Autophagy impairment contributes to PBDE-47-induced developmental neurotoxicity and its relationship with apoptosis

Abstract

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.

Resveratrol Induces Autophagy and Apoptosis in Non-Small-Cell Lung Cancer Cells by Activating the NGFR-AMPK-mTOR Pathway

“…Since cytoprotective autophagy occurred prior to apoptosis [36], apoptosis did not affect cytoprotective autophagy. The relationship between lethal autophagy and apoptosis induced by 2,2 ,4,4 -tetrabromodiphenyl ether and andrographolide analogue in neuroendocrine pheochromocytoma PC12 cells and human leukemic U937 cells, respectively, was similar to our findings: autophagy inhibition disrupted apoptosis, and apoptosis impairment facilitates autophagy [37,38]. In addition, autophagy induced by fucoxanthin in SGC-7901 cells elevated apoptosis but was unaffected by apoptosis [36].…”

Melatonin protects against developmental PBDE‐47 neurotoxicity by targeting the AMPK/mitophagy axis

“…As support, previous research has shown neuromotor behavioral impairments in open field test in C57BL/6 mice following single exposure to PBDE‐47 (1, 10, or 30 mg/kg) on PND 10 20 . Additionally, these findings are in line with our earlier report that perinatal PBDE‐47 exposure from before pregnancy to PND 21 at comparable dosage (1.0 and 10 mg/kg/day) produced poor performance in the MWM test 21 . More importantly, these data are in accord with the epidemiological research that PBDEs exposure during developmental periods is related to delayed mental and motor development, as well as declined mental ability and attention deficit in the preschool stage 22,23 .…”

“…20 Additionally, these findings are in line with our earlier report that perinatal PBDE-47 exposure from before pregnancy to PND 21 at comparable dosage (1.0 and 10 mg/kg/day) produced poor performance in the MWM test. 21 More importantly, these data are in accord with the epidemiological research that PBDEs exposure during developmental periods is related to delayed mental and motor development, as well as declined mental ability and attention deficit in the preschool stage. 22,23 Overall, our findings provide additional evidence that PBDEs are developmental neurotoxicants.…”

“…Our results are also in accord with our earlier research that perinatal PBDE-47 exposure resulted in the same altered autophagic processes in rat hippocampi. 21 In contrast, PBDE-209 exposure during gestation led to a significant increase in Beclin 1, along with reduced LC3-II and p62 levels in hippocampi of newly born rats, suggesting that autophagy was activated and enhanced. 31 Differences in congener, timing of exposure, exposure duration and timing of determination may explain the discrepancies.…”

Compound essential oils relieve oxidative stress caused by PM2.5 exposure by inhibiting autophagy through the AMPK/mTOR pathway

“…Changes in the endoplasmic reticulum and mitochondria are induced by external pressure, such as reactive oxygen species, and autophagy and apoptosis are subsequently induced. The similar or opposite functions of autophagy and apoptosis reveal the possible structural relationship underlying autophagy 15,16 . Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that plays an important role in promoting metabolism and participates in apoptosis, autophagy and other physiological processes 17 .…”