traits of Caenorhabditis elegans and determined potential ecological risks in groundwater. L1 larvae of wild-type N2 C. elegans were exposed to measured concentrations of EE2 (0.001, 0.75, 5.1, 11.8 mg/L) or SMX (0.001, 1, 10, 100 mg/L) or co-exposed to EE2 (0.75 mg/L, no observed adverse effect level derived from its reproductive toxicity) and SMX (0.001, 1, 10, 100 mg/L) in groundwater. Growth and reproduction were monitored on days 0 - 6 of the exposure period. Toxicological data were analyzed using DEBtox modeling to determine the physiological modes of action (pMoAs) and the predicted no-effect concentrations (PNECs) to estimate ecological risks posed by EE2 and SMX in global groundwater. Early-life EE2 exposure significantly inhibited the growth and reproduction of C. elegans, with lowest observed adverse effect levels (LOAELs) of 11.8 and 5.1 mg/L, respectively. SMX exposure impaired the reproductive capacity of C. elegans (LOAEL = 0.001 mg/L). Co-exposure to EE2 and SMX exacerbated ecotoxicity (LOAELs of 1 mg/L SMX for growth, and 0.001 mg/L SMX for reproduction). DEBtox modeling showed that the pMoAs were increased growth and reproduction costs for EE2 and increased reproduction costs for SMX. The derived PNEC falls within the range of detected environmental levels of EE2 and SMX in groundwater worldwide. The pMoAs for EE2 and SMX combined were increased growth and reproduction costs, resulting in lower energy threshold values than single exposure. Based on global groundwater contamination data and energy threshold values, we calculated risk quotients for EE2 (0.1 - 123.0), SMX (0.2 - 91.3), and combination of EE2 and SMX (0.4 - 341.1). Our findings found that co-contamination by EE2 and SMX exacerbates toxicity and ecological risk to non-target organisms, suggesting that the ecotoxicity and ecological risk of co-contaminants of pharmaceuticals should be considered to sustainably manage groundwater and aquatic ecosystems.

Sulfate-modified nanosized polystyrene impairs memory by inhibiting ionotropic glutamate receptors and the cAMP-response element binding protein (CREB) pathway in Caenorhabditis elegans.

Nanoplastic contamination is an emerging environmental concern worldwide. In particular, sulfate anionic surfactants often appear along with nanosized plastic particles in personal care products, suggesting that sulfate-modified nanosized polystyrene (S-NP) may occur, remain, and spread into the environment. However, whether S-NP adversely affects learning and memory is unknown. In this study, we used a positive butanone training protocol to evaluate the effects of S-NP exposure on short-term associative memory (STAM) and long-term associative memory (LTAM) in Caenorhabditis elegans. We observed that long-term S-NP exposure impairs both STAM and LTAM in C. elegans. We also observed that mutations in the glr-1, nmr-1, acy-1, unc-43, and crh-1 genes eliminated the STAM and LTAM impairment induced by S-NP, and the mRNA levels of these genes were also decreased upon S-NP exposure. These genes encode ionotropic glutamate receptors (iGluRs), cyclic adenosine monophosphate (cAMP)/Ca2+ signaling proteins, and cAMP-response element binding protein (CREB)/CRH-1 signaling proteins. Moreover, S-NP exposure inhibited the expression of the CREB-dependent LTAM genes nid-1, ptr-15, and unc-86. Our findings provide new insights into long-term S-NP exposure and the impairment of STAM and LTAM, which involve the highly conserved iGluRs and CRH-1/CREB signaling pathways.

Dietary Transfer of Zinc Oxide Nanoparticles Induces Locomotive Defects Associated with GABAergic Motor Neuron Damage in Caenorhabditis elegans.

The widespread use of zinc oxide nanoparticles (ZnO-NPs) and their release into the environment have raised concerns about the potential toxicity caused by dietary transfer. However, the toxic effects and the mechanisms of dietary transfer of ZnO-NPs have rarely been investigated. We employed the bacteria-feeding nematode Caenorhabditis elegans as the model organism to investigate the neurotoxicity induced by exposure to ZnO-NPs via trophic transfer. Our results showed that ZnO-NPs accumulated in the intestine of C. elegans and also in Escherichia coli OP50 that they ingested. Additionally, impairment of locomotive behaviors, including decreased body bending and head thrashing frequencies, were observed in C. elegans that were fed E. coli pre-treated with ZnO-NPs, which might have occurred because of damage to the D-type GABAergic motor neurons. However, these toxic effects were not apparent in C. elegans that were fed E. coli pre-treated with zinc chloride (ZnCl2). Therefore, ZnO-NPs particulates, rather than released Zn ions, damage the D-type GABAergic motor neurons and adversely affect the locomotive behaviors of C. elegans via dietary transfer.

Assessing the ecological risk and ecotoxicity of the microbially mediated restoration of heavy metal-contaminated river sediment.

Anthropogenic activities such as mining, smelting industries, and the application of pesticides in agriculture might result in contamination of multiple heavy metals in the environment. Heavy metal contamination of sediment is a serious environmental problem, and thus the remediation of contaminated sediment is a worldwide challenge. Several strategies have been developed for the remediation of contaminated sediment, however the ecological risk and ecotoxicity of the restored sediment have rarely been evaluated. We assessed whether river sediment highly contaminated with heavy metals could be restored using microbial bioleaching followed by evaluating the residual toxicity and ecological risk of the microbially remediated sediment. Sequential extraction revealed that the bioavailable levels of Cu, Ni, and Zn in the contaminated sediment exceeded sediment quality guideline (SQG) thresholds. It was consequently found that acidophilic sulfur-oxidizing Acidicaldus sp. SV5 effectively bioleached Cu, Ni, and Zn from the contaminated sediment, reducing the bioavailable fraction of these elements below SQG thresholds. The ecological risk assessment indicated that SV5-driven remediation significantly reduced the potential ecological risk of the contaminated sediment. The residual ecotoxicity of the microbially remediated sediment was also tested with the soil nematode Caenorhabditis elegans. There was a significant decrease in the body burden of Cu, Ni, and Zn in C. elegans and a reduction in the toxicological effect on survival, growth, and reproduction in the microbially remediated sediment. Our study suggests that a combination of chemical analysis, chemical-based ecological risk assessment, and ecotoxicity tests would be helpful for the development of efficient and eco-friendly strategies for the restoration of contaminated sediment, which could be incorporated into sediment quality management practices.

Dietary Methylglyoxal Exposure Induces Alzheimer's Disease by Promoting Amyloid ß Accumulation and Disrupting Autophagy in Caenorhabditis elegans.

Methylglyoxal (MG) is a precursor of advanced glycation end products usually generated during cooking. The high level of MG in the brain is correlated to the pathogenesis of Alzheimer's disease (AD). However, it is not clear if MG consumed through the diet can cause AD-related toxicity. Herein, the Caenorhabditis elegans (C. elegans) AD model was used to investigate the neurotoxicity after long-term MG exposure at dietary levels. The results showed that C. elegans locomotive behaviors were significantly decreased after 0.1, 0.5, and 1 mM MG exposure (p < 0.001). In amyloid ß (Aß)-expressing transgenic C. elegans strains, 0.5 mM MG significantly promoted Aß accumulation by around 50% in day-8 CL2006 (p < 0.001), enhanced paralysis in CL4176 (p < 0.001) and CL2006 (p < 0.01), and made CL2355 around 17% more vulnerable to 5-HT, indicating impaired serotonin reuptake (p < 0.05). Additionally, 0.5 mM MG significantly increased the reactive oxygen species level (p < 0.001) by inhibiting the expression of stress-response genes including sod-3, gst-4, and hsp-16.2 in day-8 aged worms. Moreover, the autophagic pathway was disrupted through lgg-1, vps-34, and bec-1 expression after MG exposure and Aß accumulation. Treatment with the citrus flavonoid nobiletin reduced the MG-induced toxicity (p < 0.001). Overall, these findings imply that it is possible to exacerbate AD pathogenesis by MG exposure through the diet.

Chronic exposure to environmentally relevant levels of di(2-ethylhexyl) phthalate (DEHP) disrupts lipid metabolism associated with SBP-1/SREBP and ER stress in C. elegans.

DEHP is commonly found in the environment, biota, food, and humans, raising significant health concerns. Whether developmental stage and exposure duration modify the obesogenic effects of DEHP is unclear, especially the underlying mechanisms by which chronic exposure to DEHP as well as its metabolites remain largely unknown. This study investigated the obesogenic effects of chronic DEHP exposure, with levels below environmentally-relevant amounts and provide the mechanism in Caenorhabditis elegans. We show that early-life DEHP exposure resulted in an increased lipid and triglyceride (TG) accumulation mainly attributed to DEHP itself, not its metabolite mono-2-ethylhexyl phthalate (MEHP). In addition, developmental stage and exposure timing influence DEHP-induced TG accumulation and chronic DEHP exposure resulted in the most significant effect. Analysis of fatty acid composition shows that chronic DEHP exposure altered fatty acid composition and TG, resulting in an increased ω-6/ω-3 ratio. The increased TG content by chronic DEHP exposure required lipogenic genes fat-6, fat-7, pod-2, fasn-1, and sbp-1. Moreover, chronic DEHP exposure induced XBP-1-mediated endoplasmic reticulum (ER) stress which might lead to up-regulation of sbp-1. This study suggests the possible involvement of ER stress and SBP-1/SREBP-mediated lipogenesis in chronic DEHP-induced obesogenic effects. Results from this study implies that chronic exposure to DEHP disrupts lipid metabolism, which is likely conserved across species due to evolutionary conservation of molecular mechanisms, raising concerns in ecological and human health.

Levels of bioavailable manganese in river sediment may elevate reproductive risk in model organism Caenorhabditis elegans.

Manganese occurs naturally in sediment, yet anthropogenic sources, such as industrial wastewater and mining, increases Mn concentration. However, the environmental risk of bioavailable Mn is often overlooked and infrequently addressed. A probabilistic risk assessment was conducted to determine the effects of bioavailable Mn in river sediments on reproduction in model organism Caenorhabditis elegans using in utero egg counts and germline apoptosis as biomarkers. The lowest-observed-adverse-effect level (LOAEL) of sediment Mn that decreases in utero egg counts or increases germline apoptosis in C. elegans was 50 or 10 mg of Mn(II) per kg of dry weight sediment, respectively. Effect and exposure analyses were conducted using Hill model-simulated concentration-response curves and Mn concentrations of Laojie River sediment. Risk quotients (RQs) and exceedance risk (ER) analyses showed that bioavailable levels of Mn in Laojie River sediments from downstream sites collected during the dry season elevate reproductive risk as measured by germline apoptosis. These findings suggest that bioavailable levels of Mn in sediment exert negative impacts, and germline apoptosis is a sensitive biomarker for reproductive risk assessment. Our results also suggest that the anthropogenic Mn pollution in river sediment and spatial-seasonal bioavailability of Mn should be considered to improve sediment quality control.

Early-life chronic di(2-ethylhexyl)phthalate exposure worsens age-related long-term associative memory decline associated with insulin/IGF-1 signaling and CRH-1/CREB in Caenorhabditis elegans.

The ubiquitous contamination of di(2-ethylhexyl)phthalate (DEHP) in the environment, biota, and food poses potential ecological and human health risks. DEHP exposure can adversely affect learning and memory, yet the underlying mechanisms remain unclear. In this study, Caenorhabditis elegans was used to investigate the effect of early-life DEHP exposure on age-related long-term associative memory (LTAM) decline, as well as the associations with the cAMP-responsive element-binding protein (CREB) transcription factor and insulin/IGF-1 signaling (IIS). We showed that early-life exposure to DEHP reduced LTAM in wild-type worms at day-0 adulthood. Chronic exposure to DEHP from the L1 stage to day-5 adulthood worsened the age-dependent decline of LTAM. Moreover, the effect of DEHP on age-related LTAM requires CRH-1, a homolog of CREB. Mutations in daf-2, the sole receptor of C. elegans IIS, ameliorated the inhibition of LTAM by DEHP, and the effect depended on daf-16. In addition, daf-2 mutation restored the CRH-1 level in DEHP-exposed worms, and the effect required daf-16. Our study suggests that early-life chronic exposure to DEHP worsens age-related LTAM decline and the effect is associated with CRH-1 and IIS in C. elegans. The evolutionary conservation of IIS and CREB implies possible adverse effects by DEHP across species.

Chronic exposure of zearalenone inhibits antioxidant defense and results in aging-related defects associated with DAF-16/FOXO in Caenorhabditis elegans.

Zearalenone (ZEN), a mycotoxin with endocrine disruptive activity and oxidative stress generating ability, has been a worldwide environmental concern for its prevalence and persistency. However, the long-term effect of ZEN on aging process is not fully elucidated. Thus, the present study applied the Caenorhabditis elegans model to investigate the aging-related toxic effect and possible underlying mechanisms under prolonged and chronic ZEN exposure. Our results showed that locomotive behaviors significantly decreased in ZEN (0.3, 1.25, 5, 10, 50 µM) treated C. elegans. In addition, lifespan and aging markers including pharyngeal pumping and lipofuscin were also adversely affected by ZEN (50 µM). Furthermore, ZEN (50 µM) increased ROS level and downregulated antioxidant genes resulted from inhibition of nuclear DAF-16 translocation in aged C. elegans, which was further confirmed by more significant aging-related defects observed in ZEN treated daf-16 mutant. In conclusion, our findings suggest that the aging process and aging-related decline were induced by long-term exposure of ZEN in C. elegans, which is associated with oxidative stress, inhibition of antioxidant defense, and transcription factor DAF-16/FOXO.

Early-life and chronic exposure to di(2-ethylhexyl) phthalate enhances amyloid-ß toxicity associated with an autophagy-related gene in Caenorhabditis elegans Alzheimer's disease models.

The widespread use of di(2-ethylhexyl) phthalate (DEHP) has resulted in its ubiquitous presence in the environment, which has led to serious health concerns. One of these concerns is its possible link to Alzheimer's disease (AD), which is the most common neurodegenerative disease in aged individuals. This study investigated whether early-life and chronic exposure to DEHP affects AD via the toxicity of amyloid-ß (Aß), which has been implicated in the pathogenesis of AD, using Caenorhabditis elegans AD models (strains CL4176 and CL2006). We show that early-life DEHP exposure increased Aß toxicity in C. elegans strains CL4176 and CL2006. Early-life and chronic exposure to DEHP also significantly increased intracellular ROS levels and Aß deposition in aged CL2006 nematodes. Moreover, it was found that DEHP-induced Aß toxicity does not require transcription factors DAF-16 or SKN-1, while early-life and chronic exposure to DEHP significantly increased the accumulation of lysosome-related organelles and the mRNA levels of the autophagy-related gene bec-1 in aged CL2006 nematodes. Our findings suggest that early-life and chronic exposure to DEHP enhances Aß toxicity, which may be associated with the autophagy-lysosomal degradation pathway in C. elegans.

The bioavailability and potential ecological risk of copper and zinc in river sediment are affected by seasonal variation and spatial distribution.

River sediment is the ultimate sink for heavy metal pollution. Copper (Cu) and zinc (Zn) are consistently found at environmentally significant levels in sediments worldwide. We hypothesized that the bioavailability and potential ecological risk of Cu and Zn in river sediments may be affected by seasonal variations and spatial distribution. In this study, we tested our hypothesis using highly industrialized river sediments (Laojie River) as an example. The concentration of heavy metals, pollution indexes, and risk indexes were evaluated and multivariate statistical analyses were performed. We found that seasonal variations affect heavy metal contamination, pollution indexes, and potential ecological risk in sediments and this effect was more severe in the dry season. In addition, higher levels of metal contamination, pollution indexes, and potential ecological risk were observed midstream and downstream of the Laojie River. We found that Cu and Zn were the primary contaminants in Laojie River sediments and may originate from common anthropogenic sources. Analysis of the chemical fractions further revealed that Cu and Zn exhibited high mobility and potential bioavailability risk. In addition, a high percentage and amount of Cu and Zn were found in exchangeable fractions, suggesting they pose a great risk to aquatic organisms. Our results indicate that seasonal variations and spatial distribution affect the bioavailability and potential ecological risk of Cu and Zn in river sediments. These findings suggest that seasonal variations and spatial distribution are important parameters to consider for environmental monitoring and environmental management in aquatic environments.

Early life exposure to di(2-ethylhexyl)phthalate causes age-related declines associated with insulin/IGF-1-like signaling pathway and SKN-1 in Caenorhabditis elegans.

Di(2-ethylhexyl)phthalate (DEHP) is an ubiquitous and emerging contaminant that is widely present in food, agricultural crop, and the environment, posing a potential risk to human health. This study utilized the nematode Caenorhabditis elegans to decipher the toxic effects of early life exposure to DEHP on aging and its underlying mechanisms. The results showed that exposure to DEHP at 0.1 and 1.5 mg/L inhibited locomotive behaviors. In addition, DEHP exposure significantly shortened the mean lifespan of the worms and further adversely affected pharyngeal pumping rate and defecation cycle in aged worms. Moreover, DEHP exposure also further enhanced accumulation of age-related biomarkers including lipofuscin, lipid peroxidation, and intracellular reactive oxygen species in aged worms. In addition, exposure to DEHP significantly suppressed gene expression of hsp-16.1, hsp-16.49, and hsp-70 in aged worms. Further evidences showed that mutation of genes involved in insulin/IGF-1-like signaling (IIS) pathway (daf-2, age-1, pdk-1, akt-1, akt-2, and daf-16) restored lipid peroxidation accumulation upon DEHP exposure in aged worms, whereas skn-1 mutation resulted in enhanced lipid peroxidation accumulation. Therefore, IIS and SKN-1 may serve as an important molecular basis for DEHP-induced age-related declines in C. elegans. Since IIS and SKN-1 are highly conserved among species, the age-related declines caused by DEHP exposure may not be exclusive in C. elegans, leading to adverse human health consequences due to widespread and persistent DEHP contamination in the environment.

Chronic exposure to triadimenol at environmentally relevant concentration adversely affects aging biomarkers in Caenorhabditis elegans associated with insulin/IGF-1 signaling pathway.

Triadimenol, an agricultural fungicide, is an emerging environmental concern due to its wide usage, detection in the environment, and its chemical persistency. Triadimenol has been found to disrupt endocrine signaling and alter function of several transcription factors, yet its age-related toxicity effects remain unclear. This study used Caenorhabditis elegans as an in vivo model organism to elucidate the age-related effects of triadimenol and its underlying mechanisms. The results showed that chronic exposure to triadimenol at environmentally relevant concentrations (3, 30, and 300 µg/L) adversely affected several toxicity endpoints including growth, total brood size, and locomotive behaviors. In addition, triadimenol (300 µg/L) significantly reduced the mean lifespan of wild-type N2 C. elegans from 17.9 to 16 days. Chronic exposure to triadimenol (300 µg/L) also significantly affected age-related behavioral changes, with a decreased pharyngeal pumping rate and an increased defecation cycle. Moreover, an increased accumulation of aging biomarkers including lipofuscin, lipid peroxidation, and reactive oxygen species (H2O2 and O2-) level upon chronic triadimenol exposure was observed in aged worms. Furthermore, chronic triadimenol exposure increased the transcriptional factor DAF-16 nuclear localization. Finally, mutation of daf-2, age-1, pdk-1, akt-1, or akt-2 restored the accumulation of lipofuscin in aged worms upon chronic triadimenol exposure, while mutation of daf-16 led to more enhanced lipofuscin accumulation. Therefore, the insulin/IGF-1 signaling pathway may serve as an important molecular basis for triadimenol induced aging declines in C. elegans.

Prolonged exposure of di(2-ethylhexyl) phthalate induces multigenerational toxic effects in Caenorhabditis elegans.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is an emerging organic contaminant that has represented a risk for organisms present in the environment. However, there is still limited information regarding DEHP-induced multigenerational toxicity and the underlying mechanisms. In this study we investigated the multigenerational toxic effects including locomotive behaviors and reproduction upon prolonged DEHP exposure (from larval L1 to adult) and the underlying mechanisms in the nematode Caenorhabditis elegans. The multigenerational effects were examined over 6 generations (F0-F5) with only parental C. elegans (F0) was exposed to DEHP from larval L1 to adults (72h), and the subsequent offsprings (F1-F5) were grown under DEHP-free conditions. The results showed that prolonged exposure (72h) to various concentrations of DEHP caused dose-dependent locomotive impairments and reproduction defects in C. elegans and that a concentration of 0.2mg/L DEHP was enough to cause such sublethal effects. The results showed that after prolonged exposure to DEHP in the F0 generation, abnormal locomotive behaviors such as reduced body bends and head thrashes were observed from generations F0 to F5. Additionally, prolonged exposure to DEHP (20mg/L) in F0 significantly reduced total brood size in F0, and this parental exposure was sufficient to cause multigenerational reproductive toxicity in the offspring generations (F1-F5) as well. Furthermore, the expressions of reproduction-related genes such as vit-2 and vit-6 were down-regulated by about 20% until F3, and the expression of H3Kme2 demethylase, spr-5, was downregulated in F1 by about 40%. Results from this study demonstrate that prolonged exposure to DEHP only at F0 adversely affected reproduction and locomotive behaviors in C. elegans across generations and might be associated with inadequate vitellogenin production and malfunction of H3Kme2 demethylase. This study implies that parentally prolonged exposure to DEHP caused multigenerational defects in both reproduction and locomotive behaviors raising the potential health and ecological risk.

PBPK/PD assessment for Parkinson's disease risk posed by airborne pesticide paraquat exposure.

Exposure to several specific pesticides has led to an increase of Parkinson's disease (PD) risk. However, it is difficult to quantify the PD population risk related to certain pesticides in regions where environmental exposure data are scarce. Furthermore, the time trend of the prevalence and incidence of PD embedded in the background relationship between PD risk and pesticide exposures has not been well characterized. It has been convincingly identified that a key pesticide associated significantly with an increased risk trend of PD is paraquat (PQ). Here, we present a novel, probabilistic population-based exposure-response approach to quantify the contribution from PQ exposure to prevalence risk of PD. We found that the largest PQ exposure contributions occurred in its positive trend during 2004-2011, with the PQ contributing nearly 21 and 24%, respectively, to the PD prevalence rates among the age groups of 70-79 and ≥ 80 years in Taiwan. We also employed the present population risk model to predict the PQ-induced PD prevalence based on the projected rates of increase in PQ exposure associated with age-specific population. The predicted outcome can be used as an early warning signal for public health authorities. We suggest that a mechanistic understanding of the contribution of a specific pesticide exposure to PD risk trends is crucial to enhance our insights into the perspective on the impacts of environmental exposure on the neurodegenerative diseases.

Assessing exposure risks for freshwater tilapia species posed by mercury and methylmercury.

Waterborne and dietborne exposures of freshwater fish to mercury (Hg) in the forms of inorganic (Hg(II)) and organic (methylmercury or MeHg) affect their growth, development, and reproduction. However, an integrated mechanistic risk model framework to predict the impact of Hg(II)/MeHg on freshwater fish is lacking. Here, we integrated biokinetic, physiological and biogeographic data to calibrate and then establish key risk indices-hazardous quotient and exceedance risk-for freshwater tilapia species across geographic ranges of several major rivers in Taiwan. We found that Hg(II) burden was highest in kidney followed by gill, intestine, liver, blood, and muscle. Our results showed that Hg was less likely to pose mortality risk (mortality rate less than 5 %) for freshwater tilapia species. However, Hg is likely to pose the potential hazard to aquatic environments constrained by safety levels for aquatic organisms. Sensitivity analysis showed that amount of Hg accumulated in tilapia was most influenced by sediment uptake rate. Our approach opens up new possibilities for predicting future fish population health with the impacts of continued Hg exposure to provide information on which fish are deemed safe for human consumption.

Arsenite exposure accelerates aging process regulated by the transcription factor DAF-16/FOXO in Caenorhabditis elegans.

Arsenic is a known human carcinogen and high levels of arsenic contamination in food, soils, water, and air are of toxicology concerns. Nowadays, arsenic is still a contaminant of emerging interest, yet the effects of arsenic on aging process have received little attention. In this study, we investigated the effects and the underlying mechanisms of chronic arsenite exposure on the aging process in Caenorhabditis elegans. The results showed that prolonged arsenite exposure caused significantly decreased lifespan compared to non-exposed ones. In addition, arsenite exposure (100 µM) caused significant changes of age-dependent biomarkers, including a decrease of defecation frequency, accumulations of intestinal lipofuscin and lipid peroxidation in an age-dependent manner in C. elegans. Further evidence revealed that intracellular reactive oxygen species (ROS) level was significantly increased in an age-dependent manner upon 100 µM arsenite exposure. Moreover, the mRNA levels of transcriptional makers of aging (hsp-16.1, hsp-16.49, and hsp-70) were increased in aged worms under arsenite exposure (100 µM). Finally, we showed that daf-16 mutant worms were more sensitive to arsenite exposure (100 µM) on lifespan and failed to induce the expression of its target gene sod-3 in aged daf-16 mutant under arsenite exposure (100 µM). Our study demonstrated that chronic arsenite exposure resulted in accelerated aging process in C. elegans. The overproduction of intracellular ROS and the transcription factor DAF-16/FOXO play roles in mediating the accelerated aging process by arsenite exposure in C. elegans. This study implicates a potential ecotoxicological and health risk of arsenic in the environment.