Integrating aggregate exposure pathway and adverse outcome pathway for micro/nanoplastics: A review on exposure, toxicokinetics, and toxicity studies.

Micro/nanoplastics (MNPs) have emerged as a significant environmental concern due to their widespread distribution and potential adverse effects on human health and the environment. In this study, to integrate exposure and toxicity pathways of MNPs, a comprehensive review of the occurrence, toxicokinetics (absorption, distribution, and excretion [ADE]), and toxicity of MNPs were investigated using the aggregate exposure pathway (AEP) and adverse outcome pathway (AOP) frameworks. Eighty-five papers were selected: 34 papers were on detecting MNPs in environmental samples, 38 papers were on the ADE of MNPs in humans and fish, and 36 papers were related to MNPs toxicity using experimental models. This review not only summarizes individual studies but also presents a preliminary AEP-AOP framework. This framework offers a comprehensive overview of pathways, enabling a clearer visualization of intricate processes spanning from environmental media, absorption, distribution, and molecular effects to adverse outcomes. Overall, this review emphasizes the importance of integrating exposure and toxicity pathways of MNPs by utilizing AEP-AOP to comprehensively understand their impacts on human and ecological organisms. The findings contribute to highlighting the need for further research to fill the existing knowledge gaps in this field and the development of more effective strategies for the safe management of MNPs.

Mixture and individual effects of benzene, toluene, and formaldehyde in zebrafish (Danio rerio) development: Metabolomics, epigenetics, and behavioral approaches.

In this study, we aimed to investigate the potential hazards of volatile organic compounds (VOCs) on the development of zebrafish. To this end, zebrafish embryos were exposed in two different windows, either alone or in a mixture with VOCs (benzene, toluene, and formaldehyde) [EW1: 4 ± 2 h post-fertilization (hpf) to 24 hpf and EW2: 24 ± 2 hpf to 48 hpf]. Alterations in global DNA methylation and related gene expression, behavioral responses, and stress-related gene expression were observed. In addition to these endpoints, non-targeted NMR-based global metabolomics followed by pathway analysis showed significant changes in the metabolism of various amino acids during VOC exposure. Regardless of the analyzed endpoints, toluene was the most toxic chemical when exposed individually and possibly played the most pivotal role in the mixture treatment conditions. In conclusion, our data show that exposure to VOCs at embryonic developmental stages causes physiological perturbations and adverse outcomes at later life stages.

Effect of Early-Life Exposure of Polystyrene Microplastics on Behavior and DNA Methylation in Later Life Stage of Zebrafish.

Microplastic contamination has received increasing attention in recent years, and concern regarding the toxicity of microplastics to the environment and humans has increased. In this study, we investigated the neurodevelopmental toxicity of polystyrene microplastics (PSMPs) in the zebrafish Danio rerio under different exposure scenarios. Zebrafish were exposed to PSMPs during embryonic stage and then allowed the fish to recover. The neurodevelopmental toxic responses were investigated using fish behavior and behavior-related gene expression. Early-life exposure to PSMPs did not alter fish behavior at the early stage; however, it led to hyperactivity later life stage. Generally, oxidative stress (i.e., sod2 and nrf2a)- and nervous system (i.e., slc6a4b, npy, and nrbf2)-related gene expression increased in all PSMPs-exposed fish. DNA hypomethylation was observed in fish challenged for a second time using the same PSMPs. Taken together, the current results imply that PSMPs have neurodevelopmental toxic potential when introduced early in life.

Sex and Gender Analysis of Toxicity and Epidemiology Data on Environmental Chemicals in the Three Major Toxicology Databases.

Background: As sex and gender are important considerations in the assessment of toxic chemicals, we investigated whether sex and gender issues have been adequately considered in toxicological databases. Materials and Methods: A systemic review was conducted on the toxicity and epidemiology data of eight environmental chemicals (i.e., cadmium [Cd], lead [Pb], benzene, toluene, formaldehyde, and tetrachloroethylene [TCE], bis(2-ethylhexyl) phthalate [DEHP], and bisphenol A [BPA]) that appear in three toxicological databases (i.e., Hazardous Substances Data Bank, Integrated Risk Information System, and the European Chemicals Agency databases). Results: Systemic reviews on 4160 data entries pertaining to eight chemicals in three databases revealed that only 13.5% of these were sourced from male and female combined (MF) studies, whereas, 40.6% of the total number of examined entries was sourced from the study in which the sex of the subject was not mentioned. Conclusions: To accurately evaluate the hazardous effect of chemicals, toxicity tests should be designed and conducted for both sexes, and the corresponding endpoints should cover gender concerns. Therefore, databases listing toxicity data as part of the open source literature should select information from MF toxicity and epidemiology studies.

Genetic, epigenetic, and developmental toxicity of Chironomus riparius raised in metal-contaminated field sediments: A multi-generational study with arsenic as a second challenge.

Ecotoxicity tests conducted under well-controlled lab conditions often do not reflect the real environmental conditions. To this end, we designed an ecotoxicity test using an aquatic midge, Chironomus riparius, raised in metal-contaminated field sediments (MCFS), which reflect the real environmental conditions, for five consecutive generations (F0-F4) followed by a toxic response to arsenic exposure (as a second challenge). The toxic responses (i.e. DNA damage, DNA methylation, stress response gene expression, and mortality) were compared to those organisms reared in lab sediments (LS). Under the MCFS condition, increased adult emergence was observed for the second and third generations (F1 and F2), while a decreased tendency was evident thereafter (F3 and F4) compared to that of F0. When comparing C. riparius raised in MCFS or LS exposed to arsenic, increased sensitivity (declined survival) was observed in the larvae from F2. However, that tendency was not present in F4 of the MCFS midges, indicating a possible physiological adaptation. Increased DNA damage was observed in the MCFS-exposed organisms (F0, F2, and F4) compared to the those exposed to LS, particularly at F0. Arsenic exposure induced hypermethylation at F0 and, in contrast, hypomethylation at the later generations (F2, F4) in the MCFS-exposed organisms. Global DNA methylation results were supported by the expression of genes involved in enzymatic methylation. Moreover, alterations in oxidative stress related to gene expression showed that significant oxidative stress and perturbation of glutathione reserves occurred under the MCFS and the subsequent arsenic exposure conditions. Overall, our results suggest that multigenerational rearing under MCFS conditions resulted in physiological adaptation of C. riparius to metal exposure, specifically at later generations, which in turn modulated its response to arsenic stress through possible genetic and epigenetic mechanisms.

Integrated approach of eco-epigenetics and eco-metabolomics on the stress response of bisphenol-A exposure in the aquatic midge Chironomus riparius.

The stress response mechanisms of Bisphenol A (BPA), an endocrine disrupting compound, remain to be elucidated. In this study, we explored the effects of BPA on the non-biting midge Chironomus riparius through basic ecotoxicity assays, DNA damage (comet assay), eco-epigenetics (global DNA and histone methylations) and non-targeted global metabolomics (NMR based) approaches. The reproduction failure, increase in DNA damage, global DNA hyper-methylation, and increased global histone modification (H3K36) status were evident due to BPA exposure at 10% lethal concentration (LC10: 1 mg/L, based on 48 h acute toxicity). Moreover, non-targeted global metabolomics followed by pathway analysis identified alterations of energy metabolism, amino acids, and methionine metabolisms etc. Most importantly, we found a potential cross-talk between altered epigenetics and metabolites, such as, increase in methionine and o-phosphocholine metabolites corresponds with the phenomena of global hyper-methylation in DNA and H3K36 mark. Overall, our results suggests that the crosstalk of global metabolomics and epigenetic modification was fundamental of the underlying mechanisms in BPA-induced stress response in C. riparius.