Gene expression changes induced by the human carcinogen aristolochic acid I in renal and hepatic tissue of mice

Abstract

Aristolochic acid (AA) is the causative agent of urothelial tumors associated with AA nephropathy and is also implicated in the development of Balkan endemic nephropathy‐associated urothelial tumors. These tumors contain AA‐characteristic TP53 mutations. We examined gene expression changes in Hupki (human TP53 knock‐in) mice after treatment with aristolochic acid I (AAI) by gavage (5 mg/kg body weight). After 3, 12 and 21 days of treatment gene expression profiles were investigated using Agilent Whole Mouse 44K Genome Oligo Array. Expression profiles were significantly altered by AAI treatment in both target (kidney) and nontarget (liver) tissue. Renal pathology and DNA adduct analysis confirmed kidney as the target tissue of AAI‐induced toxicity. Gene ontology for functional analysis revealed that processes related to apoptosis, cell cycle, stress response, immune system, inflammatory response and kidney development were altered in kidney. Canonical pathway analysis indicated Nfκb, aryl hydrocarbon receptor, Tp53 and cell cycle signaling as the most important pathways modulated in kidney. Expression of Nfκb1 and other Nfκb‐target genes was confirmed by quantitative real‐time PCR (qRT‐PCR) and was consistent with the induction of Nfκb1 protein. Myc oncogene, frequently overexpressed in urothelial tumors, was upregulated by AAI on the microarrays and confirmed by qRT‐PCR and protein induction. Collectively we found that microarray gene expression analysis is a useful tool to define tissue‐specific responses in AAI‐induced toxicity. Several genes identified such as TP53, Rb1, Mdm2, Cdkn2a and Myc are frequently affected in human urothelial cancer, and may be valuable prognostic markers in future clinical studies.

Transcriptomic alterations induced by Monuron in rat and human renal proximal tubule cells in vitro and comparison to rat renal-cortex in vivo

“…An increase in the expression of cell cycle genes is a common finding with a number of renal nephrotoxins and renal carcinogens. [21][22][23] The enrichment of the cell cycle genes after short term exposure is consistent with the small increase in cell proliferation observed in the kidney after 7 days exposure to MON. 13 Some of the gene increase is involved in cell division with role in chromosome stability, alignment and segregation and we cannot at this stage rule out the possibility of adverse chromosomal events in the kidney following MON.…”

Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines

“…Gene association network (GAN) analysis further suggests hepatocyte nuclear factor 4a gene (Hnf4a) and Tp53 inhibition in AAI-treated Hupki mouse liver (DNA adduct nontarget; refs. 16,17). AA-like mutational signatures in 11 HCC genomes/exomes have also been reported (18).…”

“…AAI can also induce tumors in multiple organs of mice within 56 weeks after the start of a 3-week treatment (15). Notably, NF-kB1 and c-Myc oncoprotein expression in kidney reach a peak at 12-day AAI administration of Hupki (human TP53 knock-in) mice (16,17), suggesting a critical role of renal tumorigenesis in the short-term duration of AAI (16,17). Gene association network (GAN) analysis further suggests hepatocyte nuclear factor 4a gene (Hnf4a) and Tp53 inhibition in AAI-treated Hupki mouse liver (DNA adduct nontarget; refs.…”

“…Short-term AAI exposure markedly upregulates c-Myc oncoprotein expression in the kidney of Hupki mice (16). Overexpression of c-Myc can induce HCC with a high frequency in mice (20).…”

“…Direct control of miRNA expression by oncogenic and tumor suppressor networks results in frequent dysregulation of miRNAs, which contributes to tumorigenesis (21). Short-term AAI exposure also causes NF-kB1 overexpression in the kidney of Hupki mice (16). In the immune system, enhanced regulation of NF-kB signaling is crucial for maintaining the normal function of immune cells and avoidance of tumorigenesis (28,29).…”