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Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

ABSTRACT: Aims:This study investigated the neurotoxic effects of prenatal alcohol and nicotine exposure in the cortex and hippocampus of rodents. Main methods:Behavioral alterations, electrophysiological changes, and biochemical markers associated with cholinergic neurotransmission, neural oxidative stress, mitochondrial function, and apoptosis were evaluated. Key findings:Prenatal alcohol exposure induced the generation of ROS, nitrite and lipid peroxide, decreased mitochondrial Complex-I and IV activities, increased Caspase-1 and 3 activities, had no effect on cholinergic neurotransmission, increased expression of PSD-95, decreased LTP and decreased performance on spatial memory tasks. However, nicotine exposure, in addition to alcohol exposure, was found to mitigate the negative effects of alcohol alone on ROS generation and spatial memory task performances. Furthermore, we also studied the role of ILK in prenatal alcohol and nicotine exposure. Significance:Prenatal Smoking and/or drinking is a major health concern around the world. Thus, our current study may lead to better insights into the molecular mechanisms of fetal alcohol and nicotine exposure on the developing offspring.

SUBMITTER: Bhattacharya D

PROVIDER: S-EPMC6953639 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

Bhattacharya Dwipayan D Fujihashi Ayaka A Majrashi Mohammed M Bloemer Jenna J Bhattacharya Subhrajit S Buabeid Manal M Escobar Martha M Moore Timothy T Suppiramaniam Vishnu V Dhanasekaran Muralikrishnan M

Heliyon 20200108 1

<h4>Aims</h4>This study investigated the neurotoxic effects of prenatal alcohol and nicotine exposure in the cortex and hippocampus of rodents.<h4>Main methods</h4>Behavioral alterations, electrophysiological changes, and biochemical markers associated with cholinergic neurotransmission, neural oxidative stress, mitochondrial function, and apoptosis were evaluated.<h4>Key findings</h4>Prenatal alcohol exposure induced the generation of ROS, nitrite and lipid peroxide, decreased mitochondrial Com ...[more]

PMID: 31938742

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Project description:Brain developmental lesions are a devastating consequence of prenatal alcohol exposure (PAE). We recently showed that PAE affects cortical vascular development with major effects on angiogenesis and endothelial cell survival. The underlying molecular mechanisms of these effects remain poorly understood. This study aimed at characterizing the ethanol exposure impact on the autophagic process in brain microvessels in human fetuses with fetal alcohol syndrome (FAS) and in a PAE mouse model. Our results indicate that PAE induces an increase of autophagic vacuole number in human fetal and neonatal mouse brain cortical microvessels. Subsequently, ex vivo studies using green fluorescent protein (GFP)-LC3 mouse microvessel preparations revealed that ethanol treatment alters autophagy in endothelial cells. Primary cultures of mouse brain microvascular endothelial cells were used to characterize the underlying molecular mechanisms. LC3 and p62 protein levels were significantly increased in endothelial cells treated with 50?mM ethanol. The increase of autophagic vacuole number may be due to excessive autophagosome formation associated with the partial inhibition of the mammalian target of rapamycin pathway upon ethanol exposure. In addition, the progression from autophagosomes to autolysosomes, which was monitored using autophagic flux inhibitors and mRFP-EGFP vector, showed a decrease in the autolysosome number. Besides, a decrease in the Rab7 protein level was observed that may underlie the impairment of autophagosome-lysosome fusion. In addition, our results showed that ethanol-induced cell death is likely to be mediated by decreased mitochondrial integrity and release of apoptosis-inducing factor. Interestingly, incubation of cultured cells with rapamycin prevented ethanol effects on autophagic flux, ethanol-induced cell death and vascular plasticity. Taken together, these results are consistent with autophagy dysregulation in cortical microvessels upon ethanol exposure, which could contribute to the defects in angiogenesis observed in patients with FAS. Moreover, our results suggest that rapamycin represents a potential therapeutic strategy to reduce PAE-related brain developmental disorders.

Project description:Background: Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems. We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. The current study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females Methods: Adult females from PAE, pair-fed [PF], and ad libitum-fed control [C]) groups were injected with either saline or complete FreundM-bM-^@M-^Ys adjuvant. Animals were terminated at the peak of inflammation or during resolution (days 16 and 39 post-injection, respectively); cohorts of saline-injected PAE, PF and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole genome mRNA expression microarrays. Results: Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions: These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression, demonstrating long-term effects of PAE on the CNS response under steady-state conditions and following an inflammatory insult. Key words: prenatal alcohol exposure (PAE), ethanol, inflammation, arthritis, gene expression, rat. 192 samples, including 20 hybridization replicates

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Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

Publications

Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

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