Non-monotonic Dose Response Research Articles

The ENDOMIX perspective: how everyday chemical mixtures impact human health and reproduction by targeting the immune system†.

Endocrine disruptor chemicals (EDCs) are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to EDCs has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between EDCs and disease outcomes has limitations. Epidemiological and experimental research on EDCs faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and EDC mechanistic insights, in particular regarding their impact on the immune system. The ENDOMIX project, funded by the EU's Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of EDC mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and EDC mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of EDCs on immune-reproductive health.

7849 The EDC Mixture “NeuroMix” Has Developmental, Anxiolytic, And Obesogenic Effects In Rats

Abstract Disclosure: E. Morales-Grahl: None. L. M. Thompson: None. E.N. Hilz: None. A.C. Gore: None. Humans are exposed to a variety of endocrine disrupting chemicals (EDCs) on a daily basis through drinking water, food, and contact with everyday objects. Safety guidelines aim to keep exposure to individual EDCs below certain levels but don’t take into account the potentially unpredictable effects of simultaneous exposure to multiple EDCs. Furthermore, EDCs may exhibit non-monotonic dose responses. The present study assessed the effect of an EDC mixture at three different doses on two sets of behaviors implicated in EDC research: anxiety, and high fat and sugar consumption. Beginning in early pregnancy and until pups were weaned at day 21, Sprague Dawley rats were fed daily with NeuroMix, our lab’s EDC mixture containing 9 common industrial chemicals, at three doses (0.1x, 1x, 10x). The base dose (1x) contained EDCs below the no observed adverse effect level in humans (NOAEL). In adulthood, the female and male offspring were then subjected to an open field and light/dark test, followed by a high fat and high sucrose preference test. 0.1x NeuroMix exposure advanced the timing of vaginal opening in female offspring, while all doses increased anogenital distance in males, marking differences in sexual development. 1x NeuroMix exposure in male rats increased their time in the open field corners and their time immobile in the corners, indicating higher anxiety. No difference was seen in sucrose preference. Female rats exposed to 1x NeuroMix showed a higher preference for a high-fat diet, and gained more weight compared to the controls while on this diet. These findings demonstrate that a mixture of human-relevant chemicals, when administered perinatally to rats, have developmental, anxiogenic and obesogenic effects in a sexually dimorphic manner. We also show a non-monotonic response to our chemical mixture, with the 1x dose showing greater effects than the 10x dose. Overall, we provide evidence that even at levels considered safe for individual EDCs, there are adverse developmental and behavioral effects of EDCs when combined. Grant support: R35 ES035024, F32 ES034257. Presentation: 6/1/2024

Exposure to benzyl butyl phthalate (BBP) leads to increased double-strand break formation and germline dysfunction in Caenorhabditis elegans.

Benzyl butyl phthalate (BBP), a plasticizer found in a wide range of consumer products including vinyl flooring, carpet backing, food packaging, personal care products, and children's toys, is an endocrine-disrupting chemical linked to impaired reproduction and development in humans. Despite evidence that BBP exposure perturbs the integrity of male and female gametes, its direct effect on early meiotic events is understudied. Here, using the nematode Caenorhabditis elegans, we show that BBP exposure elicits a non-monotonic dose response on the rate of X-chromosome nondisjunction measured using a high-throughput screening platform. From among the range of doses tested (1, 10, 100 and 500 μM BBP), we found that 10 μM BBP elicited the strongest effect on the germline, resulting in increased germ cell apoptosis and chromosome organization defects. Mass spectrometry analysis shows that C. elegans efficiently metabolizes BBP into its primary metabolites, monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP), and that the levels of BBP, MBP, and MBzP detected in the worm are within the range detected in human biological samples. Exposure to 10 μM BBP leads to germlines with enlarged mitotic nuclei, altered meiotic progression, activation of a p53/CEP-1-dependent DNA damage checkpoint, increased double-strand break levels throughout the germline, chromosome morphology defects in oocytes at diakinesis, and increased oxidative stress. RNA sequencing analysis indicates that BBP exposure results in the altered expression of genes involved in xenobiotic metabolic processes, extracellular matrix organization, oocyte morphogenesis, meiotic cell cycle, and oxidoreduction. Taken together, we propose that C. elegans exposure to BBP leads to increased oxidative stress and double-strand break formation, thereby compromising germline genomic integrity and chromosome segregation.

Embryonal exposure to 4-methylbenzylidene camphor induces reproduction impairment in adult zebrafish (Danio rerio)

This study investigated how early exposure to xenobiotics can lead to disease in adulthood, which is challenging for toxicologists. We employed a ‘cradle to grave’ approach using zebrafish (Danio rerio) embryos exposed to 4-methylbenzylidene camphor (4-MBC), a commonly used organic UV filter. Molecular docking and simulation studies confirmed the predictive toxicity and stable interaction of 4-MBC with androgen and estrogen receptors, with binding energies of −9.28 and −9.01 kcal/mol, respectively. Exposure to 4-MBC at 5, 50, and 500 μg/L concentrations resulted in significantly altered transcriptional and translational responses of ar, esr1, and vtg1 genes in embryos at 120 h post-fertilization (hpf). The exposure induced a non-monotonic dose-response pattern (NMDR), a characteristic feature of endocrine-disrupting chemicals. Additionally, a significant decrease in fertilization was observed in adults. Although fecundity was not affected in inter- and intra-breeding performances, developmental deformities were observed in F1 progenies with impaired survival at 10 days post-fertilization. The findings of this study show that embryonic exposure to 4-MBC is likely to induce reproductive and transgenerational toxicity in D. rerio and exhibit endocrine disruption in aquatic non-target organisms. This work is the first to elucidate the low-level long-term effects of 4-MBC from the embryonic stage to adulthood.

Interference with Systemic Negative Feedback Regulation as a Potential Mechanism for Nonmonotonic Dose-Responses of Endocrine-Disrupting Chemicals.

Endocrine-disrupting chemicals (EDCs) often exhibit nonmonotonic dose-response (NMDR) relationships, posing significant challenges to health risk assessment and regulations. Several molecular mechanisms operating locally in cells have been proposed, including opposing actions via different receptors, mixed-ligand heterodimer formation, and receptor downregulation. Systemic negative feedback regulation of hormone homeostasis, which is a common feature of many endocrine systems, has also been invoked as a mechanism; however, whether and how exactly such global feedback structure may underpin NMDRs is poorly understood. We hypothesize that an EDC may compete with the endogenous hormone for receptors (i) at the central site to interfere with the feedback regulation thus altering the physiological hormone level, and (ii) at the peripheral site to disrupt the hormone action; this dual-action may oppose each other, producing nonmonotonic endocrine effects. The objective here is to explore - through computational modeling - how NMDRs may arise through this potential mechanism and the relevant biological variabilities that enable susceptibility to nonmonotonic effects. We constructed a dynamical model of a generic hypothalamic-pituitary-endocrine (HPE) axis with negative feedback regulation between a pituitary hormone and a terminal effector hormone (EH). The effects of model parameters, including receptor binding affinities and efficacies, on NMDR were examined for EDC agonists and antagonists. Monte Carlo human population simulations were then conducted to systemically explore biological parameter conditions that engender NMDR. When an EDC interferes sufficiently with the central feedback action of EH, the net endocrine effect at the peripheral target site can be opposite to what is expected of an agonist or antagonist at low concentrations. J/U or Bell-shaped NMDRs arise when the EDC has differential binding affinities and/or efficacies, relative to EH, for the peripheral and central receptors. Quantitative relationships between these biological variabilities and associated distributions were discovered, which can distinguish J/U and Bell-shaped NMDRs from monotonic responses. The ubiquitous negative feedback regulation in endocrine systems can act as a universal mechanism for counterintuitive and nonmonotonic effects of EDCs. Depending on key receptor kinetic and signaling properties of EDCs and endogenous hormones, some individuals may be more susceptible to these complex endocrine effects.

Chronic Toxicity of Per- and Polyfluoroalkyl Substance-Free Firefighting Foams to Aquatic Organisms.

Amid global concern regarding the health and environmental impacts of per- and polyfluoroalkyl substances (PFAS), there is an urgent need to develop and implement alternative products without PFAS. Consequently, PFAS-free firefighting foams used for fire suppression have been developed for use in military and residential settings. To facilitate the selection of lower-risk PFAS-free foams, the present study focused on the chronic toxicity of seven PFAS-free and one PFAS-containing foam to six aquatic species. Target species included two cladocerans, Daphnia magna and Ceriodaphnia dubia; the chironomid Chironomus dilutus; the mysid Americamysis bahia; and two fish species, Pimephales promelas and Cyprinodon variegatus, with endpoints including growth, development, reproduction, and survival. To facilitate comparison and product toxicity rankings, effective concentrations (20%, 50%) and no- and lowest-observed-effect concentrations (NOECs and LOECs, respectively) were calculated. Effective concentrations, NOECs, and LOECs varied by over an order of magnitude among foams and species, with several of the PFAS-free formulations ranked as highly toxic based on US Environmental Protection Agency alternatives assessment hazard criteria. Overall, the PFAS-free foams were found to exhibit either similar or greater toxicity compared to the PFAS-containing reference foam across several species and endpoints. Nonmonotonic and hormetic dose responses were observed in D. magna for several of the tested foams, with increased reproduction and growth at intermediate exposures. Generally, tested foam toxicity rankings were consistent with a related acute toxicity study using the same species and formulations, and other research using soil invertebrates. Combined with related efforts for other taxa including mammals, birds, and plants, the present research will facilitate the selection of appropriate PFAS-free firefighting foams that minimize harm to the environment. Environ Toxicol Chem 2024;43:2436-2454. © 2024 SETAC.

Evaluation of Low-Dose Effects and Non-Monotonous Dose Response of Butyl p-hydroxybenzoate, or Butylparaben on Female Wistar Rats

Butylparaben (BP) is an extensively used synthetic preservative that has been testified as an endocrine disruptor and speculated to be toxic for the body all together. The present study evaluated the possible noxious impact of BP at minimum doses, i.e., 1, 5, and 10 mg/kg BW/day, on female Wistar rats following consecutive subcutaneous exposure for 7 and 21 days. The results of the genotoxic study exhibited that BP at a dose of 10 mg/kg BW/day significantly (p ˂ 0.05) induced micronucleated polychromatic erythrocytes (MNPCEs) formation in bone marrow of rats, both in short (7.3 ± 0.87 MNPCEs/1000 PCEs) and long-term exposures (6.6 ± 0.33 MNPCEs/1000 PCEs), which was in line with the results obtained for 17β-estradiol (E2)-treated reference control rats. Levels of hepatic toxicity marker enzymes, i.e., aspartate transaminase (AST) and alanine transaminase (ALT), were not altered substantially in any of the study durations, but the alkaline phosphatase (ALP) level increased significantly (p ˂ 0.05) at all BP doses, including E2. Variations in the serum HDL as well as cholesterol levels were found to be non-monotonous with respect to the applied BP doses. However, contrasting specifics were observed for triglycerides in terms of the study durations. Conclusively, the current study established that BP, even at low doses, could evidently disturb the circulating lipid content, hepatic enzyme levels, and even cause genotoxicity, and also pointed toward its non-monotonous dose response.

Investigating thermoluminescence signal saturation in quartz and feldspar using emission spectrometry

Luminescence-based thermometry and dating often requires determination of the saturation level for specific signals and the corresponding dose. However, previous studies found non-monotonic dose responses for some monochromatic thermoluminescence (TL) and optically stimulated luminescence (OSL) signals from quartz as well as spectral overlap of emission bands, substantially complicating data interpretation. Therefore, the present study examines (1) the variability in the TL emission spectrum of quartz and feldspar from bedrock and sediment of different provenances and, (2) the saturation characteristics of the blue emission band for both quartz and feldspar in the dose range from 0.25 kGy to 50 kGy. The experimental results confirm differences in the spectra which appear to be characteristic of their geological origin and chemical composition. Spectral analysis shows that in the temperature range 175–220 °C the blue emission band at ∼2.5 eV dominates over other bands for all quartz samples studied. A broad UV-blue TL signal peaking at ∼2.5−3.0 eV and composed of probably three overlapping, individual bands is characteristic for K-feldspar, while one Na-feldspar exhibits an additional band at ∼2.2 eV.In the studied dose range, the emissions at ∼2.5 eV and ∼2.6 eV increase as a function of dose up to 6 kGy for both quartz and feldspar. A difference in dose response was observed for high doses (>6 kGy) where feldspar samples reached a stable saturation level while for quartz the blue emission band intensity decays until 50 kGy after having attained a maximum. Our results suggest the suitability of feldspar TL for palaeothermometry and thermochronometry from the perspective of signal saturation characteristics. However, the spectral overlap of several bands in the UV-blue emission requires careful optical filter selection to isolate the signal of interest. The non-monotonic dose response of the ∼2.5 eV emission of quartz around 200 °C glow curve temperature probably precludes its use for temperature sensing based on relative trap saturation levels.

Placental-brain axis in females detected within broadly impacted metabolic gene networks protects against prenatal PCB exposure.

Neurodevelopmental disorders have a strong male bias that is poorly understood. Placenta is a rich source of molecular information about environmental interactions with genetics (including biological sex), that affect the developing brain. We investigated placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). To understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta by RNAseq, we used weighted gene correlation network analysis (WGCNA) to create correlated gene networks that could be compared across sex or tissue. WGCNA revealed that expression within most correlated gene networks was significantly and strongly associated with PCB exposures, but frequently in opposite directions between male-female and placenta-brain comparisons. In both WGCNA and differentially expressed gene analyses, male brain showed more PCB-induced transcriptional changes than male placenta, but the reverse pattern was seen in females. Furthermore, non-monotonic dose responses to PCBs were observed in most gene networks but were most prominent in male brain. The transcriptomic effects of low dose PCB exposure were significantly reversed by dietary folic acid supplementation across both sexes, but these effects were strongest in female placenta. PCB-dysregulated and folic acid-reversed gene networks were commonly enriched in functions in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipids, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. The female protective effect in prenatal PCB exposures appears to be mediated by dose-dependent sex differences in transcriptional modulation of metabolism in placenta.

Reproductive toxicity and molecular responses induced by telmisartan in Daphnia magna at environmentally relevant concentrations

With aging population increasing globally, the use of pharmaceutically active compounds is rising. The cardiovascular drug telmisartan has been widely detected in various environmental compartments, including biota, surface waters, and sewage treatment plant effluents at concentrations ranging from ng/L to μg/L levels. This study evaluated the effects of telmisartan on the microcrustacean Daphnia magna at a wide range of concentrations (0.35, 0.70, 1.40, 500, and 1000 μg/L) and revealed significant ecotoxicological implications of this drug, even at environmentally relevant concentration. Acute exposure to telmisartan (1.40, 500, and 1000 μg/L) resulted in a notable decrease in heart rate, while chronic exposure accelerated the time to the first brood by 3 days and reduced neonate body size. Molecular investigations revealed marked downregulation of vitellogenin genes (Vtg1 and Vtg2). Non-monotonic dose responses were observed for gene expression, early-stage body length, and the total number of offspring produced, while the heart rate and time to the first brood showed clear concentration-dependent responses. These findings highlight the potential risks, notably to reproductive capacity, associated with exposure to telmisartan in environmentally relevant concentration, suggesting the need for further studies on the potential long-term ecological consequences.

Associations of Serum Per- and Polyfluoroalkyl Substances with Hyperuricemia in Adults: A Nationwide Cross-Sectional Study.

There has been widespread concern about the health hazards of per- and polyfluoroalkyl substances (PFAS), which may be the risk factor for hyperuricemia with evidence still insufficient in the general population in China. Here, we conducted a nationwide study involving 9,580 adults aged 18 years or older from 2017 to 2018, measured serum concentrations of uric acid and PFAS (PFOA, PFOS, 6:2 Cl-PFESA, PFNA, PFHxS) in participants, to assess the associations of individual PFAS with hyperuricemia, and estimated a joint effect of PFAS mixtures. We found positive associations of higher serum PFAS with elevated odds of hyperuricemia in Chinese adults, with the greatest contribution from PFOA (69.37%). The nonmonotonic dose-response (NMDR) relationships were observed for 6:2 Cl-PFESA and PFHxS with hyperuricemia. Participants with less marine fish consumption, overweight, and obesity may be the sensitive groups to the effects of PFAS on hyperuricemia. We highlight the potential health hazards of legacy long-chain PFAS (PFOA) once again because of the higher weights of joint effects. This study also provides more evidence about the NMDR relationships in PFAS with hyperuricemia and emphasizes a theoretical basis for public health planning to reduce the health hazards of PFAS in sensitive groups.

Associations of serum persistent organic pollutant concentrations with incident diabetes in midlife women: The Study of Women’s Health Across the Nation Multi-Pollutant Study

BackgroundOrganochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that can negatively impact metabolic health through pathways including endocrine disruption. Few studies have evaluated diabetes risk associated with PBDEs. Little is known about the joint effect of exposure to POP mixtures on diabetes risk. ObjectivesWe investigated the relationship between POPs, individually and as mixtures, and diabetes development over 18 years (1999–2016) in midlife women. MethodsWe measured lipid-standardized serum concentrations of 34 PCBs, 19 OCPs, and 14 PBDEs in 1040 midlife women aged 45–56 years from the Study of Women’s Health Across the Nation. We tested the association between POPs measured in 1999/2000 and incident diabetes using Cox proportional hazards models. We evaluated diabetes risk associated with the overall POP mixture using Quantile-Based G-Computation (QBGC). ResultsFor most mixture components, single pollutant and mixtures analyses indicated null associations with diabetes risk, however results were inconsistent. After adjustment, hazard ratios (HRs) of developing diabetes (95% CI) associated with upper exposure tertiles (T2/T3) compared with the first tertile (T1), were 1.7 (1.0, 2.8) at T2 and 1.5 (0.84, 2.7) at T3 for hexachlorobenzene and 1.9 (1.1, 3.3) at T2 and 1.6 (0.88, 2.9) at T3 for PCB 123. A doubling of PBDE 47 was associated with 1.11 (1.00, 1.24) times the risk of T2D. QBGC identified no association for the overall joint effect of the POP mixture on diabetes (HR = 1.04 [0.53, 2.07]). ConclusionExposure to a mixture of PCBs, OCPs, and PBDEs was not associated with incident diabetes in midlife U.S. women, although some individual POPs demonstrated significant yet inconsistent associations with diabetes. Non-linear and non-monotonic dose-response dynamics deserve further exploration. More research is needed on the diabetogenic effects of PBDEs.

Effect of an antidepressant on aquatic ecosystems in the presence of microplastics: A mesocosm study

Emerging pollutants, such as pharmaceuticals and microplastics have become a pressing concern due to their widespread presence and potential impacts on ecological systems. To assess the ecosystem-level effects of these pollutants within a multi-stressor context, we simulated real-world conditions by exposing a near-natural multi-trophic aquatic food web to a gradient of environmentally relevant concentrations of fluoxetine and microplastics in large mesocosms over a period of more than three months. We measured the biomass and abundance of different trophic groups, as well as ecological functions such as nutrient availability and decomposition rate. To explore the mechanisms underlying potential community and ecosystem-level effects, we also performed behavioral assays focusing on locomotion parameters as a response variable in three species: Daphnia magna (zooplankton prey), Chaoborus flavicans larvae (invertebrate pelagic predator of zooplankton) and Asellus aquaticus (benthic macroinvertebrate), using water from the mesocosms. Our mesocosm results demonstrate that presence of microplastics governs the response in phytoplankton biomass, with a weak non-monotonic dose-response relationship due to the interaction between microplastics and fluoxetine. However, exposure to fluoxetine evoked a strong non-monotonic dose-response in zooplankton abundance and microbial decomposition rate of plant material. In the behavioral assays, the locomotion of zooplankton prey D. magna showed a similar non-monotonic response primarily induced by fluoxetine. Its predator C. flavicans, however, showed a significant non-monotonic response governed by both microplastics and fluoxetine. The behavior of the decomposer A. aquaticus significantly decreased at higher fluoxetine concentrations, potentially leading to reduced decomposition rates near the sediment. Our study demonstrates that effects observed upon short-term exposure result in more pronounced ecosystem-level effects following chronic exposure.

CeO2 nanoparticle dose and exposure modulate soybean development and plant-mediated responses in root-associated bacterial communities

Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg−1. Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops.

Lipid responses to perfluorooctane sulfonate exposure for multiple rat organs

Perfluorooctane sulfonate (PFOS) is a persistent chemical that has long been a threat to human health. However, the molecular effects of PFOS on various organs are not well studied. In this study, male Sprague–Dawley rats were treated with various doses of PFOS through gavage for 21 days. Subsequently, the liver, lung, heart, kidney, pancreas, testis, and serum of the rats were harvested for lipid analysis. We applied a focusing lipidomic analytical strategy to identify key lipid responses of phosphorylcholine-containing lipids, including phosphatidylcholines and sphingomyelins. Partial least squares discriminant analysis revealed that the organs most influenced by PFOS exposure were the liver, kidney, and testis. Changes in the lipid profiles of the rats indicated that after exposure, levels of diacyl-phosphatidylcholines and 22:6-containing phosphatidylcholines in the liver, kidney, and testis of the rats decreased, whereas the level of 20:3-containing phosphatidylcholines increased. Furthermore, levels of polyunsaturated fatty acids-containing plasmenylcholines decreased. Changes in sphingomyelin levels indicated organ-dependent responses. Decreased levels of sphingomyelins in the liver, nonmonotonic dose responses in the kidney, and irregular responses in the testis after PFOS exposure are observed. These lipid responses may be associated with alterations pertaining to phosphatidylcholine synthesis, fatty acid metabolism, membrane properties, and oxidative stress in the liver, kidney, and testis. Lipid responses in the liver could have contributed to the observed increase in liver to body weight ratios. The findings suggest potential toxicity and possible mechanisms associated with PFOS in multiple organs.

Disruption of functions of primary human neonatal melanocytes cultured in the presence of bisphenol A and its analogs bisphenol F and bisphenol S

Bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) are contaminants of emerging concern (CECs) that humans are exposed to. In silico and zebrafish studies have linked BPA, BPF, and BPS exposure to pigmentation abnormalities, but no studies have examined their impact on primary human melanocytes. Herein, we examined the effects of BPA, BPF, and BPS exposure using human epidermal neonatal melanocytes. BPA induced the greatest cytotoxicity, followed by BPS, whereas BPF did not affect viability. BPA did not alter cellular melanin, whereas BPF and BPS diminished it at 100 µM. BPA decreased dendricity, as did BPF and BPS, although BPF was a potent suppressor of dendricity than BPS. BPA inhibited tyrosinase activity, followed by BPF, while BPS weakly suppressed tyrosinase activity. The tyrosinase activity was mostly recovered after the cessation of bisphenol treatments, although it remained lower for BPA and BPF. All bisphenols elevated cellular ROS production, although BPA and BPS showed non-monotonic dose responses. BPA and BPS augmented IL-6 cytokine secretion in melanocyte cultures treated with lipopolysaccharide, but BPF did not, suggesting that they exacerbate melanocyte inflammation. Collectively, these findings indicate BPA, BPF, and BPS, may impair melanocyte function and pose health hazards, warranting more study.

Chronic exposure to low levels of phenanthrene induces histological damage and carcinogenic risk in the uterus of female mice.

Phenanthrene (Phe), a polycyclic aromatic hydrocarbon with low molecular weight, is detected in the environment at high frequency. To study the toxic effects of Phe on the uterine structure and function, female Kunming mice were exposed to Phe (0.05, 0.5, 5ng/mL) for 270days by drinking water. Pathological alterations and their action pathways were analyzed using immunohistochemical and biomolecular technology. Phe significantly increased the percentage of blood vessel area, the number of endometrial neutrophils (indicating the occurrence of inflammation), collagen deposition (indicating fibrosis), and the percentage of Ki-67-positive cells (indicating carcinogenesis) in the uterus. Transcriptome sequencing identified differentially expressed genes that were mainly enriched in some signaling pathways, including inflammation and carcinogenesis, suggesting a carcinogenic risk in the Phe-exposed uterus. Elevated serum estrogen levels and decreased progesterone levels exhibited a disturbance of steroid hormone balance, which might be related to uterine damage. Upregulated protein levels of uterine androgen receptor and estrogen receptor α were linked to the pathological effects. Most of the effects exhibited a nonmonotonic dose response, which might be attributed to the corresponding change in the serum levels of Phe. The results suggest that exposure to low levels of Phe could exert adverse effects on the uterus.

Understanding the differential impacts of two antidepressants on locomotion of freshwater snails (Lymnaea stagnalis)

There is growing evidence of negative impacts of antidepressants on behavior of aquatic non-target organisms. Accurate environmental risk assessment requires an understanding of whether antidepressants with similar modes of action have consistent negative impacts. Here, we tested the effect of acute exposure to two antidepressants, fluoxetine and venlafaxine (0–50 µg/L), on the behavior of non-target organism, i.e., freshwater pond snail, Lymnaea stagnalis. As compounds interact with chemical cues in the aquatic ecosystems, we also tested whether the effects altered in the presence of bile extract containing 5α-cyprinol sulfate (5α-CPS), a characterized kairomone of a natural predator, common carp (Cyprinus carpio). Behavior was studied using automated tracking and analysis of various locomotion parameters of L. stagnalis. Our results suggest that there are differences in the effects on locomotion upon exposure to venlafaxine and fluoxetine. We found strong evidence for a non-monotonic dose response on venlafaxine exposure, whereas fluoxetine only showed weak evidence of altered locomotion for a specific concentration. Combined exposure to compounds and 5α-CPS reduced the intensity of effects observed in the absence of 5α-CPS, possibly due to reduced bioavailability of the compounds. The results highlight the need for acknowledging different mechanisms of action among antidepressants while investigating their environmental risks. In addition, our results underline the importance of reporting non-significant effects and acknowledging individual variation in behavior for environmental risk assessment.Graphical

Association of serum bisphenols, parabens, and triclosan concentrations with Sjögren Syndrome in the Hangzhou, China population

Exposure to endocrine-disrupting chemicals (EDCs) has been linked to various immune deficiency disorders, including autoimmune diseases like Sjögren Syndrome (SjS). However, the detrimental effects of exposure to EDCs, including bisphenols, parabens, and triclosan (TCS), on SjS have been inadequately documented. Thus, we conducted a cross-sectional study that included both healthy individuals (controls) and patients with SjS (cases). We assessed serum concentrations of bisphenol A (BPA), bisphenol S (BPS), methyl parabens (MeP), ethyl parabens (EtP), and TCS. The relationship between the five EDCs levels and the risk of SjS was also explored. Additionally, we conducted an in-depth analysis of the collective influence of these EDCs mixtures on SjS, employing a weighted quantile sum regression model. Out of the five EDCs analyzed, EtP displayed the highest mean concentration (2.80 ng/mL), followed by BPA (2.66 ng/mL) and MeP (1.99 ng/mL), with TCS registering the lowest level (0.36 ng/mL). Notably, BPS exposure was significantly positively associated with the risk of being diagnosed with SjS (with an odds ratio [OR] of 1.17, p = 0.042). No statistically significant associations with SjS were observed for BPA, MeP, EtP, and TCS (p > 0.05). And we did not observe any significant effects of the EDCs mixture on SjS. To the best of our knowledge, this study is the first to suggest that BPS may potentially increase the risk of SjS. Although no significant effects were observed between other EDCs and SjS risk, we cannot disregard the potential harm of EDCs due to their non-monotonic dose response.

Dietary intakes of dioxins and polychlorobiphenyls (PCBs) and mortality: EPIC cohort study in 9 European countries

Dioxins and polychlorinated biphenyls (PCBs) are toxic, endocrine disruptors and persistent chemicals for which the main exposure source is diet due to their bioaccumulation and biomagnification in food chains. Cohort studies in the general populations have reported inconsistent associations between these chemicals in serum/plasma and mortality. Our objective was to study the association between dietary intake of 17 dioxins and 35 PCBs and all-cause, cancer-specific and cardiovascular-specific mortalities were assessed in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Dietary intake of dioxins and PCBs was assessed combining EPIC food consumption data with European food contamination data provided by the European Food Safety Authority. We applied multivariable Cox regressions. The analysis included 451,390 adults (mean ± SD age:51.1 ± 9.7 years) with 46,627 deaths and a median follow-up of 17.4 years (IQR = 15.2–19.1). A U-shaped non-linear association with all-cause mortality for dietary intake of dioxins (Pnon-linearity<0.0001), DL-PCB (Pnon-linearity = 0.0001), and NDL-PCBs (Pnon-linearity<0.01) was observed. For example, the hazard ratios (95%Confidance interval) for all-cause mortality obtained with the spline model was equal to 1.03 (1.02–1.05) for low levels of intake to dioxins (7 pg TEQ/day), 0.93 (0.90–0.96) for moderate levels of intake (25 pg TEQ/day), while for high levels of intake (55 pg TEQ/day) it was 1.03 (0.97–1.09). Intake of dioxins, DL-PCBs and NDL-PCBs was not associated with cardiovascular mortality. There was no association between intakes of dioxins and cancer mortality, but a U-shaped association was observed for intake of DL-PCBs and intakes of NDL-PCBs and cancer mortality. The PCBs and dioxins are known to have endocrine disrupting properties which can lead to non-monotonic dose responses. These results need to be interpreted with caution and further studies are needed to better clarify the association between dietary intake of dioxins and PCB and mortality in the general population.