Maternal Exposure of SD Rats to Benzo[a]Pyrene Impairs Neurobehavior and Hippocampal Synaptic Ultrastructure in Offspring via Downregulating Synaptic-Associated Factors.

Abstract

Benzo[a]pyrene (B[a]P) is a carcinogenic contaminant widely present in the environment. Recently, increasing studies have paid attention to the developmental neurotoxicity of B[a]P in offspring in their early life stages; however, the underlying molecular mechanisms have not been clearly elucidated. In this study, we aimed to evaluate the effects of prenatal B[a]P exposure on neurobehavior of pups during their brain growth spurt (BGS) period and also explore the potential underlying mechanisms. Pregnant Sprague-Dawley (SD) rats were intraperitoneally exposed to 0, 10, 20, or 40 mg/kg-bw B[a]P for three consecutive days during embryonic days 17-19. The physiological development index of pups was observed, and a series of neurobehavioral tests assessing sensory and motor maturation were performed. The complexity of dendritic branches and the basal dendritic spine density of CA1 pyramidal neurons were examined using Golgi-Cox staining during PND 1-14. In addition, the mRNA and protein expression levels of hippocampal BDNF, SYP, Arc, PSD-95, DNMT1, and DNMT3a, and the level of 5-mC were detected using RT-qPCR, Western blotting, or immunohistochemical staining, respectively. We noted that prenatal B[a]P exposure induced body weight loss and neurobehavioral impairments in the early life stages. Furthermore, this study firstly revealed that maternal exposure to B[a]P impaired the dendritic arborization and complexity of pyramidal neurons in the hippocampus CA1 subfield in offspring during the early postnatal period, and the damage of B[a]P to basal dendritic spine density was also observed in a dose-dependent manner. Correspondingly, maternal exposure to B[a]P markedly reduced BDNF, Arc, SYP, and PSD-95 mRNA and protein levels in the offspring hippocampus. Meanwhile, the levels of hippocampal DNMT1, DNMT3a, and 5-mC significantly increased in the offspring prenatally exposed to B[a]P. In summary, this study firstly demonstrated that maternal B[a]P exposure induced neurobehavioral deficits by destroying the hippocampal synaptic ultrastructure, which was possibly associated with the downregulation of BDNF, Arc, SYP, and PSD95 in the hippocampus through increased DNMTs-mediated DNA methylation in offspring during the BGS period.