BDE-209 induces male reproductive toxicity via cell cycle arrest and apoptosis mediated by DNA damage response signaling pathways

Acrolein is a ubiquitous environmental pollutant that produced by the incomplete combustion of cigarette smoke, forest fires, petroleum fuels, plastic materials, and cooking fumes. Inhalation is a common form of people exposure to acrolein, increasing evidence demonstrates that acrolein impairs the cardiovascular system by targeting vascular endothelial cells. However, the molecular mechanism of the cytotoxicity of acrolein exposure on vascular endothelial cells remains unclear. This work focused on the toxicity of acrolein on human umbilical vein endothelial cells (HUVECs). The molecular mechanism was studied based on oxidative stress, DNA damage response (DDR), and mitochondrial apoptosis pathways. After HUVECs were treated with 12.5, 25, and 50 μM acrolein for 24 h, cell viability, cell colony formation, mitochondrial membrane potential, and adenosine triphosphate content significantly reduced, and acrolein increased intracellular reactive oxygen species, apoptosis rate, and 8-hydroxy-2 deoxyguanosine (8-OHdG) level. Furthermore, p38MAPK and c-Jun N-terminal kinase signaling pathways were activated in response to oxidative stress. Moreover, acrolein induced G0/G1phase arrest, promoted the expression of γ-H2AX, activated the DDR signaling pathway (Ataxia-Telangiectasia-Mutated [ATM] and Rad-3-related/Chk1 and ATM/Chk2), and triggered the consequent cell cycle checkpoints. Finally, the protein expression of Bax/Bcl-2 and cleaved Caspase-3 was up-regulated, suggesting apoptosis was induced by triggering the mitochondrial apoptosis pathway. All these results indicated that acrolein induced HUVECs cytotoxicity by regulating oxidative stress, DNA damage, and apoptosis. This study provides a novel perspective on the mechanism of acrolein-induced cardiovascular toxicity, it will be helpful for the prevention of acrolein-induced cardiovascular disease.

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“…The cell cycle of HUVECs was analyzed by detecting the DNA content of different cell phases by using flow cytometry (Becton-Dickinson, USA). 39…”

Section: Analysis Of Cell Cycle In Vitromentioning

confidence: 99%

Mechanisms of acrolein induces toxicity in human umbilical vein endothelial cells: Oxidative stress, DNA damage response, and apoptosis

Liú

Cheng

Mei

et al. 2021

Environmental Toxicology

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“…Exposure of adult mice to 7.5, 25, or 75 mg/kg/BW/day of BDE-209 also resulted in significantly reduced sperm numbers, while only 25 and 75 mg/kg significantly reduced sperm motility [48]. Histopathological examinations also showed a dose-dependent significant reduction in the height of germinal epithelium for the three doses [48].…”

Section: Adult Effectsmentioning

confidence: 88%

“…Exposure to 0.0015, 1.5, 10, and 30 mg/kg BDE-3 for six consecutive weeks resulted in decreased sperm counts in mice exposed to 1.5 mg/kg or higher doses, decreased germ cells in seminiferous tubules, and also decreased mature spermatozoa in the epididymis of animals exposed to 30 mg/kg BDE-3 [47]. Exposure of adult mice to 7.5, 25, or 75 mg/kg/BW/day of BDE-209 also resulted in significantly reduced sperm numbers, while only 25 and 75 mg/kg significantly reduced sperm motility [48]. Histopathological examinations also showed a dose-dependent significant reduction in the height of germinal epithelium for the three doses [48].…”

Section: Adult Effectsmentioning

confidence: 91%

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers

Arowolo¹,

Pilsner²,

Sergeyev³

et al. 2022

Preprint

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Polybrominated diphenyl ethers (PBDE) are a group of flame retardants used in a variety of artificial materials. Despite phasing out in most industrial countries, they persist in the environment and human tissues due to their persistence, lipophilicity, and bioaccumulation. Populational and experimental studies demonstrate male reproductive toxicity of PBDEs including increased incidence of genital malformations (hypospadias and cryptorchidism), altered weight of testes and other reproductive tissues, altered testes histology and transcriptome, decreased sperm production and sperm quality, altered epigenetic regulation of developmental genes in spermatozoa and altered secretion of reproductive hormones. A broad range of mechanistic hypotheses of PBDE reproductive toxicity has been suggested. Among these hypotheses, oxidative stress, disruption of estrogenic signaling, and mitochondria disruption are affected by PBDE concentrations much higher, than concentrations found in human tissues, making them unlikely links between exposures and adverse reproductive outcomes in the general population. Robust evidence suggests that at environmentally relevant doses, PBDEs and their metabolites may affect male reproductive health via mechanisms including AR antagonism and the disruption of a complex network of metabolic signaling.

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“…It is therefore unsurprising that antioxidant deficiencies or interruption of their endogenous functions can indirectly contribute to the acquisition of genomic lesions if sustained over time. Maternal multivitamin supplementation during pregnancy has been shown to both reduce the incidence of ASD onset [ 37 , 93 ] and buffer against oxidative DNA damage [ 94 , 95 ], whereas ASD toxicants such as formaldehyde, a gaseous chemical used in the production of building materials, and flame retardant constituents including polybrominated diphenyl ethers disrupt antioxidant status in both gametal [ 96 – 98 ] and non-reproductive cells [ 99 ], potentiating oxidative imbalances and ROS-induced DNA damage in afflicted tissues.…”

Section: Mutagenicity and Genotoxicity Of Early-exposure To Establish...mentioning

confidence: 99%

“…Maternal exposure to lead during pregnancy increases oxidative stress in the developing foetus in mammalian models [ 164 ] Nickel a Birth residence in census tracts with elevated nickel air pollution is associated with increased risk of ASD (OR = 1.46-1.65) [ 66 , 67 ] Exposure to nickel in vitro has been associated with increased ROS generation and DNA strand breaks in human neuronal analogues [ 165 ] and human lymphocytes [ 166 ]. a Exposure to nickel sulphide in vitro has been shown to increase mutagenesis in mRNA transcripts of ASD susceptibility gene FHIT in mammalian bronchial epithelial cells [ 167 ] Herbicides Pyrethroids Maternal proximity to pyrethroid insecticide applications in the pre-conception and/or third trimester period of pregnancy is associated with increased risk of ASD (OR = 1.7-2.3) [ 52 ] Oral administration of pyrethroid congener fenpropathrin results in increased oxidative stress and DNA strand breaks in mammalian sperm cells in vivo [ 168 ]; in vitro exposure to pyrethroid congeners cyfluthrin, alpha-cypermethrin, and beta-cypermethrin elicits dose-dependent increases in ROS generation in human neuronal analogues [ 169 ] Industrial chemicals Polybrominated Diphenyl Ethers Trends in polybrominated diphenyl ether application positively correlates with increases in ASD prevalence in the United States [ 17 ]; maternal blood serum concentrations of polybrominated diphenyl ether congeners during pregnancy is associated with increases in idiosyncratic ASD behaviours in offspring [ 170 ] Exposure to polybrominated diphenyl ether congeners results in increased oxidative stress in mammalian testicular tissue in vivo and increased ROS activity and expression of DNA repair genes in mammalian sperm cells in vitro [ 98 ]; high-dose concentrations of polybrominated diphenyl ether congeners elicit ROS generation and disrupted antioxidant status in human fibroblast cells in vitro [ 99 ] Parental health factors Maternal diabetes Pre-existing maternal diagnosis of type II diabetes (HR = 1.33) and development of gestational diabetes mellitus during pregnancy (HR = 1.42) [ 35 ], as well as maternal pre-pregnancy obesity and diabetes (HR = 3.91) and comorbid obesity and gestational diabetes (HR = 3.04) [ 34 ] increase the risk of ASD in offspring Maternal diabetes during pregnancy increases the frequency of oxidative DNA double-strand breaks and DNA repair responses in mammalian embryos in vivo and mammalian neural stem cells in vitro [ …”

Section: Introductionmentioning

confidence: 99%

Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

et al. 2021

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Although the full aetiology of autism spectrum disorder (ASD) is unknown, familial and twin studies demonstrate high heritability of 60–90%, indicating a predominant role of genetics in the development of the disorder. The genetic architecture of ASD consists of a complex array of rare and common variants of all classes of genetic variation usually acting additively to augment individual risk. The relative contribution of heredity in ASD persists despite selective pressures against the classic autistic phenotype; a phenomenon thought to be explained, in part, by the incidence of spontaneous (or de novo) mutations. Notably, environmental exposures attributed as salient risk factors for ASD may play a causal role in the emergence of deleterious de novo variations, with several ASD-associated agents having significant mutagenic potential. To explore this hypothesis, this review article assesses published epidemiological data with evidence derived from assays of mutagenicity, both in vivo and in vitro, to determine the likely role such agents may play in augmenting the genetic liability in ASD. Broadly, these exposures were observed to elicit genomic alterations through one or a combination of: (1) direct interaction with genetic material; (2) impaired DNA repair; or (3) oxidative DNA damage. However, the direct contribution of these factors to the ASD phenotype cannot be determined without further analysis. The development of comprehensive prospective birth cohorts in combination with genome sequencing is essential to forming a causal, mechanistic account of de novo mutations in ASD that links exposure, genotypic alterations, and phenotypic consequences.

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BDE-209 induces male reproductive toxicity via cell cycle arrest and apoptosis mediated by DNA damage response signaling pathways

Cited by 35 publications

References 61 publications

Mechanisms of acrolein induces toxicity in human umbilical vein endothelial cells: Oxidative stress, DNA damage response, and apoptosis

Mechanisms of acrolein induces toxicity in human umbilical vein endothelial cells: Oxidative stress, DNA damage response, and apoptosis

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers

Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands

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