JOURNAL OF HAZARDOUS MATERIALS
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2023
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IF 13.6
Jun Wu,Fuming Deng,Xiangliang Tang,Wenbin Chen,Rui Zhou,Tianxin Zhao,Xiangming Mao,Fangpeng Shu
Although it has been reported that perinatal, especially prenatal exposure to polybrominated diphenyl ethers (PBDEs) alters offspring's fertility, but little is known regarding their longitudinal effects over time. In the current study, we determined the associations between prenatal exposure to 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE-99) of environmentally relevant levels in pregnant ICR mice and spermatogenic impairments in male offspring on postnatal day 70. Then, we monitored functional injuries in spermatogenic cells (GC-1 spg) exposed to PBDE-99 in vitro. Furthermore, transcriptome sequencing and bioinformatic analysis were used to investigate the underlying mechanism of PBDE-99 exposure to GC-1 spg. Additionally, the expression levels of key genes in the relevant pathways were quantified. Our findings indicated that exposure to PBDE-99 caused significantly spermatogenic injuries, which partly owing to the accumulation of reactive oxygen species , dysregulation of autophagy, and finally induced spermatogenic cell apoptosis. Rescue validation experiments showed that stimulating autophagy could alleviate spermatogenic cell injury induced by PBDE-99. In conclusion, our findings indicated that the dysfunction of autophagy played a significant role in long-term reproductive toxicity following prenatal exposure to environmental concentrations of PBDE-99.
研究领域:
毒理学
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生殖生物学
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环境健康
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PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2022
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IF 10.753
Yanfeng Wang,Qihua Wang,Lina Zhou,Zhijun Zeng,Chunxia Zhao,Lei You,Xin Lu,Xinyu Liu,Runze Ouyang,Yuting Wang,Xijin Xu,Xiwen Tian,Yufeng Guo,Xia Huo,Guowang Xu
Background Effects of polybrominated diphenyl ethers (PBDEs) on neonatal birth outcomes vary across previous studies, and the related mechanism investigation remains poorly understood, especially at the metabolic level. Objectives To evaluate the associations between prenatal PBDEs exposure and neonatal birth outcomes including gestational age, neonatal weight, birth length, head circumference (HC), Apgar score at 1 min (Apgar1) and 5 min, and further reveal the underlying metabolic disorders in a population-based birth cohort study. Methods Gas chromatography-triple quadrupole tandem mass spectrometry (GC–MS/MS) based targeted method and GC–MS based untargeted method were respectively conducted to obtain PBDE levels and metabolic profiles of 200 placental tissue samples from a typical e-waste recycling area (Guiyu) and reference area (Haojiang) in China. Spearman correlation and regression analyses were applied to assess the associations between the placental PBDE levels and birth outcomes. Metabolome-wide association studies and the meet-in-the-middle approach were employed to explore disruptions linking PBDE exposures and the corresponding adverse birth outcomes. Results Eight out of 27 PBDE congeners were detected in placenta with more than 50% frequency in at least one district and significantly higher in Guiyu than those in Haojiang. The lower HC and Apgar1 had significant associations with PBDE exposures after adjustment for potential confounders. A total of 66, 16 and 14 metabolites were significantly correlated with PBDE exposures, HC and Apgar1, respectively. 4 and 12 PBDE-related metabolites were significantly associated with the risks of decreasing neonatal HC and Apgar1. The disrupted metabolites were mainly involved in the pentose phosphate pathway, ascorbate metabolism, threonine metabolism, butanoate metabolism, lipid metabolism , and arginine biosynthesis. Conclusions In this birth cohort, higher placental PBDE levels were significantly associated with the lower HC and Apgar1. The associations might be modified by multiple metabolic disturbances through increasing oxidative stress , mediating neurotoxicity, maternal gut microbiota dysbiosis and vasodilatation regulation.
研究领域:
环境科学
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医学
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毒理学
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代谢组学
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DOI
PubMed
高影响因子
TOXICOLOGY AND INDUSTRIAL HEALTH
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2024
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IF 1.7
Yuxin Wang,Yi Guo,Jiajia Ren,Qiling Liu,Chong Wang
Earlier research has demonstrated that developmental exposure to bisphenol A (BPA) has persistent impacts on both adult brain growth and actions. It has been suggested that BPA might obstruct the methylation coding of the genes in the brain. In this study, the methylation changes in the hippocampus tissue of male rat pups were examined following prenatal BPA exposure. Pregnant Sprague-Dawley rats were treated with either vehicle (tocopherol-stripped corn oil) or BPA (4, 40, or 400 μg/kg·body weight/day) throughout the entire duration of gestation and lactation. At 3 weeks of age, the male rat offspring were euthanized, and the hippocampus were dissected out for analysis. The expression levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) and DNA demethylases (TET1, Gadd45a, Gadd45b, and Apobec1) were analyzed in the hippocampus by means of quantitative real-time polymerase chain reaction and Western blotting, respectively. The results showed that prenatal exposure to BPA upregulated the expression of enzymes associated with DNA methylation and demethylation processes in the hippocampus of male rat offspring. These findings suggest that prenatal exposure to a low dose of BPA could potentially disrupt the balance of methylation and demethylation in the hippocampus, thereby perturbing epigenetic modifications. This may represent a neurotoxicity mechanism of BPA.
研究领域:
神经科学
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表观遗传学
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毒理学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Nan Zhao,Wei Song,Tianshu Sun,Weiwei Wu,Yongliang Feng,Ning Ma,Suping Wang
Prenatal exposure to Benzo[ a ]pyrene (BaP) has been shown to increase the risk of adverse birth outcomes, potentially through disruption of maternal metabolic homeostasis. However, the underlying pathways and mechanisms remain unclear. To address this knowledge gap, we employed a multi-omics approach combining experimental and epidemiological investigations. In the mouse model, untargeted metabolomics profiling revealed niacinamide (NAM) metabolism as the most significantly altered pathway in both maternal serum and placenta following BaP exposure. Mechanistically, BaP exposure reduced nicotinamide adenine dinucleotide (NAD+) synthesis while increasing its catabolism through activation of poly (ADP-ribose) polymerase 1 (PARP1) in placental tissue. Subsequent transcriptomic analysis showed that BaP-induced NAD+ depletion led to sirtuin 1 (SIRT1) suppression and consequent exacerbation of the NF-κB-mediated inflammatory response. These experimental findings were substantiated in human populations through targeted metabolomic analysis of a Chinese birth cohort, where significant NAM metabolic disturbances were observed in women with high BaP exposure experiencing preterm delivery. Our study provides novel mechanistic evidence that BaP-induced dysregulation of NAM metabolism mediates adverse birth outcomes through NAD+ deficiency and subsequent inflammatory response. These findings not only identify potential therapeutic targets but also highlight the urgent need for evidence-based environmental policy interventions and nutritional supplementation strategies to protect maternal-fetal health in high-risk populations.
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2023
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IF 13.6
Rui Zhang,Jingyao Guo,Yupeng Wang,Rundong Sun,Guangzhu Dong,Xinru Wang,Guizhen Du
The increased usage of bisphenol S (BPS) results in wide distribution in pregnant women. In this study, pregnant mice were given multiple-dose BPS during gestation. Results showed that prenatal BPS exposure (50 μg/kg/day) induced increased weight gain, dyslipidemia, higher liver triglyceride (TG), adipocyte hypertrophy, and hepatic lipid deposition in male offspring . Exosomes play important roles in regulating lipid metabolism . Here, serum exosomes and adipose miRNA sequencing of male offspring indicated a remarkable decrease in miR-29a-3p expression. To clarify whether adipocyte-derived exosomes mediate hepatic lipid deposition, exosomes were extracted from BPS-treated adipocytes and co-cultured with hepatocytes. These exosomes could be taken up by hepatocytes and promoted lipid deposition, and notably, exosomal miR-29a-3p was downregulated. Furthermore, miR-29a-3p knockdown in adipocyte-derived exosomes promoted hepatocyte lipid deposition, whereas overexpression led to the opposite effect. Also, the role of miR-29a-3p was demonstrated in hepatocytes by overexpressing or knocking it down. Subsequent studies have shown that miR-29a-3p can promote lipid deposition by directly targeting Col4a1 . Taken together, prenatal BPS exposure could lead to lower miR-29a-3p yield in adipocyte-derived exosomes and decrease miR-29a-3p content transported to hepatocytes, which further negatively regulate Col4a1 and promote hepatic lipid deposition. Our findings provided clues to maternal environmental exposure-induced liver metabolic diseases.
研究领域:
毒理学
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分子生物学
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内分泌学
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发育生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2022
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IF 7.129
Jiabin Hong,Xiaoxun Lu,Jieyu Wang,Mengzhu Jiang,Qian Liu,Juntong Lin,Wenjing Sun,Jing Zhang,Yanwei Shi,Xiaoshan Liu
Epidemiological studies have shown that prenatal triphenyl phosphate (TPhP) exposure is related to abnormal neurobehavior in children. However, the neurodevelopmental toxicity of TPhP in mammals is limited. To study the neurodevelopmental toxicity of TPhP in mammals and investigate the underlying mechanism, we used a mouse intrauterine TPhP exposure model. We measured the inflammatory factors (IL-6, TNFα) and NFκB levels, and tryptophan metabolism in placentae, detected the fetal brain transcriptome, hippocampal neuron development and neurobehavioral in the male offspring. The results showed that the protein level of IL-6, TNFα and NFκB in the placenta of the TPhP treatment group (1, 5 mg/kg) were significantly increased. Change of the protein level of these pro-inflammatory factors in maternal serum or fetal brain was not observed. Expression of genes along tryptophan-serotonin metabolism pathway were significantly decreased. While, the concentration of 5-HT levels in the placenta or fetal brain were significantly increased. Consistent with the increased 5-HT, the Nissl body was reduced in the hippocampus of treatment group. The expression of serotonergic neuron gene markers including Tph2 , Htr1A , Htr2A , Pet1 and Lmx1b in the hippocampus of treatment group was significantly decreased. The neurobehavioral test showed that TPhP decreased center time that represent anxiety-like behavior, and reduced learning and memory in male offspring. Meanwhile, expression of genes along tryptophan-kynurenine metabolism pathway were significantly increased. The result of the transcriptome analysis of fetal brain showed that the differentially expressed genes are mainly involved in the transcription regulation of DNA as a template in the nucleus, and the enriched pathways are mainly signal pathways regulated by axon guidance and neurotrophic factors, dopaminergic and cholinergic synapses, suggest that not only serotonergic neuronal was affected. Overall, this study demonstrates that TPhP has the potential to induce placental inflammatory response in the placenta, disturb placental tryptophan metabolism, compromise the neuronal development and synaptic transmission, and cause abnormal neurobehavior in male offspring.
研究领域:
毒理学
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神经科学
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发育生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
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IF 6.8
Yin Zhuang,Xiangying Sun,Siting Deng,Ya Wen,Qiujin Xu,Quanquan Guan
Background Bisphenol A (BPA) is known to exhibit endocrine disrupting activities and is associated with adiposity. We examined the obesogenic effect of prenatal BPA exposure in the present study. Methods Pregnant ICR mice were exposed to vehicle or BPA via the drinking water at a dose of 0.5 μg/kg·d throughout the gestation. Obesity-related indexes were investigated in the 12-wk-old offspring. Primary mouse embryonic fibroblasts (MEFs) collected from treated embryos were used to test effects of BPA on adipocyte differentiation. Results Offspring presented a significantly higher rate of weight gain than the control, with impaired insulin sensitivity and increased adipocyte size. Differentiation of MEFs from BPA-treated mice showed a higher propensity for the adipocyte commitment as well as up-regulation of genes enriched in lipid biosynthesis. TGF-β signaling pathway was found to modulate obesogenic effect of BPA in MEF model, but estrogen signaling pathway had no effect. Conclusions The present study provides strong evidence of the association between prenatal exposure to low dose of BPA and a significant increase in body weight in the offspring mice with a critical role played by TGF-β signaling pathway. The potential interactions modulating the binding of BPA and TGF-β that activate its obesogenic effects need to be examined.
研究领域:
毒理学
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内分泌学
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发育生物学
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PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2024
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IF 10.8
Qian Liu,Xiaoxun Lu,Ganzhong Liao,Fuhui Yan,Miaoliang Wu,Zhi Bai,Huanwen Tang,Xiaoshan Liu
Triphenyl phosphate (TPhP) is a widely used organophosphate flame retardant, the health risks of TPhP are a global concern. In this study, we found that prenatal TPhP exposure at human relevant concentration induced hyperlipidemia in male offspring, it increased serum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Placental trophoblast-derived extracellular vesicles (T-EVs) could transport to the fetus through maternal-fetal circulation. TPhP significantly upregulated the protein level of peroxisome proliferator activated receptor γ (PPARγ) in T-EVs. Similar to TPhP, gestational exposure to T-EVs isolated from TPhP exposed mice placentae induced the same effects. While, gestational intervention with GW9662 (PPARγ inhibitor) or GW4869 (EVs secretion inhibitor) would alleviate the disturbed lipid metabolism induced by TPhP. Meanwhile, in vitro experiments verified that TPhP upregulated PPARγ in HTR8/SVneo cells derived EVs, and these EVs promoted adipogenesis in preadipocyte 3T3-L1 cells. Knock down of PPARγ in HTR8/SVneo could alleviate the adipogenensis effects of EVs derived from TPhP exposed HTR8/SVneo cells. These results demonstrate that TPhP exposure induces hyperlipidemia in male offspring by upregulating PPARγ in T-EVs. Our study provides new insights into the metabolic disruptive effects of TPhP, and emphasizes the mediating effects of placental T-EVs on gestational environmental stress in fetal development.
研究领域:
环境健康
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发育生物学
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代谢
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毒理学
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PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Min He,Yahang Lin,Xiaojing Zhang,Siyi Wang,Xinyu Yang,Fengzhen Cui,Xia Sheng
Neural stem cells (NSCs) are essential for brain development due to their ability to proliferate and differentiate into various neural cell types. Neonicotinoid insecticides (NNIs), which have replaced traditional pesticides, are now widely used and frequently detected in environmental and biological samples. Prenatal exposure to NNIs has been associated with an increased risk of neurodevelopmental disorders in offspring, yet the causal relationship and the underpinning mechanism remain to be clarified. As one of the primary metabolites of chloropyridinyl neonicotinoids, 6-chloronicotinic acid (6-ClNA) has been identified as a potential neurotoxin, though its effects on NSCs have not been fully explored. Here, we demonstrate that 6-ClNA exposure significantly disrupted NSC proliferation and differentiation in vitro. Transcriptomic analyses revealed that 6-ClNA altered the expression of pathways related to proliferation, apoptosis, and inflammation, with notable activation of the C3ar1/C1qa signaling axis. Genetic ablation of C3ar1 using siRNA markedly restored NSC proliferation and neurosphere formation, as well as reduced apoptosis, suggesting a central role of C3ar1/C1qa in mediating 6-ClNA's neurotoxic effects. These findings imply that early-life exposure to NNIs may affect the fitness and function of NSCs, wherein the C3ar1 pathway plays an indispensable role.
研究领域:
神经科学
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毒理学
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发育生物学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2021
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IF 10.588
Tianxin Zhao,Xiangliang Tang,Dian Li,Jinglu Zhao,Rui Zhou,Fangpeng Shu,Wei Jia,Wen Fu,Huimin Xia,Guochang Liu
Polybrominated diphenyl ethers (PBDEs) are a widely used class of brominated flame retardants . Exposure to PBDEs could induce testicular damage in mammals, but the effects and potential mechanism of action of prenatal exposure to environmentally relevant PBDEs on testicular development remain unclear. For the in vivo study, pregnant ICR mice were exposed to environmentally relevant levels of 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE-99), a major component of commercial PBDE mixtures. We found that the anogenital index and testicular organ coefficient were significantly decreased, the incidence of cryptorchidism was increased, and testicular histology was disturbed in male offspring . Transcriptomic profiling showed that steroidogenesis disorders were significant in all PBDE-99 exposure groups. The testosterone levels, expressions of testosterone regulators, and the number of CYP11A1-positive and 11β-HSD1-positive Leydig cells were significantly decreased after PBDE-99 exposure. For the in vitro study, TM3 Leydig cells were exposed to PBDE-99 at gradient concentrations. Transcriptomic profiling and validation experiments showed that PBDE-99 upregulated reactive oxygen species , activated the ERK1/2 pathway, inhibited the ubiquitination degradation pathway, and finally induced Leydig cell apoptosis. Cumulatively, these findings revealed that prenatal exposure to environmentally relevant levels of PBDE-99 leads to steroidogenesis disorders by inducing the apoptosis of Leydig cells, causing testicular dysgenesis.
研究领域:
毒理学
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生殖生物学
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环境健康
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PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2022
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IF 5.572
Jia Lv,Yanling Li,Jianrong Chen,Rong Li,Chao Bao,Zheng Ding,Wenqiang Ren,Zhiping Du,Sheng Wang,Yichao Huang,Qu-nan Wang
Prenatal DEHP exposure can cause offspring neurodevelopmental toxicity, but the persistent effects of such exposure window are unclear. This study aimed to investigate the lasting neurobehavioral impact of DEHP on offspring following early exposure from GD9.5 (fetal neural tube closure) to GD16.5 (fetal thyroxin , TH, synthesis). Data showed maternal exposure to DEHP during the thyroid hormone-dependent stage induced a range of neurobehavioral phenotypic changes in adult and middle-aged mice, including anxiety, depression and cognitive impairment . Significant reductions in free TH, TH transporters, and TH metabolic enzyme deiodinase II (D2) were observed in the fetal brain, whereas D3 was elevated, indicating that TH signaling disruption was caused by in utero exposure. Gene expression analyses suggested the expression levels of the TH receptors Trα1 , Trβ1 and their downstream target, brain-derived neurotrophic factor, were significantly attenuated, which may partially explain the mechanisms of neurodevelopmental impairment. This study provides new evidence of the persistent effects of sex-specific neurodevelopmental impairment due to in utero DEHP exposure, possibly through damage to the fetal brain TH signaling systems that causes lifelong brain damage. These results further suggest a profound neurobehavioral toxicity of DEHP that may be programmed during early developmental stage exposure and manifested later in life.
研究领域:
神经科学
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毒理学
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发育生物学
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内分泌学
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DOI
PubMed
高影响因子
REPRODUCTIVE TOXICOLOGY
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2023
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IF 3.3
Kaiqi Chen,Xiaoqian Lu,Dan Xu,Yu Guo,Ying Ao,Hui Wang
Corn oil, sodium carboxymethyl cellulose (CMC-Na), and dimethyl sulfoxide (DMSO) are widely used as solvents or suspensions in animal experiments, but the effects of prenatal exposure to them on fetal development have not been reported. In this study, Kunming mice were given a conventional dose of corn oil (9.2 g/kg·d), CMC-Na (0.05 g/kg·d) or DMSO (0.088 g/kg·d) during gestation days 10–18, and the pregnancy outcome, fetal physical development, serum phenotype, and multi-organ function changes were observed. The results showed that corn oil decreased serum triglyceride level in males but increased their serum testosterone and CORT levels, and affected female placenta and female/male multi-organ functions (mainly bone, liver, kidney). CMC-Na increased female/male body lengths and tail lengths, decreased serum glucose and total cholesterol levels in males as well as increased their serum LDL-C/HDL-C ratio and testosterone level, decreased female serum bile acid level, and affected male/female placenta and multi-organ functions (mainly bone, liver, hippocampus). DMSO decreased male body weight and serum glucose level, decreased male/female serum bile acid levels, and affected male/female placenta and multi-organs functions (mainly bone, hippocampus, adrenal gland). In conclusion, prenatal exposure to a conventional dose of corn oil, CMC-Na or DMSO could affect fetal physical development and multi-organ functions, and has the characteristics of "multi-pathway, multi-organ and multi-target". This study provides the experimental basis for the rational selection of solvents or suspensions in pharmacology and toxicology studies.
研究领域:
药理学
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毒理学
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发育生物学
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动物科学
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DOI
PubMed
高影响因子
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