Transcriptomics analysis and hormonal changes of male and female neonatal rats treated chronically with a low dose of acrylamide in their drinking water

Abstract

Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others; animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date.

Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease

“…The rs3136441-C allele the F2 gene, which was found to be protective against coronary artery disease, showed association with increased levels of high-density lipoprotein cholesterol [ 8 ], and decreased expression of the F2 gene. Two transcription repressors such as BHLHE23 and CBX5 were in silico predicted at SNP rs3136441 in the presence of allele-C. Interestingly, expression of the BHLHE23 gene can be suppressed by environmental chemicals, including those found in the tobacco smoke [ 94 ], polycyclic aromatic hydrocarbons [ 95 ], biphenol A [ 96 ], acrylamide [ 97 ], dietary fats [ 98 ], and many of them are well known risk factors for atherosclerosis [ 99 ]. Furthermore, the atSNP tool allowed predicting that five transcription activators such as E2F2 (UniProtKB-Q14209), ETS1 (UniProtKB-P14921), ETS2 (UniProtKB-P15036) and HNF4BA (P15036) and HNF4BA (P15036), and HNF4BA (UniProt35) have an affinity for binding to a DNA motif in the presence of the rs3136441-C allele of the F2 gene.…”

Assessment of the genotoxicity of acrylamide

“…p53 gene expression was not elevated in F344 rat testis in vivo by AA under conditions where increased transcription of genes involved in calcium signalling and the cytoskeleton was observed (Recio et al, 2017 ). The WG noted that the strain of rat used by Collí‐Dulá et al ( 2016 ) (Wistar) and Chepelev et al ( 2017 ) and Recio et al ( 2017 ) (F344) differed. Chepelev et al ( 2018 ) found that in mice treated with AA, genes involved in the p53 pathway were not significantly enriched in those genes with altered expression in the Harderian gland or the lung.…”

“…Some gene expression studies showed evidence (albeit limited) for a DNA‐damage response to AA. Collí‐Dulá et al ( 2016 ) reported AA‐induced transcriptomic changes in the Wistar rat thyroid which included genes that are involved in DNA damage and repair as well as various other changes relating to, e.g. oxidative stress and motor proteins and kinases which may also relate to carcinogenicity.…”

“…In rats exposed in utero to AA (Collí‐Dulá et al, 2016 ), transcriptomic changes involved genes related to cell cycle. In these animals, plasma T3 and T4 were increased in AA‐treated rats, lending further evidence to support the disturbance of thyroid hormones by AA which was noted in the 2015 EFSA Opinion (EFSA CONTAM Panel, 2015 ) as being inconsistent.…”

CRISPR-Cas: Removing Boundaries of the Nature

“…Studies have also indicated that the destructive effects of AA or GA are by influencing sulfhydryl groups of proteins (6,7). Due to AA poisoning, the level of glutathione decreases and the body's defense system against free radicals weakens (8). Free radicals combine with cell membrane and unsaturated fatty acids, producing radical lipids with oxygen molecule and as a result, phospholipids in the endoplasmic reticulum decompose and release enzymes, which ultimately lead to cell death (9).…”