Medium-chain chlorinated paraffins (MCCPs) induce renal cell aging and ferroptosis.

PURPOSE: Medium-chained chlorinated paraffins (MCCPs) are a class of chlorinated derivatives of straight-chain n-alkanes with complex compositions, which are widely used in industry. The chlorinated paraffins (CPs) are divided into short chain chlorinated paraffins (SCCPs), medium chain chlorinated paraffins (MCCPs) and long chain chlorinated paraffins (LCCPs). SCCPs have been banned due to their severe bioaccumulation and biotoxicity. Therefore, MCCPs are used as a substitute for SCCPs. However, the toxicological data of MCCPs are still very limited. For this, we systematically investigated the toxicological impact of MCCPs on a renal cell model in the current study. Our work provides basic research data for analyzing the toxicological effects of MCCPs, suggesting that MCCPs should be restricted in their usage. METHOD: A series of biochemical experiments was performed, including Western blot, indirect immunofluorescence assay, and ELISA was performed to analyze the toxicological effects of MCCPs. RESULTS: Two renal cell lines were used as a model for assessing the toxicological effects of MCCPs. Cell proliferation assays showed that MCCPs could inhibit the proliferation of kidney cells in a dose-dependent manner. Further studies showed that MCCPs induced ferroptosis in kidney cells by evaluating a series of ferroptosis marker molecules. Additionally, MCCPs induced inflammatory response and premature senescence in HEK293 and NRK-52E cells. Molecular mechanism experiments showed that ferroptosis induced by MCCPs emerged as a significant contributor to premature aging of kidney cells. CONCLUSION: The current study provides basic research data to analyze the toxicological effects of MCCPs and their toxicity mechanisms. It also provides a theoretical basis for the assessment of the potential ecological risk of MCCPs, as well as basic experimental data for the rational and standardized use of MCCPs.

Developmental toxicity of short-chain chlorinated paraffins on early-stage chicken embryos in a shell-less (ex-ovo) incubation system.

Short-chain chlorinated paraffins (SCCPs) are listed as a category of globally controlled persistent organic pollutants (POPs) by the Stockholm Convention in 2017. However, SCCP toxicity, particularly their developmental toxicity in avian embryos, has not been well studied. In this study, we observed the early development of chicken embryos (Gallus gallus domesticus) by applying a shell-less (ex-ovo) incubation system developed in our previous studies. After exposing embryos at Hamburger Hamilton stage (HHS) 1 to SCCPs (control, 0.1% DMSO; SCCPs-L, 200 ng/g; SCCPs-M, 2000 ng/g; SCCPs-H, 20,000 ng/g), we observed the development of embryos from the 3rd to 9th incubation day. Exposure to SCCPs-M and -H induced a significant reduction in survival, with an LD50 of 3100 ng/g on the 9th incubation day. Significant dose-dependent decreases in body length were observed from days 4-9. We also found that SCCPs-H decreased the blood vessel length and branch number on the 4th incubation day. Additionally, SCCPs-H significantly reduced the heart rate on the 4th and 5th incubation days. These findings suggest that SCCPs may have potential of developmental and cardiovascular toxicity during the early stages of chicken embryos. Quantitative PCR of the mRNA of genes related to embryonic development showed that SLC16A10 (a triiodothyronine transporter) level decreased in the SCCPs-H group, showing a significant positive correlation with the body length of embryos. THRA level, a thyroid hormone receptor, was significantly decreased in the SCCPs-H group, whereas that of DIO3 level, a deiodinase was significantly increased. These results suggest that SCCPs exposure induces developmental delays via the thyroxine signaling pathway. Analysis of thyroid hormones (THs) in blood plasma also indicated a significant reduction in thyroxine (T4) levels in the SCCPs-H group on the 9th incubation day of embryos. In conclusion, SCCPs induce developmental toxicity by disrupting thyroid functions at the early-life stage of chicken embryos.

Positive association between chlorinated paraffins and the risk of allergic diseases in children and adolescents.

Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.

Effects of environmentally relevant concentration of short-chain chlorinated paraffins on BV2 microglia activation and lipid metabolism, implicating altered neurogenesis.

Short-chain chlorinated paraffins (SCCPs), a class of persistent organic pollutants, have been found to cause diverse organ and systemic toxicity. However, little is known about their neurotoxic effects. In this study, we exposed BV2, a mouse microglia cell line, to environmentally relevant concentration of SCCPs (1 µg/L, 10 µg/L, 100 µg/L) for 24 h to investigate their impacts on the nervous system. Our observations revealed that SCCPs induced the activation of BV2 microglia, as indicated by altered morphology, stimulated cell proliferation, enhanced phagocytic and migratory capabilities. Analysis at the mRNA level confirmed the activation status, with the downregulation of TMEM119 and Tgfbr1, and upregulation of Iba1 and CD11b. The upregulated expression of genes such as cenpe, mki67, Axl, APOE and LPL also validated alterations in cell functions. Moreover, BV2 microglia presented an M2 alternative phenotype upon SCCPs exposure, substantiated by the reduction of NF-κB, TNF-α, IL-1ß, and the elevation of TGF-ß. Additionally, SCCPs caused lipid metabolic changes in BV2 microglia, characterized by the upregulations of long-chain fatty acids and acylcarnitines, reflecting an enhancement of ß-oxidation. This aligns with our findings of increased ATP production upon SCCPs exposure. Intriguingly, cell activation coincided with elevated levels of omega-3 polyunsaturated fatty acids. Furthermore, activated microglial medium remarkably altered the proliferation and differentiation of mouse neural stem cells. Collectively, exposure to environmentally relevant concentrations of SCCPs resulted in activation and lipid metabolic alterations in BV2 microglia, potentially impacting neurogenesis. These findings provide valuable insights for further research on the neurotoxic effect of SCCPs.

Metabolic disturbance of short- and medium-chain chlorinated paraffins to zebrafish larva.

Chlorinated paraffins (CPs) are widely produced chemicals. Short-chain CPs (SCCPs) and medium-chain CPs (MCCPs) were listed as Persistent Organic Pollutants (POPs) and candidate POPs under the Stockholm Convention, respectively. The present study explored the developmental toxicity and metabolic disruption caused by SCCPs and MCCPs in zebrafish (Danio rerio) larvae. CPs exposure at environmentally relevant levels caused no obvious phenotypic changes with zebrafish larvae except that the body length shortening was observed after exposure to CPs at 1-200 µg/L for 7 day post fertilization. A further metabolomic approach was conducted to explore the early biological responses of developmental toxicity induced by CPs at low dose (1, 5, and 10 µg/L). The results of metabolic disorder, pathway analysis and chronic values indicated that, compared with SCCPs, MCCPs exhibited more risks to zebrafish larvae at low doses. Lipid metabolism was markedly affected in SCCPs exposure group, whereas MCCPs primarily disturbed lipid metabolism, amino acid, and nucleotide metabolisms. Compare with SCCPs, the relatively higher lipid solubility, protein affinity and metabolic rate of MCCPs can probably explain why MCCP-mediated metabolic disruption was significantly higher than that of SCCP. Notably, SCCPs and MCCPs have the same potential to cause cancer, but no evidence indicates the mutagenicity. In summary, our study provides insight into the potential adverse outcome for SCCP and MCCP at low doses.

[Metabolomic interference induced by short-chain chlorinated paraffins in human normal hepatic cells].

Short-chain chlorinated paraffins (SCCPs) are an emerging class of persistent organic pollutants (POPs) that are widely detected in environmental matrices and human samples. Because of their environmental persistence, long-range transport potential, bioaccumulation potential, and biotoxicity, SCCPs pose a significant threat to human health. In this study, metabolomics technology was applied to reveal the metabolomic interference in human normal hepatic (L02) cells after exposure to low (1 µg/L), moderate (10 µg/L), and high (100 µg/L) doses of SCCPs. Principal component analysis (PCA) and metabolic effect level index (MELI) values showed that all three SCCP doses caused notable metabolic perturbations in L02 cells. A total of 72 metabolites that were annotated by MS/MS and matched with the experimental spectra in the Human Metabolome Database (HMDB) or validated by commercially available standards were selected as differential metabolites (DMs) across all groups. The low-dose exposure group shared 33 and 36 DMs with the moderate- and high-dose exposure groups, respectively. The moderate-dose exposure group shared 46 DMs with the high-dose exposure group. In addition, 33 DMs were shared among the three exposure groups. Among the 72 DMs, 9, 9, and 45 metabolites participated in the amino acid, nucleotide, and lipid metabolism pathways, respectively. The results of pathway enrichment analysis showed that the most relevant metabolic pathways affected by SCCPs were the lipid metabolism, fatty acid ß-oxidation, and nucleotide metabolism pathways, and that compared with low-dose exposure, moderate- and high-dose SCCP exposures caused more notable perturbations of these metabolic pathways in L02 cells. Exposure to SCCPs perturbed glycerophospholipid and sphingolipid metabolism. Significant alterations in the levels of phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins indicated SCCP-induced biomembrane damage. SCCPs inhibited fatty acid ß-oxidation by decreasing the levels of short- and medium-chain acylcarnitines in L02 cells, indicating that the energy supplied by fatty acid oxidation was reduced in these cells. Furthermore, compared with low- and moderate-dose SCCPs, high-dose SCCPs produced a significantly stronger inhibition of fatty acid ß-oxidation. In addition, SCCPs perturbed nucleotide metabolism. The higher hypoxanthine levels observed in L02 cells after SCCP exposures indicate that SCCPs may induce several adverse effects, including hypoxia, reactive oxygen species production, and mutagenesis in L02 cells.

In vitro assessment of potential endocrine disrupting activities of chlorinated paraffins of various chain lengths.

The production of chlorinated paraffins (CPs) has risen in the past two decades due to their versatile industrial applications. Consequently, CPs are now widely detected in human food sources, the environment, and in human matrices such as serum, the placenta and breast milk. This raises concern about prenatal and postnatal exposure. While some studies suggest that certain short-chained CPs (SCCPs) may have endocrine disrupting properties, knowledge about potential endocrine disrupting potential of medium- (MCCP) and long-chained CPs (LCCPs) remains relativity sparse. Here, we used a panel of in vitro assays to investigate seven pure CPs and two technical mixtures of CPs. These varied in chain length and, chlorination degree. The in vitro panel covered androgen, estrogen, and retinoic acid receptor activities, transthyretin displacement, and steroidogenesis. One of the SCCPs inhibited androgen receptor (AR) activity. All SCCPs induced estrogen receptor (ER) activity. Some SCCPs and MCCPs increased 17ß-estradiol levels in the steroidogenesis assay, though not consistently across all substances in these groups. SCCPs exhibited the most pronounced effects in multiple in vitro assays, while the tested LCCPs showed no effects. Based on our results, some CPs can have endocrine disrupting potential in vitro. These findings warrant further examinations to ensure that CPs do not cause issues in intact organisms, including humans.

Stress Response in the Honeybee (Apis mellifera L.) Gut Induced by Chlorinated Paraffins at Residue Levels Found in Bee Products.

Chlorinated paraffins (CPs) have become global pollutants and are of considerable concern as a result of their persistence and long-distance transmission in the environment and toxicity to mammals. However, their risks to pollinating insects are unknown. Honeybees are classical pollinators and sensitive indicators of environmental pollution. Herein, the effects of CPs on the gut microenvironment and underlying mechanisms were evaluated and explored using Apis mellifera L. Both short- and medium-chain CPs had significant sublethal effects on honeybees at a residue dose of 10 mg/L detected in bee products but did not significantly alter the composition or diversity of the gut microbiota. However, this concentration did induce significant immune, detoxification, and antioxidation responses and metabolic imbalances in the midgut. The mechanisms of CP toxicity in bees are complicated by the complex composition of these chemicals, but this study indicated that CPs could substantially affect intestinal physiology and metabolic homeostasis. Therefore, CPs in the environment could have long-lasting impacts on bee health. Future studies are encouraged to identify novel bioindicators of CP exposure to detect early contamination and uncover the detailed mechanisms underlying the adverse effects of CPs on living organisms, especially pollinating insects.

Toxic effects and toxicological mechanisms of chlorinated paraffins: A review for insight into species sensitivity and toxicity difference.

Chlorinated paraffins (CPs), a group of chlorinated alkane mixtures, are frequently detected in various environmental matrices and human bodies. Recently, CPs have garnered considerable attention owing to their potential to induce health hazards in wildlife and human. Several reviews have discussed short-chain CPs (SCCPs) induced ecological risk; however, a comprehensive understanding of the underlying toxic mechanisms and a comparison among SCCPs, medium-, and long-chain CPs (MCCPs and LCCPs, respectively) are yet to be established. This review summarizes the latest research progress on the toxic effects and the underlying molecular mechanisms of CPs. The main toxicity mechanisms of CPs include activation of several receptors, oxidative stress, disturbance of energy metabolism, and inhibition of gap junction-mediated communication. The sensitivity of different species to CP-mediated toxicities varies markedly, with aquatic organisms exhibiting the highest sensitivity to CP-induced toxicity. The toxicity comparison analysis indicated that MCCPs may be unsafe as potential substitutes for SCCPs.

Effects of exposure to chlorinated paraffins on human health: A scoping review.

Chlorinated paraffins (CPs) belong to an emerging class of persistent organic pollutants (POPs) widely detected in environmental matrices and human samples. The potential health risks of CPs on humans have initiated intense concerns but there have been few studies focusing on the said topic. Addressing the gap, we make a scoping review on the current global body of evidence from epidemiological and toxicological studies. Furthermore, the management strategies and regulations related to CPs are presented and discussed. There were 70 articles among 11,280 records, including four epidemiological studies, one case report, another twenty-nine studies reporting human body burden, and thirty-six toxicological studies, finally included in this review. Additionally, twenty-three management regulation relevant documents/websites were included. CPs exist in human blood, breast milk, placenta, and other tissues. Population-based and laboratory studies suggest that CPs may cause liver and kidney toxicity, developmental toxicity, neurotoxicity, endocrine disorder, immune dysfunction, and reproductive toxicity. CPs with shorter carbon chains and higher chlorine content may be more harmful. In particular, the combined effect of CPs with other pollutants is of great concern. Population-based studies are far from sufficient at present, and most of them are conducted in China or developed countries. Besides, the toxicity assessment studies of CPs are inadequate. In addition, most studies focus on short-chain CPs (SCCPs) while few studies explored the effect of long-chain CPs (LCCPs). Thus, conducting more epidemiological studies in larger populations and toxicological studies combined with new technology methods are of great significance for better understanding the adverse health effects of CPs, which may promote CPs management regulations.

Chronic oral exposure to short chain chlorinated paraffins induced testicular toxicity by promoting NRF2-mediated oxidative stress.

As a widespread environmental contaminant, short chain chlorinated paraffins (SCCPs) has attracted great attention. However, the toxicity of SCCPs on male reproductive system remains ambiguous. In this study, we treated mice with SCCPs by gavage and investigated the toxic effects of SCCPs on testis. According to the results, the sperm parameters of mice were significantly reduced after exposure to 1, 10, 100 mg/kg body mass per day SCCPs for 35 days. SCCPs resulted in disorderly arranged seminiferous epithelium and increased apoptotic cells in testes. Both in vivo and in vitro experiments indicated that the oxidative stress was induced after SCCPs exposure, and dysfunction of nuclear factor erythroid-related factor (NRF2) signaling pathway played a role in this process. Moreover, resveratrol, an NRF2 activator, could alleviate the damage of SCCPs onmale reproductive system. Our study indicated that oxidative stress is the key point for explaining the testicular toxicity caused by SCCPs, and NRF2 could be used as a potential target for clinical treatment to alleviate the reproductive toxicity induced by SCCPs.

Evaluation of the immunomodulatory effects of C9-13-CPs in macrophages.

Short-chain chlorinated paraffins (SCCPs) have been listed as a new class of persistent organic pollutants by the Stockholm Convention. SCCPs exhibit carcinogenic-, endocrine-, and metabolism-disrupting effects. However, the knowledge of the immunomodulatory effects of SCCPs and their underlying mechanisms, especially in specific immune cells, remains limited. In addition to SCCPs, C9-13-CPs have also been detected in humans. In this study, murine RAW264.7 macrophages were exposed to C9-13-CPs at environmentally relevant concentrations to investigate whether or how C9-13-CPs exhibit immunomodulatory effects. The results showed that the exposure of RAW264.7 cells to C9-13-CPs increased cell viability, as assayed by MTT analysis at 490 nm, and also promoted cell proliferation, as indicated by EdU uptake assay, which was measured at excitation and emission wavelengths of 488 and 512 nm, respectively. In addition, exposure to C9-13-CPs not only led to elevated ATP level and intracellular Ca2+ level but also caused AMPK signaling activation and NF-κB signaling inhibition. Moreover, molecular docking showed that the ß2-AR receptor could bind to C9-13-CPs. Taken together, these results suggest that the immune dysfunction of RAW264.7 cells caused by C9-13-CPs is closely related to the ß2-AR/AMPK/NF-κB signaling axis.

Metabolomic mechanisms of short chain chlorinated paraffins toxicity in rats.

Short chain chlorinated paraffins (SCCPs) have received increased interest worldwide since they were added to the list of controlled POPs in Annex A of the Stockholm Convention in 2017. Although many toxicological studies have already shown that SCCPs are hepatotoxic, nephrotoxic, and thyrotoxic to rodents, there have been few studies to date that have characterized changes in the metabolic pathways targeted by SCCPs. In this study, a UPLC-Q-TOF-MS based plasma metabolomics approach was used to investigate the toxicity of SCCPs in rats. Liver and kidney injury occurred rapidly after high-dose SCCP exposure, and the most relevant pathways affected were energy metabolism, amino acid metabolism, glycerophospholipid metabolism, nucleotide metabolism, and vitamin B metabolism. Exposure to SCCPs inhibited the tricarboxylic acid cycle and accelerated degradation. Fluctuating levels of phospholipids and nucleotides may have contributed to the neurotoxicity of SCCPs. In addition, the down regulation of folic acid induced by SCCPs may have led to malformations during the early development of laboratory animals. These results suggested that high exposure levels of SCCPs may have serious health risks and more research is needed to assess the health status of relevant occupational groups.

Effect of short-chain chlorinated paraffins (SCCPs) on lipid membranes: Combination of molecular dynamics and membrane damage experiments.

In recent years, more attention has been paid to the biological effects of short-chain chlorinated paraffin (SCCP). Studies have shown that SCCPs exposure could cause metabolic damage and lipid metabolic damage. In the present work, based on E. coli membrane damage experiments and molecular dynamics (MD) simulation, the effects of SCCPs on the membrane structure and membrane properties were studied to explore the possible toxic damage effects of SCCPs on cell membrane. Experiments results showed that SCCPs had a significant inhibitory effect on E. coli. The E. coli cell membrane of the bacteria was broken and the macromolecules of the cell flowed out when exposed to SCCPs. SCCPs would lead to the decrease and depolarization of cell membrane potential, and then affect the integrity and permeability of cell membrane. The further molecular dynamic simulation revealed that SCCP molecules can easily enter the lipid DPPC membranes from the aqueous phase and tended to aggregate inside bilayer stably. The bound of SCCPs could lead to significant variations in DPPC bilayer with a less dense, more disorder and rougher layer, which thus made the damage of cell membrane. In a word, although the overall toxicity of SCCPs to cell was relatively weak, the damage to the cell membrane may be one of the mechanisms of its toxicity. MAIN FINDING OF THE WORK: The exposure of SCCPs could cause structural change of cell membrane in E. coli, which verified the damage to the cell membrane may be one of the mechanisms of its toxicity.

In vitro human cell-based TTR-TRß CALUX assay indicates thyroid hormone transport disruption of short-chain, medium-chain, and long-chain chlorinated paraffins.

Over the last decades, short-chain chlorinated paraffins (SCCPs), medium-chain chlorinated paraffins (MCCPs), and long-chain chlorinated paraffins (LCCPs) have become the most heavily produced monomeric organohalogen compound class of environmental concern. However, knowledge about their toxicology is still scarce, although SCCPs were shown to have effects on the thyroid hormone system. The lack of data in the case of MCCPs and LCCPs and the structural similarity with perfluoroalkyl substances (PFAS) prompted us to test CPs in the novel TTR-TR CALUX assay for their thyroid hormone transport disrupting potential. Four self-synthesized and additionally purified single chain length CP mixtures (C10-CPs, C11-CPs, C14-CPs and C16-CPs) and two each of industrial MCCP and LCCP products were tested in parallel with PFOA. All CP mixtures influenced the TTR binding of T4, giving activities of 1,300 to 17,000 µg/g PFOA equivalents and lowest observable effect concentrations (LOELs) of 0.95 to 0.029 mM/L incubate. Highest activities and lowest LOELs were observed for C16-CPs (48.3% Cl content, activity 17,000, LOEL 0.047 mM/L) and a LCCP mixture (71.7% Cl content; activity 10,000; LOEL 0.029 mM/L). A trend of higher activities and lower LOELs towards longer chains and higher chlorination degrees was implied, but could not be statistically confirmed. Irrespectively, the less well examined and current-use LCCPs showed the highest response in the TTR-TRß CALUX assay.

Impurities in technical mixtures of chlorinated paraffins show AhR agonist properties as determined by the DR-CALUX bioassay.

Chlorinated paraffins (CPs) are produced at more than one million tons per year. Technical CPs mixtures may contain impurities, which end up in consumer products. In the present study, 17 technical CPs mixtures were investigated for the potential occurrence of potential impurities. By applying the DR-CALUX bioassay, 3 out of 17 technical mixtures were shown to elicit responses at 4 h exposure time, but much lower at 48 h. Constitutional defined CPs materials did not show responses. Subsequently different groups of known AhR-agonists and compounds suspected to be present in technical CPs mixtures were investigated. Benzene, (poly)chlorobenzene, non-dioxin like polychlorinated naphthalenes (PCNs), and three-ringed polyaromatic hydrocarbons (PAHs) did not result in a significant response at 4 h or 48 h. TCDD, non-ortho PCBs, dioxin-like PCNs, four or five ringed PAHs and their chlorinated analogues resulted in a significant response. TCDD and the non-ortho PCBs showed the highest potency and stability, while dioxin-like PCNs, PAHs, and the chlorinated PAHs were clearly inactivated (metabolized) at longer incubation. Altogether, the present findings substantiate that AhR-mediated responses of CPs technical mixtures in the DR-CALUX bioassay are caused by impurities, most likely some intermediate stable AhR-agonists such as dioxin-like PCNs or (chlorinated) PAHs. The current study shows that impurities in CPs technical mixtures need to be investigated for assessing the safety of technical CPs mixtures.

Effect of short-chain chlorinated paraffins on metabolic profiling of male SD rats.

The toxic effect of high-dose of short-chain chlorinated paraffins (SCCPs) has been extensively studied, however the possible health risks induced by SCCPs at low-dose remain largely unknown. In this study, a comprehensive toxicology analysis of SCCPs was conducted with the exposure levels from the environmental dose to the Lowest Observed Adverse Effect Level (LOAEL) of 100 mg/kg/day. General toxicology analysis revealed inconspicuous toxicity of the environmental dose of SCCPs, high dose SCCP exposure inhibited the growth rate and increased the liver weight of rat. Metabolomics analysis indicated that SCCP-induced toxicity was triggered at environmentally relevant doses. First, inhibition of energy metabolism was observed with the decrease in blood glucose and the dysfunction of TCA cycle, which may have contributed to lower body weight gain in rats exposed to a high dose of SCCPs. Second, the increase of free fatty acids indicated the acceleration of lipid metabolism to compensate for the energy deficiency caused by hypoglycemia. Lipid oxidative metabolism inevitably leads to oxidative stress and stimulates the up-regulation of antioxidant metabolites such as GSH and GSSH. The up-regulation of polyunsaturated fatty acids (PUFAs) and phospholipids composed of arachidonic acid indicates the occurrence of inflammation. Dysfunction of lipid metabolism can be an indicator of SCCP-induced liver injury.

Increased adverse effects during metabolic transformation of short-chain chlorinated paraffins by cytochrome P450: A theoretical insight into 1-chlorodecane.

Short-chain chlorinated paraffins (SCCPs), frequently detected in human tissues or organs, can result in threat to human health by disturbing normal metabolism. However, their metabolism mechanisms and fates are largely unclear. Therefore, to better understand the impacts of SCCPs and their metabolites on the human health, the metabolic mechanism and kinetics of SCCPs by cytochrome P450 enzymes (CYPs) were explored using density functional theory employed 1-chlorodecane as a model SCCPs. The results show that 1-chlorodecane could be readily metabolized by CYPs, and the rate constant reaches up 42.3 s-1 in human body. Dechlorination of 1-chlorodecane is unlikely to occur and hydroxylation is dominated via H-abstraction pathways, especially from the intermediate C atom of 1-chlorodecane. The toxicity assessments suggest that the two metabolites, 10-chloro-decan-5-ol and 1-chlorodecanol could exhibit higher bioaccumulation, carcinogenicity and more serious damage on cardiovascular system after the metabolism of 1-chlorodecane. To our knowledge, this is the first study from the viewpoint of theoretical analysis to explore the metabolism of typical SCCPs in human body. It may provide deep insight into the metabolic transformation mechanism of SCCPs and cause the concerns about the adverse effects of their metabolites in human body.

Advances in Studies on Toxic Effects of Short-Chain Chlorinated Paraffins (SCCPs) and Characterization of Environmental Pollution in China.

Short-chain chlorinated paraffins (SCCPs) were included in the Stockholm Convention in 2017. SCCPs have persistence, bioaccumulation, long-range environmental mobility and biological toxicity, significant toxicity to aquatic organisms, and potential carcinogenicity. Little study was on the progress research on the current environmental pollution in China. We reviewed the pollution conditions of SCCPs in air, soil, and water and their accumulation in food and organisms in China, especially for the contaminations of aquatic ecosystem. Meanwhile, we summarize the recent studies on the toxic effects and toxicological mechanisms of SCCPs on aquatic organisms and mammals. Finally, the further direction and trends for SCCP research were proposed. More efforts are necessary to conduct a comprehensive risk assessment and evaluate the relative importance of the various exposure routes.

Integration of metabolomics and transcriptomics reveals short-chain chlorinated paraffin-induced hepatotoxicity in male Sprague-Dawley rat.

BACKGROUND: Short-chain chlorinated paraffins (SCCPs) used in various industrial applications have been listed as new POPs. Previous studies based on high-dose exposures indicate their hepatotoxicity. However, their mechanisms of toxicity or adverse outcome pathways and health risks remain largely unknown. OBJECTIVES: This study aimed to evaluate metabolic consequences of chronic dietary exposure to SCCPs at low doses and reveal the molecular mechanisms underlying hepatotoxicity of SCCPs. METHODS: A combination of transcriptomics and metabolomics, together with general pathophysiological tests were performed to assess the hepatic response of male rats exposed to SCCPs. RESULTS: Our results highlight two major modes of action: Inhibition of energy metabolism and activation of the peroxisome proliferator-activated receptor α (PPARα). Exposure to SCCPs suppressed oxidative phosphorylation, glycolysis, gluconeogenesis and turnover of ATP-ADP-AMP and thus results in deficiencies of amino acids and nucleotides in liver of the rat. Exposure to SCCPs affected expression levels of 13 genes downstream of PPARα that encode proteins associated with metabolism of fatty acids. As a result, peroxisomal and mitochondrial fatty acid ß-oxidation, microsomal fatty acid ω-oxidation, and lipogenesis were accelerated. CONCLUSIONS: Results of this work strongly support the conclusion that low-dose exposure to SCCPs can result in adverse outcomes in the rat model. Significant SCCP-induced inhibition of energy metabolism occurs at environmentally relevant dosages, which suggests that SCCPs exhibit metabolic toxicity. Interactions of SCCPs with PPARα signaling pathway can explain the disruption of lipids and amino acids metabolism.