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Artificial sweeteners (ASs) entered the environments after application and emissions. Recent studies showed that some ASs had obesogenic risks. However, it remained unclear whether such risks are common and how they provoke such effects. Presently, the effects of 8 widely used ASs on lipid accumulation were measured in Caenorhabditis elegans. Potential mechanisms were explored with feeding and locomotion behavior, lipid metabolism and neural regulation. Results showed that acesulfame (ACE), aspartame (ASP), saccharin sodium (SOD), sucralose (SUC) and cyclamate (CYC) stimulated lipid accumulation at μg/L levels, showing obesogenic potentials. Behavior investigation showed that ACE, ASP, SOD, SUC and CYC biased more feeding in the energy intake aspect against the locomotion in the energy consumption one. Neotame (NEO), saccharin (SAC) and alitame (ALT) reduced the lipid accumulation without significant obesogenic potentials in the present study. However, all 8 ASs commonly disturbed enzymes (e.g., acetyl-CoA carboxylase) in lipogenesis and those (e.g., carnitine palmitoyl transferase) in lipolysis. In addition, ASs disturbed PPARγ (via expressions of nhr-49), TGF-β/DAF-7 (daf-7) and SREBP (sbp-1) pathways. Moreover, they also interfered neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh), with influences in Gsα (e.g., via expressions of gsα-1, ser-7), glutamate (e.g., mgl-1), and cGMP-dependent signaling pathways (e.g., egl-4). In summary, environmental ASs commonly disturbed neural regulation connecting behavior and lipid metabolism, and 5 out of 8 showed clear obesogenic potentials. ENVIRONMENTAL IMPLICATION: Artificial sweeteners (ASs) are become emerging pollutants after wide application and continuous emission. Recent studies showed that some environmental ASs had obesogenic risks. The present study employed Caenorhabditis elegans to explore the influences of 8 commonly used ASs on lipid metabolisms and also the underlying mechanisms. Five out of 8 ASs stimulated lipid accumulation at μg/L levels, and they biased energy intake against energy consumption. The other three ASs reduced the lipid accumulation. ASs commonly disturbed lipogenesis and lipolysis via PPARγ, TGF-β and SREBP pathways, and also influenced neurotransmitters with Gsα, glutamate and cGMP-dependent signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Di-n-octyl phthalate (DOP) is one important phthalate analog whose toxicities need comprehensive investigation to fully demonstrate phthalates health risks. In the present study, apical effects of DOP on behavior, lifespan and reproduction and the underlying mechanisms were explored in Caenorhabditis elegans for four consecutive generations (F1 to F4) and the trans-generational effects were also measured in the great-grand-children (T4 and T4') of F1 and F4. Multi-generational results showed that DOP caused both stimulation and inhibition on head swing, body bending, reverse, Omega steering, pharyngeal pump and satiety quiescence. The stimulation and inhibition altered over concentrations and across generations, and the alteration was the greatest in reverse locomotion which showed both concentration-dependent hormesis and trans-hormesis. DOP stimulated lifespan and inhibited reproduction, showing trade-off relationships. Significant trans-generational residual effects were found in T4 and T4' where the exposure was completed eliminated. Moreover, both similar and different effects were found in comparisons between F1 and F4, between F1 and T4, between F4 and T4' and also between T4 and T4'. Further analysis showed close connections between effects of DOP on neurotransmitters (including dopamine, acetylcholine, γ-aminobutyric acid and serotonin) and enzymes in lipid metabolism (including lipase, acetyl CoA carboxylase, fatty acid synthetase, carnitine palmitoyl-transferase, glycerol phosphate acyltransferase and acetyl CoA synthetase). Moreover, the close connections were also found between biochemical and apical effects. Notably, the connections were different in multi- and trans-generational effects, which urged further studies to reveal the response strategies underlying the exposure scenarios., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Environmental obesogens contributed significantly to the obesity prevalence. Recently, antibiotics joined the list of environmental obesogens, while the underlying mechanisms remained to be explored. In the present study, effects of erythromycin (ERY), one widely used macrolide antibiotic, were measured on C. elegans to investigate the obesogenic mechanism. Results showed that ERY at 0.1 μg/L significantly increased the fat content by 17.4% more than the control and also stimulated triacylglycerol (TAG) levels by 25.7% more than the control. Regarding the obesogenic mechanisms, ERY provoked over-eating by stimulation on the pharyngeal pumping and reduction on the satiety quiescence percentage and duration. Such effects were resulted from stimulation on the neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh). The nervous responses involved the up-regulation of Gsα (e.g., ser-7, gsa-1, acy-1 and kin-2) signaling pathway and the down-regulation of TGFβ (daf-7) but not via cGMP-dependent regulations (e.g., egl-4). Moreover, ERY stimulated the activities of fatty acid synthase (FAS) and glycerol-3-phosphateacyl transferases (GPAT) that catalyze lipogenesis, while ERY inhibited those of acyl-CoA synthetase (ACS), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) that catalyze lipolysis. The unbalance between lipogenesis and lipolysis resulted in the fat accumulation which was consistent with up-regulation on mgl-1 and mgl-3 which are the down-steam of TGFβ regulation. Such consistence supported the close connection between nervous regulation and lipid metabolism. In addition, ERY also disturbed insulin which connects lipid with glucose in metabolism., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Per-and polyfluoroalkyl substances (PFASs), especially perfluorooctanoic acid (PFOA), have been showed to induce obesogenic effects which may last over generations. However, the underlying mechanisms are not yet clear. In the present study, wild-type N2 Caenorhabditis elegans and the daf-2 mutant were exposed to PFOA for 4 consecutive generations (F0 to F3) at 1.0 ng/L. Effects on fat content and fat metabolism in the directly exposed F0 to F3 generations, the offspring of F0 (T1 to T3) and also those of F3 (T1' to T3'). Results showed that PFOA significantly stimulated the fat contents in F0 (with the percentage of the control as 184.1%), T1 (189.5%), F1 (167.3%), F2 (238.0%), T2' (193.9%) and T3' (159.4%) while inhibited them in T3 (70%). The changes of fat contents over generations were accompanied with significant changes in enzymes facilitating fatty acid synthesis (e.g., acetyl-CoA carboxylase, fatty acid synthase and desaturase, and glycerol phosphate acyltransferase) and those in fatty acid consumption (e.g., acetyl CoA synthetase, fatty acid transport protein, acyl-CoA oxidase and carnitine palmitoyl transferase). Furthermore, RNA-Seq analysis was performed on F0, F3 and T3 generations. Based on the KEGG analysis of differential genes, PFOA exposure affected lipid metabolism signaling pathways including MAPK, fatty acid degradation, TGF-β signaling pathways. Notably, PFOA exposure provoked significantly different effects in daf-2 nematodes on fat contents, lipid metabolizing enzymes and even different signaling pathways. The overall results demonstrated that the obesogenic effects of PFOA were resulted from a complex combination of various enzymes and pathways with essential involvement of insulin signaling pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Influences on lipid metabolism and multi-generational obesogenic effects raised new concerns on lipophilic pollutants (e.g., lindane). Yet, the mechanisms remained unanswered. The present study exposed Caenorhabditis elegans to lindane for 4 consecutive generations (F0 to F3) at 1.0 ng/L, and measured effects in the directly exposed generations (F0 to F3), indirectly exposed ones (T1 and T1') and un-exposed ones (T3 and T3'). Lindane stimulated fat storages in all generations. At the biochemical level, lindane stimulated both acetyl-CoA carboxylase (ACC) and carnitine palmitoyl-transferases (CPT) in F0, T1 and T2, while inhibited them in F3, T1' and T3', demonstrating the balance between fatty acid synthesis and its depletion toward fat accumulation over generations. Moreover, lindane caused different effects on insulin among generations. It inhibited insulin in F0 and F3 and exhibited consistent effects on the expression changes of daf-2, sgk-1 and daf-16 genes in insulin-like signal pathway. Lindane also inhibited insulin in T1 and T3 but exhibited consistent effects on the expression changes of daf-2, akt-1 and daf-16. Different roles of sgk-1 and akt-1 indicated the response strategies from tolerance (F0 and F3) to avoidance (T1 and T3). Lindane stimulated insulin in T1' and T3' and exhibited consistent effects on expression changes of daf-2, sgk-1 and daf-16 genes that were similar in F0 and F3., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ionic liquids (ILs) belong to emerging pollutants, and their hormesis earned particular attentions on their ecological impacts at low concentrations with long-term exposure. As one representative IL, N-ethylpyridinium bromide ([epyr]Br) was chosen as the target chemical. Its reproductive toxicities on Caenorhabditis elegans were determined with multi- and trans-generational exposure arrangements, and effects on the metabolites and enzyme activities in lipid metabolism were explored to elucidate the mechanisms. In the multi-generational exposure over 11 consecutive generations, [epyr]Br at 0.53 mg⋅L-1 caused stimulation on the reproduction in F1, F2, F3, F7, F8, F9 and F10, and provoked inhibition in F6 and F11. At 53 mg⋅L-1, it caused greater inhibitions in more generations than at 0.53 mg⋅L-1. In the trans-generational influences, [epyr]Br at both concentrations caused significant residual inhibition in the first non-exposed offspring of F1 (i.e., T3). Meanwhile, the residual effects of [epyr]Br exposure at the low concentration in the first non-exposed offspring of F11 (i.e., T3') showed stimulation, and those at the high did not show significant residual effects. The effects of [epyr]Br on the lipid metabolites, e.g., triacylglycerol (TG) and acetyl-CoA (ACA), and those on the activities of enzymes, e.g., glycerol-3-phosphate acyltrans-ferases (GPAT) and carnitine palmitoyl transferase (CPT), also showed oscillation between stimulation and inhibition over generations. Moreover, close relationships were found among the effects of [epyr]Br on the bio-indicators and also between the biochemical effects and the reproductive toxicities with influences by the exposure concentrations. In T3 and T3', [epyr] also showed significant residual effects on the biochemical indicators. Summing up, the reproductive toxicities of [epyr]Br in multi-generational exposure scenario and the residual effects in the trans-generational scenario were closely connected to effects on the lipid metabolism with influences by exposure concentrations. [ABSTRACT FROM AUTHOR]

Phthalate esters (PAEs) raised serious concerns on their health risk due to their toxicities. However, toxicities of low‐molecular‐weight PAEs, for example, dimethyl phthalates (DMPs), remained poorly investigated. In the present study, the reproductive toxicities of dimethyl (o‐)phthalate (DMOP), dimethyl (p‐)phthalate (DMPP), and dimethyl (m‐)phthalate (DMMP) were measured on Caenorhabditis elegans with mechanical exploration. Results showed that DMPP, DMOP, and DMMP commonly inhibited the total reproduction while stimulated lifespan, showing trade‐off effects. In effects on gene expressions, DMPP, DMOP, and DMMP caused different regulations on the expressions of vab‐1, ceh‐18, and gsa‐1 which are involved in oocyte growth, ovulation, and maturation. Meanwhile, they commonly downregulated those of rme‐2 and rcy‐4 that regulate germ cells and gonads and lipid metabolism in oocytes. Moreover, the effects on biochemicals that regulate reproductive processes showed alteration between stimulation and inhibition over life stages. In addition, effects at apical, biochemical, and molecular levels clearly showed the structure influences on the toxicities. Summing up, reproductive toxicities of DMPs depended on the exposure life stages and also the chemical structures. [ABSTRACT FROM AUTHOR]

Short-chained perfluorobutane sulfonate (PFBS, four-carbon) and perfluorohexane sulfonate (PFHxS, six-carbon) are widely employed to substitute long-chained per- and poly-fluoroalkyl substances (PFASs). Recent studies showed the potential persistence of PFBS and PFHxS, and also reported their correlation with obesity. However, the long-term outcome and underlying mechanisms remained poorly understood. Presently, the effects of PFBS and PFHxS were studied on C. elegans with multi- and trans -generational experiments. The multi-generational effects were measured in continuous four generational exposure (i.e., F1 to F4). Results showed that PFBS did not stimulate the fat content in F1 but in F4 with continuous but different disturbances on the lipid metabolism and the insulin and insulin-like (IIS) pathway. PFHxS stimulated the fat content in F1 and F4 with similar disturbances on the lipid metabolism and IIS pathway. The trans -generational results showed that the effects of PFBS and PFHxS on the lipid metabolism and IIS pathway were not totally recovered in the offspring of F1 (i.e., T1-T3) and F4 (i.e., T1′-T3′) which were not continuously exposed. PFHxS showed a common pattern to up-regulate daf-7 in both multi- and trans -generational effects. The long-term consequences of the short-chained PFASs substitutes should be concerned and epigenetic regulations should be considered in future mechanism studies. [Display omitted] • PFBS stimulated the fat content not in F1 but in F4 generation. • PFBS disturbed lipid metabolism and IIS pathway differently from F1 to F4. • PFHS stimulated the fat content in F1 and F4 generation. • PFHS had similar disturbances on lipid metabolism and IIS pathway from F1 and F4. • PFHS commonly up-regulated daf-7 in both multi- and trans -generational effects. [ABSTRACT FROM AUTHOR]