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ETHNOPHARMACOLOGICAL RELEVANCE: The popularity of herbal medicine is expanding globally due to the common belief that herbal products are natural and nontoxic. Thymelaea hirsuta leaves are traditionally used for the treatment of recurrent abortion in humans and animals. However, a lack of safety evaluation of the plant, particularly in pregnant women, raises serious concerns regarding its potential embryotoxic effects. AIM OF THE STUDY: Therefore, the present study investigated the safety of Thymelaea hirsuta leaves aqueous extract (THLE) during pregnancy and lactation following maternal rat treatment. MATERIALS AND METHODS: THLE phytochemical compounds were identified using high-performance liquid chromatography (HPLC). THLE was orally administered to pregnant rats and lactating dams at dosages of 0, 250, 500, and 1000 mg/kg/day. At the end of the study, dam s' and pups' body weights, serum biochemical and hematological indices, and histopathological changes were investigated. For the fetal observation and histopathological changes were also evaluated. RESULTS: Our findings revealed that THLE is rich in different phenolic and flavonoid compounds. However, biochemical and hormonal parameters such as ALT, AST, and prolactin were significantly increased in dams treated with a higher dosage of THLE when compared to the control dams (P ≤ 0.05). Additionally, external, visceral and skeletal examinations of fetuses revealed a marked increase of malformation rates in treated fetuses. CONCLUSIONS: The results revealed that higher oral dosing of THLE during pregnancy could affect embryonic development in rats, while lower doses are safe and can be used during pregnancy and lactation to attain its beneficial effects.

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4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.

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Goodeinae is a subfamily of critically endangered fish native to central Mexico. Populations of Skiffia lermae, a species belonging to this subfamily, have significantly decreased in the past two decades. A previous study showed that S. lermae is sensitive to acute nitrate-nitrogen (NO3-N) exposure, leading to noticeable changes in both behavioral and histopathological bioindicators. The aim herein was to determine the vulnerability of S. lermae to NO3-N exposure at realistic concentrations registered in freshwater ecosystems in central Mexico where the species was historically reported. Offspring of S. lermae were chronically exposed during 60 days to concentrations of 5, 10 and 20 mg NO3-N/L, with 2 mg NO3-N/L used as the reference value (control). Survival rate, feeding behavior, aquatic surface respiration, body growth, scaled mass index, immature red blood cells, as well as histopathological changes in branchial, hepatic and gonadal tissues were evaluated. Additionally, this study analyzed water quality in freshwater ecosystems where S. lermae presently persists. The results showed decreased survival as NO3-N concentration increased, as well as increased feeding latency, aquatic surface respiration and histological damage in the gills and liver. These organs showed differential sex-dependent responses to NO3-N exposure; females were more sensitive than males. In the ovaries, a decreased density of stage III oocytes was associated with increased NO3-N concentrations. No changes were observed in body growth and number of immature red blood cells. Concentrations recorded in the three freshwater ecosystems that S. lermae inhabit were below 2 mg NO3-N/L. Together, the results could explain why the species has disappeared from more contaminated freshwater ecosystems where NO3-N levels exceed 5 mg/L. Moreover, the study warns about the risks of increasing NO3-N concentrations in the current sites where the species lives.

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Aphis gossypii Glover is one of the most agriculturally important phloem-feeding economic pests, causing tremendous loss in crop yield annually. The hormesis is an important cause of A. gossypii resistance formation, population resurgence, and re-outbreak. However, whether the hormesises induced by different insecticides interact mutually remain largely unclear. In the study, four-generation A. gossypii experiment found that the 24-h sublethal-dose (LC20) sulfoxaflor treatment on G0 significantly increased the net reproductive rate (R0) and fecundity of G1 and G2 generation A. gossypii, but it did not significantly affect the fecundity of G3 and G4 individuals. Transcriptomic analyses revealed that the insecticide-induced significant up-regulation of pathways ribosome, energy metabolism, and the DNA replication and reparation might be responsible for the enhancement of fecundity in G1 and G2 A. gossypii. Notably, G0 exposure to LC20 sulfoxaflor followed by G1 exposure to LC30 deltamethrin resulted in a stronger reproductive stimulation than sulfoxaflor or deltamethrin exposure alone. Our findings provide valuable reference for optimizing sulfoxaflor application in integrated pest management strategies.

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6:2 Chlorinated polyfluorinated ether sulfonate, commonly known as F-53B, is widely used as a mist suppressant in various industries and is frequently detected in the environment. Despite its prevalent presence, the adverse effects of F-53B are not well understood and require future investigation. This study utilized zebrafish embryos and adults to examine the toxic effects of F-53B. Our findings revealed that F-53B impaired gill structure and increased erythrocyte numbers in adult zebrafish. Notably, F-53B demonstrated a higher sensitivity for inducing mortality (LC50 at 96 h) in adult zebrafish compared to embryos. Additionally, F-53B disrupted the expression of critical steroidogenic genes and hindered sex hormone production, which negatively affecting egg production. In conclusion, this study underscores the detrimental impact of F-53B on gill structure and reproductive toxicity in zebrafish, providing valuable insights into its overall toxicity.

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For the first time, on the basis of complex research, scientifically based and experimentally proven zootechnical feasibility of using the Prevention-N-A biologics developed by us based on the polysaccharide complex of yeast cells Saccharomyces cerevisiae and the aminoglycoside group bactericidal preparation in the technology of obtaining and growing calves in comparison with the previously approved PS-2 preparation. It is proved that three-time intramuscular injection of PS-2 and Prevention-N-A biologics to down-calvers 45-40, 25-20 and 15-10 days before calving in a dose of 10 ml prevents gynecological diseases and increases reproductive function. Under the influence of preparations in cows, the time of separation of the fetal membranes was reduced by 6.0 and 6.4 hours, retention of placenta, post-parturient complications and breast diseases were prevented. The risk of subinvolution of the uterus and endometritis in the first case decreased by 3.0 and 2.0 times, respectively, and in the second - was excluded (P<0.05). Against the background of immunocorrection in cows, the time of onset of heat by 11.6 and 14.2 days, the insemination index by 1.6 and 1.8 times, the service period by 22.4 and 28.4 days, and fertilization in 1 oestrus increased by 2.5 and 3.0 times (P<0.05-0.01). It was found that twice intramuscular injection of PS-2 and Prevention-N-A to calves on 2...3rd and 7... 9th day of life in a dose of 3 ml stimulates their growth and development, reduces the incidence. By the end of the growing period, the animals of the 1st and 2nd experimental groups were superior in live weight to control peers by 4.6 and 7.0 kg, rearing - 13.8 and 17.0 kg, and fattening - by 19.4 and 24.2 kg, respectively (P<0.05-0.01). A similar pattern occurred in the nature of changes in exterior measurements and the growth coefficient of animals of the compared groups. In calves of the experimental groups, the incidence of respiratory and digestive organs decreased by 2.3 and 7.0 times, the recovery time - by 1.3 and 4.3 days, respectively, compared to the control (P<0.05).

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Environmental Arsenic (As) exposure is one of the main health challenges in different area of the world. As is a significant factor responsible to the reproductive system toxicity in both male and female. In this study, the most important effects mechanisms and biomarkers related to environmental exposure to As and the reproductive system toxicity, and infertility risk are reviewed in male and female. The results showed that the most important As-induced reproductive system toxicity in the male were alteration in the quantity and quality of semen, testicular toxicity, oxidative stress, testosterone reduction, and sperm apoptosis. For female were oxidative stress, spontaneous miscarriage, reproductive cycle disruption, decrease in the estradiol, progesterone, and testosterone levels and impair fecundity. The main mechanisms of reproductive system toxicity caused by As exposure in male were, genotoxic effects, reduction of glutathione, disruption of sex hormones, sperm flagellum formation impairment, inhibition of spermatogenesis, disruption of cell signaling pathways, and metabolites disruption. For female were abnormal signaling in gene expression, hormonal homeostasis, As-accumulation in placental tissue and creation of reactive oxygen, disruption in the neurotransmitters balance, and sex hormones disruption. The suitable biomarkers for As-induced reproductive toxicity in male were changes in testosterone, one-carbon and lipid metabolism, noncoding RNAs, and steroid hormone homeostasis, and for female was human chorionic gonadotropin (hCG) changes. Finaly, taking selenium, zinc, silymarin, vitamins (C and E) and phytonutrients can be effective in reducing the As-induced reproductive system toxicity and infertility risk.

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Less than 10% of the candidate drug compounds are associated with male reproductive toxicity. Genetic and/or epigenetic information on sperm may be crucial for fetal development. Therefore, developmental toxicity, such as paternally transmitted birth defects, is possible if genetic abnormalities in the male germ line persist and accumulate in the sperm during spermatogenesis. First, this study provides an overview of chemical and male reproductive toxicity, which may lead to developmental toxicity from the perspective of male reproduction. Second, we demonstrate methods for evaluating male reproductive toxicity to anticipate male-mediated developmental toxicity. We developed a novel staining technique for evaluating sperm quality, as well as a noninvasive imaging analysis of male reproductive toxicity. The former is a mammalian male germ cell-specific staining method using reactive blue 2 dye (RB2), as previously confirmed in human sperm, and a method for detecting the early-stage DNA fragmentation in a single nucleus from mouse spermatozoa using single-cell pulsed-field gel electrophoresis. The latter is a new, ready-to-use, and compact magnetic resonance imaging (MRI) platform utilizing a high-field permanent magnet to evaluate male reproductive toxicity. The histopathological analysis supported the suitability of the MRI platform. The present study, for the first time, revealed a rapid, noninvasive evaluation of male reproductive toxicity in vivo using compact MRI. These novel toxicity assessments can help predict male-mediated developmental toxicity, contributing to accelerated drug discovery and drug repositioning.

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Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999-2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396-0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (ß: 0.667, 95 % CI: 0.120-1.213) and reproductive lifespan (ß: 0.686, 95 % CI: 0.092-1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

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Globally, monitoring of the surface waters is largely limited to the physico-chemical analysis of water in rivers and lakes. Sediment state in the aquatic systems including sediment chemical content or the structure and diversity of benthic communities or ecotoxicological studies with natural sediments remains largely overlooked by the monitoring programs. Hence we assessed the potential toxicity of three riverine sediments on the life-cycle traits (emergence and reproduction) of midge Chironomus riparius via an ecotoxicological testing method over two generations (according to OECD test 233 guidelines). In addition, the riverine sediments were spiked with polyamide (nylon) microplastic particles (1 g kg-1) to analyze an additive effect of microplastic on the sediment toxicity. As model river systems, three rivers (Karchaghbyur, Gavaraget, Argichi) in the Lake Sevan basin (Armenia) were selected. Results of ecotoxicity testing were compared with the indices of water quality (derived from the physico-chemical analysis) and the indices of the ecological status of the rivers (derived from the analysis of benthic communities). The results of testing demonstrated an unexpectedly low emergence of midges after the first generation exposed to the sediment of the river having ''good ecological status'' - the Argichi. Sediments of the Karchaghbyur and Gavaraget rivers impeded the emergence and reproduction of midges after the second generation. An addition of polyamide particles to the sediments did not significantly affect the life-cycle traits of C. riparius indicating the primary effect of the sediments' condition. The discrepancy of biotesting result with that of the other two methods (which indicated ''average water quality'' and "good ecological status") underlies the importance of designing more comprehensive monitoring programs for better assessment and protection of aquatic systems and resources.

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Prochloraz is a widely used fungicide worldwide. It is classified as an endocrine disrupting pesticide that affects the reproductive system. This study aimed to examine the impact of exposure to prochloraz of male mice on the reproductive system of their offspring male mice. Male father mice were intragastrically administered different dosages of prochloraz (group MA: 0 mg/kg/day; MB: 53.33 mg/kg/day; MD:160 mg/kg/day). Then, the testicular average weight of male offspring in the dose groups was found to be significantly lower than those in the control group (MB:0.312g, MD:0.294g, and MA:0.355 g; P < 0.05). Additionally, the testicular coefficient index in the MB and MD groups was also lower than that of the control group. Secondly,we observed that there were significantly different expressed genes clustered in groups B and D, in contrast to the control. Finally, the findings demonstrated a significant alteration in the response of male mice reproductive relative genes to prochloraz invasion. Two genes (Mt-nd6 and Slc12a4) were found to be involved in the regulation of sperm mitochondria function and six genes (Greb1, Esrrb, Catsperb, Mospd2, Sohlh1 and Specc1) were closely linked to sperm functions and estrogen response. The study revealed a significant impact of prochloraz on the reproductive system of male mice, thereby supporting further investigation into the reproductive toxicological effects of the drug.

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Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label.

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Two factors influencing female reproduction have been repeatedly studied in different animal species and humans, namely, 1. secondary plant compounds, especially phytoestrogens (mainly isoflavones (IFs)), and 2. the physical constitution/metabolic phenotype (e.g., obesity). So far, these research results have only been considered separately. In this study, we investigated the influence on reproduction of both phytochemicals, mainly dietary IFs, and the metabolic phenotype represented by three mouse models considered as three distinct genetic groups (a control group, a mouse model with high metabolic activity, and a mouse line with obese body weight). The IF content in different investigated standard chows with similar macronutrient profiles varied significantly (p < 0.005), leading to high mean total plasma IF levels of up to 5.8 µmol/L in juvenile and 6.7 µmol/L in adult female mice. Reproductive performance was only slightly affected; only an IF dose-dependent effect on gestation length was observed in all genetic groups, as well as an effect on pregnancy rate in obese mice. Dietary IF exposure, however, caused earlier onset of vaginal opening by 4-10 days in juvenile mice (p < 0.05), dependent on the genetic group, resulting in a slight acceleration of sexual maturation in the already precocious obese model and to a strong earlier maturation in the otherwise late-maturing sporty model, bred for high treadmill performance. Therefore, our results may help to draw the missing line between the effect of dietary secondary plant constituents, such as IFs, and metabolic phenotype on sexual development.

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BACKGROUND: When developing new antimalarial drugs, considering their potential use during pregnancy as preventive or curative therapy is crucial. This prevents the parasite from affecting embryonic development and reduces maternal and fetal death risks. Consequently, understanding the exposure and safety of antimalarial drugs during pregnancy is crucial, with well-designed animal studies playing a key role in this assessment. METHODS: As part of the drug development program for cabamiquine, a series of developmental and reproductive toxicity studies were conducted in rats and rabbits. Additionally, the zebrafish embryo model was used to further improve embryo exposure, minimize confounding factors related to maternal toxicity, and assess developmental risks of cabamiquine. RESULTS: In these studies, although maternal toxicity was observed, there were no cabamiquine-related adverse effects on fertility, embryonic, or fetal development at maternal exposures representing significant multiples (up to five and 10 times higher in rabbit and rats, respectively) than the exposure at the anticipated efficacious human dose. Similarly, no adverse effects were observed on ZF embryonic development, even though cabamiquine concentrations in the embryos were 10-fold higher than nominal concentrations. CONCLUSIONS: The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates.

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To boost the immune function around parturition, recombinant bovine granulocyte colony-stimulating factor (rbG-CSF) has been used to increase the number of neutrophils. Therefore, the aim of this study was to quantify the effect of rbG-CSF administration on the incidence of postpartum pathologies, reproductive performance, and milk production during the first three months of lactation. A total of 199 Holstein cows from one herd were included and were randomly allocated into two groups: Control (n = 103) and rbG-CSF (n = 96). Cows in the rbG-CSF group received 2 doses of a rbG-CSF injectable formulation, one 7 days before the expected date of calving and the other within 24 h after calving. For 6 weeks following calving, animals were examined weekly to assess the presence of postpartum pathologies. Milk production, protein and fat content, and somatic cell count were determined monthly by the regional dairy herd improvement association. Data about the reproductive performance were collected from on-farm software. To analyse the effect of treatment on the incidence of postpartum pathologies, Pearson's χ2 test and multivariable logistic regressions were performed. The effect on reproductive performance was analysed using Cox proportional hazard regression analysis for days open, binary logistic regression for first service conception rate and Oneway ANOVA test for the number of artificial inseminations. The effects of treatment on milk yield and milk composition were checked using GLM repeated measures analysis. No statistically significant differences were observed between treatment groups for any of the parameters evaluated. Only parity had a significant effect on days open and milk production (p < 0.05). In conclusion, in the present study no evidence was found that rbG-CSF could have an effect on the reproductive and productive parameters evaluated.

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This study examines the effects of Roundup Transorb® (RDT) exposure on reproductive functions and ovarian miRNA expression in Austrolebias charrua. Exposure to RDT (at 0.065 or 5 mg. L-1 for 96 h) significantly disrupts fertility, evidenced by changes in fertilization rates and egg diameter. Profiling of ovarian miRNAs identified a total 205 miRNAs in A. charrua. Among these, three miRNAs were upregulated (miR-10b-5p, miR-132-3p, miR-100-5p), while ten miRNAs were downregulated (miR-499-5p, miR-375, miR-205-5p, miR-206-3p, miR-203a-3p, miR-133b-3p, miR-203b-5p, miR-184, miR-133a-3p, miR-2188-5p) compared to non-exposed fish. This study reveals that differentially expressed miRNAs are linked to molecular pathways such as steroid hormone biosynthesis, lipid and carbohydrate metabolism, bioenergetics, and antioxidant defense. It also analyzes molecular interactions between miRNAs and target genes during RDT exposure in annual killifish, providing insights into biomarkers in ecotoxicology. Moreover, it provides scope for developing environmental health assessment models based on epigenomic endpoints, supporting the protection of biodiversity and ecosystem services through the quantification of stress responses in living organisms exposed to pesticides.

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Cigarette butts have become one of the most common and persistent forms of debris in marine coastal areas, where they pose significant toxicity risks. This study investigated cigarette butt pollution along beaches of the Yellow Sea and used laboratory experiments to assess the toxicity of their leachate and fibers on the euryhaline rotifer Brachionus plicatilis. A pollution index confirmed pollution by this debris across all eight beaches surveyed, where the density of cigarette butts averaged 0.23 butts/m2. In controlled laboratory experiments, both the fibers and leachates from cigarette butts exhibited negative impacts on the development, reproduction, and population growth of rotifers. Unique abnormalities observed under different exposure treatments indicated toxicity specific to certain chemicals and particles. Continuous exposure to cigarette butts initially reduced rotifer fecundity, but this effect diminished over successive generations. However, the exposure induced transgenerational reproductive toxicity in the rotifers. Adaptive responses in rotifers after repeated exposure led to relative reduction in reproductive inhibition in the F3 and F4 generations. Furthermore, rotifers were capable of ingesting and accumulating cigarette butts, and maternal transfer emerged as an alternative pathway for uptake of this material in the offspring. These results increase our understanding of the ecological risks posed by cigarette butts in aquatic environments.

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Quercetin has been shown to mitigate the cytotoxic effects of heavy metals. While copper is an essential trace element for bodily functions, excessive intake has been linked to impaired female reproductive function. Transcriptome analysis was employed to identify genes that are differentially expressed in response to high copper and were validated through qRT-PCR and western blotting. ATP content and Tunel were used to identify the damage of mitochondrial and cell apoptosis. PPI analysis revealed that MKI67, TOPII, ASPM, CASP3, PLK1, and TTK are central proteins within the network. Additionally, exposure to elevated levels of copper resulted in the dysregulation of 86 genes associated with mitochondria. Conversely, treatment with quercetin (QUE) in combination with high copper led to the normalization of 42 mitochondria-related genes previously affected by high copper levels. Furthermore, CuSO4 decreases ATP content and induces cell apoptosis, which can be reversed by QUE. Results suggest that elevated copper levels could lead to oxidative stress and apoptosis by inducing mitochondrial damage, while QUE has the potential to mitigate these effects, ultimately safeguarding granulosa cells and halting the progression of cell death. This study provides novel insights into the molecular pathways involved in female reproductive toxicity caused by excessive copper exposure.

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Here, we subjected the marine copepod Tigriopus japonicus to environmentally-relevant concentrations of microplastics (MPs) and mercury (Hg) for three generations (F0-F2) to investigate their physiological and molecular responses. Hg accumulation and phenotypic traits were measured in each generation, with multi-omics analysis conducted in F2. The results showed that MPs insignificantly impacted the copepod's development and reproduction, however, which were significantly compromised by Hg exposure. Interestingly, MPs significantly increased Hg accumulation and consequently aggravated this metal toxicity in T. japonicus, demonstrating their carrier role. Multi-omics analysis indicated that Hg pollution produced numerous toxic events, e.g., induction of apoptosis, damage to cell/organ morphogenesis, and disordered energy metabolism, ultimately resulting in retarded development and decreased fecundity. Importantly, MPs enhanced Hg toxicity mainly via increased oxidative apoptosis, compromised cell/organ morphogenesis, and energy depletion. Additionally, phosphoproteomic analysis revealed extensive regulation of the above processes, and also impaired neuron activity under combined MPs and Hg exposure. These alterations adversely affected development and reproduction of T. japonicus. Overall, our findings should offer novel molecular insights into the response of T. japonicus to long-term exposure to MPs and Hg, with a particular emphasis on the carrier role of MPs on Hg toxicity.

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