Search

Background: Excessive fluoride exposure induces skeletal fluorosis, but the specific mechanism responsible is still unclear. Therefore, this study aimed to identify the pathogenesis of fluoride-induced bone injuries., Methods: We systematically searched fluoride-induced bone injury-related genes from five databases. Then, these genes were subjected to enrichment analyses. A TF (transcription factor)-mRNA-miRNA network and protein-protein interaction (PPI) network were constructed using Cytoscape, and the Human Protein Atlas (HPA) database was used to screen the expression of key proteins. The candidate pharmacological targets were predicted using the Drug Signature Database., Results: A total of 85 studies were included in this study, and 112 osteoblast-, 35 osteoclast-, and 41 chondrocyte-related differential expression genes (DEGs) were identified. Functional enrichment analyses showed that the Atf4, Bcl2, Col1a1, Fgf21, Fgfr1 and Il6 genes were significantly enriched in the PI3K-Akt signaling pathway of osteoblasts, Mmp9 and Mmp13 genes were enriched in the IL-17 signaling pathway of osteoclasts, and Bmp2 and Bmp7 genes were enriched in the TGF-beta signaling pathway of chondrocytes. With the use of the TF-mRNA-miRNA network, the Col1a1, Bcl2, Fgfr1, Mmp9, Mmp13, Bmp2, and Bmp7 genes were identified as the key regulatory factors. Selenium methyl cysteine, CGS-27023A, and calcium phosphate were predicted to be the potential drugs for skeletal fluorosis., Conclusions: These results suggested that the PI3K-Akt signaling pathway being involved in the apoptosis of osteoblasts, with the IL-17 and the TGF-beta signaling pathways being involved in the inflammation of osteoclasts and chondrocytes in fluoride-induced bone injuries.

Polybrominated diphenyl ethers (PBDEs)-induced neurotoxicity is closely associated with mitochondrial abnormalities. Mitochondrial fusion and fission dynamics are required for the maintenance of mitochondrial homeostasis. However, little is known about how PBDEs disrupt this dynamics and whether such disruption contributes to impaired neurodevelopment. Methods : We investigated the effects of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47), the dominant congener in human samples, on mitochondrial fusion and fission dynamics using PC12 cells, a well-defined in vitro neurodevelopmental model. We also evaluated the effects of perinatal low-dose PBDE-47 exposure on hippocampal mitochondrial dynamics and its association with neurobehavioral changes in adult Sprague-Dawley rats. Results : In vitro , PBDE-47 disrupted mitochondrial dynamics by inhibiting mitochondrial fusion and fission simultaneously, accompanied by mitochondrial fragmentation, membrane potential dissipation, ATP loss, and apoptosis activation. Specifically, enhancing mitochondrial fusion by the chemical promoter M1 or adenovirus-mediated mitofusin 2 (Mfn2) overexpression rescued PBDE-47-caused mitochondrial dynamic, morphological and functional impairments, prevented the resultant apoptosis and promoted neuronal survival. Unexpectedly, either stimulating mitochondrial fission by adenovirus-mediated fission protein 1 (Fis1) overexpression or suppressing mitochondrial fission by the mitochondrial division inhibitor-1 (Mdivi-1) failed to reverse whereas aggravated PBDE-47-induced mitochondrial damage and neuronal death. Importantly, promoting mitochondrial fusion by Mfn2 overexpression neutralized the detrimental effects elicited by Fis1 overexpression after PBDE-47 treatment. Finally, perinatal oral administration of PBDE-47 elicited neurobehavioral deficits and hippocampal neuronal loss via apoptosis in adult rats, which were associated with mitochondrial dynamics alterations manifested as a fragmented phenotype. Conclusion : Our results suggest that PBDE-47 disrupts mitochondrial dynamics to induce mitochondrial abnormalities, triggering apoptosis and thus contributing to neuronal loss and subsequent neurobehavioral deficits. Targeting mitochondrial fusion may be a promising therapeutic intervention against PBDE-47 neurotoxicity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Autophagy and apoptosis are two important cellular processes that are crucial for neurodevelopment. Evidence shows that apoptosis is implicated in fluoride neurotoxicity. However, the biological roles of autophagy, especially its interplay with apoptosis in the neurotoxicity induced by long-term fluoride exposure remain unclear. Here we present in vivo and in vitro evidence that fluoride-induced defective autophagy elicits excessive apoptosis, thus inducing neurotoxicity. Using Sprague-Dawley rats exposed to sodium fluoride from 60 days before pregnancy until 6 months post-delivery as in vivo model, we showed that fluoride impaired the learning and memory abilities of offspring rats, with decreased neuronal number, suppressed autophagy and enhanced apoptosis in hippocampus. These results were validated in human neuroblastoma SH-SY5Y cells in vitro. Mechanistically, mTOR signaling, responsible for autophagy induction, was activated in vivo and in vitro, and targeting inhibition of mTOR with rapamycin protected SH-SY5Y cells from defective autophagy and excessive apoptosis, thereby enhancing neuronal survival. Furthermore, circulating levels of autophagy markers were low in children with higher fluoride body burden and lower intelligence quotient scores. Collectively, our results suggest that defective autophagy plays a pivotal role in fluoride neurotoxicity, and mTOR might be a promising target for the prevention and treatment of fluoride neurotoxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Apoptosis is involved in 2,2',4,4'- tetrabromodiphenyl ether (PBDE-47)-induced developmental neurotoxicity. However, little is known about the role of autophagy, especially its relationship with apoptosis underlying such neurotoxic process. Methods : Using female Sprague-Dawley rats exposed to low-dose PBDE-47 (0.1, 1.0 and 10 mg/kg/day) from pre-pregnancy until weaning of offspring to mimic human exposure, we investigated the effects of PBDE-47 on autophagy and apoptosis in relation to cognitive impairment of adult offspring rats. We also evaluated relationship between autophagy and apoptosis using neuroendocrine pheochromocytoma (PC12) cells, a widely used neuron-like cell line for neuronal development. Results : In vivo , perinatal exposure to PBDE-47 induced memory deficits in adult rats. This is accompanied by hippocampal neuronal loss partly as a result of apoptosis, as evidenced by caspase-3 activation and PARP cleavage. Further study identified that PBDE-47 triggered autophagic vesicles accumulation, increased levels of microtubule-associated protein 1 light chain 3 (LC3)-II, an essential protein for autophagosomes formation, and autophagy substrate sequestosome 1 (SQSTM1/p62), but reduced levels of autophagy-related protein (ATG) 7, a key protein for autophagosomes elongation, suggestive of autophagy impairment. These findings were further demonstrated by an in vitro model of PBDE-47-treated PC12 cells. Mechanistically, autophagy alteration is more sensitive to PBDE-47 treatment than apoptosis induction. Importantly, while stimulation of autophagy by the chemical inducer rapamycin and adenovirus-mediated Atg7 overexpression aggravated PBDE-47-induced apoptosis and cell death, inhibition of autophagy by the chemical inhibitor wortmannin and siRNA knockdown of Atg7 reversed PBDE-47-produced detrimental outcomes. Interestingly, blockage of apoptosis by caspase-3 inhibitor Ac-DEVD-CHO ameliorated PBDE-47-exerted autophagy impairment and cell death, though in combination with autophagy inhibitor did not further promote cell survival. Conclusion : Our data suggest that autophagy impairment facilitates apoptosis, which, in turn, disrupts autophagy, ultimately resulting in cell death, and that autophagy may act as a promising therapeutic target for PBDE-47-induced developmental neurotoxicity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Hypoxic-ischemic injury increases neuroglobin (Ngb) expression in the brain. In our previous study, we have generated a transactivator-of-transcription protein-transduction domain-neuroglobin fusion protein (TAT PTD-Ngb) that successfully mediated exogenous Ngb expression in the primary neurons. In this study, we further investigated the role of TAT PTD-Ngb in protecting neurons against hypoxia-induced apoptosis and explored the possible mechanism. The primary cultured neurons were divided into four groups: (1) the normal group (no hypoxic injury); (2) the vehicle group (vehicle treatment and hypoxia injury); (3) the TAT PTD-Ngb group (TAT PTD-Ngb treatment and hypoxia injury); and (4) the Ngb group (Ngb treatment and hypoxia injury). Translocation of TAT PTD-Ngb into neurons was detected using fluorescent immunostaining against His-tag as early as 30 min after incubation. MTT assay showed that the TAT PTD-Ngb group had significantly increased cell viability compared to the vehicle or Ngb group after hypoxia. The result of transmission electron microscopy (TEM) also displayed rescued ultrastructure in TAT PTD-Ngb neurons compared to that of apoptotic neurons. In addition, TAT PTD-Ngb neurons showed significantly increased expression of anti-apoptotic Bcl-2 protein and decreased activities of caspase-3 and caspase-9 in response to hypoxia. These results suggest that TAT PTD-Ngb fusion protein protects primary cortical neurons against hypoxia-induced injury possibly through suppressing mitochondria apoptotic pathway.

• In utero and lactation exposure of rats to environmentally relevant doses of PBDE-47. • Perinatal PBDE-47 exposure decreases thyroid hormones levels in adult female rats. • PBDE-47 induces thyroid structural abnormality, most likely as a result of hypoplasia. • PBDE-47 causes thyroid apoptosis by triggering ER stress and lysosomal destabilization. • PBDE-47 hampers thyroglobulin turnover by disrupting ER and lysosomal function. Evidence demonstrates that 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47) is able to disturb thyroid hormones (THs) homeostasis, yet the mechanisms remain unknown. We sought to investigate the effects of PBDE-47 on endoplasmic reticulum (ER) and lysosomes in thyroids. Using female Sprague-Dawley rats orally administered PBDE-47 at environmentally relevant doses (0.1, 1.0, 10 mg/kg/day) beginning ten days before breeding and ending at weaning, we showed that perinatal PBDE-47 exposure resulted in a reduction in serum THs levels and relative thyroid weight in adult female rats. These were accompanied by thyroid structural abnormalities with cell apoptosis. Mechanistically, PBDE-47 caused ER stress and activation of unfolded protein response (UPR). Moreover, PBDE-47 elicited lysosomal membrane permeabilization and the release of cathepsin. Importantly, the apoptotic cells co-localized with IRE1α, a stress sensor protein of UPR branch that mediates ER stress-induced apoptosis, or cathepsin B, a lysosomal cysteine protease that is involved in thyroglobulin, the precursor of THs, degradation and apoptosis induction. Interestingly, thyroglobulin was accumulated and predominantly presented in cells harboring compromised ER or lysosomal activity. Collectively, our findings suggest that perinatal low-dose PBDE-47 exposure hampers thyroglobulin turnover and induces thyroid cell apoptosis by triggering ER stress and lysosomal destabilization contributing to thyroid toxicity in adult female rats. [ABSTRACT FROM AUTHOR]