No abstract

The neurotoxicity of 2,2’,4,4’‐tetrabromodiphenyl ether (PBDE‐47) is closely linked to mitochondrial abnormalities while mitophagy is vital for mitochondrial homeostasis. However, whether PBDE‐47 disrupts mitophagy contributing to impaired neurodevelopment remain elusive. Here, this study showed that neonatal PBDE‐47 exposure caused learning and memory deficits in adult rats, accompanied with striatal mitochondrial abnormalities, neuronal apoptosis and the resultant neuronal loss. Mechanistically, PBDE‐47 suppressed PINK1/Parkin‐mediated mitophagy induction and degradation, inducing mitophagosome accumulation and mitochondrial dysfunction in vivo and in vitro. Additionally, stimulation of mitophagy by adenovirus‐mediated Parkin or Autophagy‐related protein 7 (Atg7) overexpression aggravated PBDE‐47‐induced mitophagosome accumulation, mitochondrial dysfunction, neuronal apoptosis and death. Conversely, suppression of mitophagy by the siRNA knockdown of Atg7 rescued PBDE‐47‐induced detrimental consequences. Importantly, melatonin, a hormone secreted rhythmically by the pineal, improved PBDE‐47‐caused neurotoxicity via preventing neuronal apoptosis and loss by restoring mitophagic activity and mitochondrial function. These neuroprotective effects of melatonin depended on activation of the AMP‐activated protein kinase (AMPK)/Unc‐51‐like kinase 1 (ULK1) signaling. Collectively, these data indicate that PBDE‐47 impairs mitophagy to perturb mitochondrial homeostasis, thus triggering apoptosis, leading to neuronal loss and consequent neurobehavioral deficits. Manipulation of the AMPK‐mitophagy axis via melatonin could be a novel therapeutic strategy against developmental PBDE‐47 neurotoxicity.

To further study the mechanism of maternal-fetal immune tolerance, the expression of Fas ligand (FasL) on the surfaces of human cytotrophoblasts in normal pregnancy was detected by using immunohistochemical method. High precise color-image measure system for immuno-histochemistry was used to quantitatively analyze the expression of FasL. The results showed that FasL were expressed on the surfaces of placental cytotrophoblasts throughout normal pregnancy. The variance among the first, second and term pregnant stages was also detected. It was suggested that the expression of FasL on the surfaces of placental cytotrophoblasts might play an important role both in the maintenance of pregnancy and in the normal development of fetus. The maternal specific T cell apoptosis induced by Fas/FasL is one of the significant mechanisms of maternal-fetal immune tolerance.