Prenatal exposure to bisphenol A alters the transcriptome-interactome profiles of genes associated with Alzheimer’s disease in the offspring hippocampus

Abstract

our recent study revealed that prenatal exposure to bisphenol A (BpA) disrupted the transcriptome profiles of genes in the offspring hippocampus. In addition to genes linked to autism, several genes associated with Alzheimer's disease (AD) were found to be differentially expressed, although the association between BPA-responsive genes and AD-related genes has not been thoroughly investigated. Here, we demonstrated that in utero BpA exposure also disrupted the transcriptome profiles of genes associated with neuroinflammation and AD in the hippocampus. The level of NF-κB protein and its AD-related target gene Bace1 were significantly increased in the offspring hippocampus in a sex-dependent manner. Quantitative RT-PCR analysis also showed an increase in the expression of Tnf gene. Moreover, the reanalysis of transcriptome profiling data from several previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with top AD candidate genes. The findings from this study suggest that maternal BPA exposure may increase AD risk in offspring by dysregulating genes associated with AD neuropathology and inflammation and reveal a possible relationship between AD and autism, which are linked to the same environmental factor. Sexspecific effects of prenatal BPA exposure on the susceptibility of AD deserve further investigation. Alzheimer's disease (AD) is the most common type of dementia and accounts for approximately 50-75% of dementia cases worldwide 1,2. AD is caused by progressive brain cell degeneration that affects wide areas of the cerebral cortices and hippocampi of patients, thus leading to various abnormalities, including memory loss, language difficulties, impaired decision making, and lack of other cognitive skills along with behavioral and emotional changes 3,4. Two major histological findings that are commonly found in the brain of AD patients are the (i) accumulation of extracellular amyloid plaques produced by abnormal aggregation of neurotoxic amyloid-β (Aβ) protein and (ii) intracellular neurofibrillary tangles (NFT) caused by hyperphosphorylation of tau 5,6. Amyloid plaque formation is often considered an upstream event in the pathogenesis of AD and is derived from the sequential cleavage of amyloid precursor protein (APP) by beta and gamma secretases 7. The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is the key enzyme responsible for APP proteolysis, initiates the cleavage

Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions

“…However, we demonstrated in this study that neonatal rat pups whose mothers were exposed to BPA at the NOAEL level during gestation exhibited disrupted transcriptome profiles, hippocampal cell viability and density, neuritogenesis, and learning/memory ability. This finding is in line with previous studies which showed that prenatal exposure to BPA could disrupt the transcriptome profiles in several brain regions, including the hippocampus, hypothalamus, and amygdala 17 , 22 , 49 – 51 . Although daily exposure levels of BPA in humans were thought to be lower than the NOAEL level 80 , a recent study has shown that the human exposure level could be much higher than what was previously reported due to the limitations of the analytical technique used in previous studies to measure BPA levels in human blood and urine samples 81 .…”

“…Significant biological functions associated with these genes were identified using Fisher's exact test ( P value < 0.05). Total RNA was used to synthesize cDNA using a RevertAid RT reverse transcription kit (Thermo Fisher Scientific, USA) according to the manufacturer’s protocol as described previously 17 , 22 . Briefly, 0.5 µg of total RNA was used to generate the first-strand cDNA in a reaction containing 1 µL of oligo dT 18 primers and DEPC-treated water.…”

“…The cDNA synthesis reaction was incubated at 25 °C for 5 min followed by incubation at 42 °C for 60 min. The cDNA reaction mixture was diluted to a volume of 50 μl with nuclease-free water and used as a template for subsequent qRT-PCR analysis as described previously 17 , 22 . qRT-PCR was performed using AccuPower 2X GreenStar qPCR MasterMix (Bioneer, Korea) according to the manufacturer’s protocol.…”

“…Product formation was confirmed by a melting curve analysis (65–95 °C). The expression levels were calculated using the 2 −ΔΔCt method with the 18S ribosomal RNA ( Rn18s ) gene as an endogenous control as described previously 17 , 22 . The sequences of the forward and reverse qPCR primers for rat Mief2 , Eif3h , Tp53bp1 , Npas3 , Cux1 , Kdm5c , Arhgap32 , Itga4 , Atp8a1 , Kmt2a , Cadps2 , Grm4 , Abca7 , and Rn18s are listed in Supplementary Table S21 .…”

“…BPA is thought to be an environmental risk factor for neurological disorders, including autism spectrum disorder (ASD) 17 – 21 , Alzheimer’s disease 22 , and others 23 , 24 . Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by (1) deficits in social interaction and communication, and (2) restricted interests and repetitive/stereotyped behaviors, with high heterogeneity of clinical manifestations and molecular signatures 25 – 30 .…”