Overview
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- Fewer than 21 genes were altered in the crypt compartment of mice exposed to 0.1-5 ppm Cr(VI) for 7 or 90 days, which
- increased to hundreds or thousands of genes at 20 ppm Cr(VI). Consistent with histological evidence for crypt
- The oral carcinogenicity of hexavalent chromium (Cr(VI)) was carcinogenicity in the mouse small intestine occurs at 30 ppm
- demonstrated in a 2-year cancer bioassay in rats and mice (NTP, and in the rat oral cavity at 180 ppm (NTP, 2008; Stout et al., 2009).
- Specifically, median and 95th percentile Cr(VI) levels in U.S. water events in mice has leveraged Cr(VI) data (Bhat et al., 2020).
- sources are 0.001 and 0.003 ppm, respectively (McNeill et al., 2012; In 2010, a research effort was initiated to specifically inform
- 180 ppm Cr(VI) for 90 days was primarily detected in the intesti- action (PCR) primer “landing sites.” Following PCR (at which
- pression in intestinal sections of mice exposed to 0.1–180 ppm ing packages in the R software environment, version 3.5.2
- tions (Figure 1). Tissue fractionation allows for the determina- deviations below the mean number of genes sequenced per
- Animal treatment and tissue preparation. Animal husbandry, study a false discovery rate (FDR) < 10% for any chosen comparison be-
- 520 mg/l. The estimated doses across the two exposure dura- ducted using the BMDExpress software (v2.2) (Phillips et al.,
- tions are shown in Table 1. After 7 and 90 days of exposure (re- 2019). Normalized expression data for all samples as generated
- tines were fixed in 10% neutral-buffered formalin, embedded in gene identifiers. A Williams trend test (with p value cutoff ¼ .05)
- Table 1. Estimated Doses of Cr(VI) Intake Based on Drinking Water Identification of pathway-level alterations across concentrations.
- (ie, an FDR of < 10% as described above) were tested for overrep- Confirmation of Tissue Compartment Isolation
- FDR < 10% were considered significantly enriched. untreated animals, as was the expression of several genes spe-
- nal crypt and villus samples from female mice exposed to tap (Figure 3 and Supplementary Table 1). These compartment-
- water or 0.1–180 ppm Cr(VI) in the drinking water for 7 or specific differences were more significant at day 91 compared
- fresh intestinal tissue and microarray analysis of gene expres- all concentrations except for 1.4 ppm relative to the time-
- villi at both time points (Table 2 and Figure 4). There was very there is a time component, the number of DEGs in the villi pla-
- minimal transcriptomic response at both days 8 and 91 in the teaued at approximately 3000 at 5 ppm (Figure 4).
- crypt at concentrations < 20 ppm (4.9 and 4.6 mg Cr(VI)/kg bw/ In addition to differences in the number of genes that were
- can be found in Supplementary Table 3). The DEGs in each of also compared between groups to understand the overlap (and
- these low-dose groups were nearly identical. For example, the lack thereof) of DEGs between the compartments. At 180 ppm
- 1.4 and 5 ppm, whereas six out of the nine DEGs at 0.1 ppm were degree of overlap, as well as similarity in the magnitude of fold
- exception of 0.1 ppm at day 8), and qualitatively appear to fol- opposite direction (cross pattern of black points in the lower
- Table 2. Number of Significantly DEGsa in Each Group
- Defined by comparison to control mice at the same timepoint with BH-adjusted p value < .1 (ie, FDR <10%).
- mg/kg bw/day shown in ranges to represent the estimated Cr(VI) dose across the 2 timepoints (see Table 1).
- Figure 5). At day 91 there was significant overlap in DEGs (black Table 3. Number of Significantly Dose-Responsive Probes and Genes
- termined by a winning model fit p value .1 (Supplementary in the crypt at day 91 (Table 4). The enrichment of these tran-
- Table 3). When probes were collapsed to individual genes, a to- scriptional signaling gene sets was driven by upregulated genes
- tal of 13 395 genes were significantly dose-responsive (Table 3 within the gene sets, and was more significant at day 91 than at
- crypts than villi, as evidenced by the different heights of the ac- median BMD values were in the villus at day 91 and included:
- cumulation curves, as well as the leftward shift in the day 91 vil- Sialic acid metabolism (downregulated genes, 0.16 mg/kg bw/
- tion of ERBB2 signaling (downregulated genes, 0.67 mg/kg bw/
- Functional Classification of Dose-Responsive Genes day; Table 5).
- Table 4. Top 5 Most Significantly Enriched Gene Sets by Functional Classification Within BMD Analysis (Defined by Lowest p Value From
- “Mitotic G1 phase and G1/S transition” (median BMDs ranging 1996). The Fanconi anemia pathway is activated by hypoxic
- concentration between 20 and 60 ppm Cr(VI)) (Figure 7 and lation of markers of hypoxic stress (eg, significant increase in
- Supplementary Table 4). The enrichment of these gene sets re- the hypoxia-inducible factor-alpha (Hif1-a) gene in the crypt at
- genes for the crypt, with such gene sets representing some of the tions of Cr(VI) (Supplementary Table 2). Gene sets related to
Methods (brief)
- while subtle in the villus, when compared with samples from time-matched controls. Minimal transcriptomic evidence of
- tional studies have proved invaluable for informing the MOA, then processed individually (total of 140 samples) at BioSpyder
- (XRF) microscopy has revealed that chromium does not distrib- transcriptome (each gene has 1–3 probes). Nuclease digestion of
- samples containing differentiated villus enterocytes exposed to braries from each sample were sequenced (single-end, 50 bp
- employed whole-genome microarray analysis of homogenized quence. Samples with an overall sequencing depth (total reads
- duodenal samples (Kopec et al., 2012a,b; Rager et al., 2017), the across all probes) lower than two standard deviations below the
- present study used RNA sequencing following microdissection mean sequencing depth across all samples, or with gene diver-
- tion of differential responses in two functionally distinct sample were excluded from the comparative analysis. Count
- regions of the intestinal mucosa that receive vastly different data from all samples that passed this sequencing depth quality
- chromium dosimetry and histopathological evidence of toxicity. was used to normalize data such that sample-to-sample varia-
- tions are shown in Table 1. After 7 and 90 days of exposure (re- 2019). Normalized expression data for all samples as generated
- Figure 1. Schematic detailing and comparing the sample preparation and study design included in this study (right) and previous studies (left) by Kopec et al. (2012a,b)
- across all samples was selected as the representative gene to be
- Figure 2. Principal components analysis plot of all samples included in the analysis. The different tissue compartments and timepoints are represented by color (see
- a molecular signaling pathway) are significantly concordant be- 90 days. All sample libraries passed quality control require-
- tween various defined groups (in the case presented herein, dif- ments for sequencing. Following sequencing, five samples were
- and control mice, using the Wald statistic as determined with section). Each failed sample was from an animal in a different
- DESeq2). The GSEA statistical method was applied within the treatment group (ie, no two failed samples were from the same
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