Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2021 Dec 15:433:115756.
doi: 10.1016/j.taap.2021.115756. Epub 2021 Oct 16.

Cadmium-mediated pancreatic islet transcriptome changes in mice and cultured mouse islets

Winifred P S Wong  1 , Janice C Wang  1 , Matthew J Schipma  2 , Xiaomin Zhang  3 , Joshua R Edwards  4 , Malek El Muayed  5
Affiliations
Comparative Study

Cadmium-mediated pancreatic islet transcriptome changes in mice and cultured mouse islets

Winifred P S Wong et al. Toxicol Appl Pharmacol. .

Abstract

Type II diabetes mellitus (T2DM) is a multifactorial disease process that is characterized by insulin resistance and impairment of insulin-producing pancreatic islets. There is evidence that environmental exposure to cadmium contributes to the development of T2DM. The presence of cadmium in human islets from the general population and the uptake of cadmium in β-cells have been reported. To identify cadmium-mediated changes in gene expression and molecular regulatory networks in pancreatic islets, we performed next-generation RNA-Sequencing (RNA-Seq) in islets following either in vivo (1 mM CdCl2 in drinking water) or ex-vivo (0.5 μM CdCl2) exposure. Both exposure regiments resulted in islet cadmium concentrations that are comparable to those found in human islets from the general population. 6-week in vivo cadmium exposure upregulates the expression of five genes: Synj2, Gjb1, Rbpjl, Try5 and 5430419D17Rik. Rbpjl is a known regulator of ctrb, a gene associated with diabetes susceptibility. With 18-week in vivo cadmium exposure, we found more comprehensive changes in gene expression profile. Pathway enrichment analysis showed that these secondary changes were clustered to molecular mechanisms related to intracellular protein trafficking to the plasma membrane. In islet culture, cadmium ex vivo significantly induces the expression of Mt1, Sphk1, Nrcam, L3mbtl2, Rnf216 and Itpr1. Mt1 and Itpr1 are known to be involved in glucose homeostasis. Collectively, findings reported here revealed a complex cadmium-mediated effect on pancreatic islet gene expression at environmentally relevant cadmium exposure conditions, providing the basis for further studies into the pathophysiological processes arising from cadmium accumulation in pancreatic islets.

Keywords: Cadmium; Insulin-producing β-cells; Islet transcriptome; Pancreatic islets; Type II diabetes mellitus; mRNA-sequencing.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.. Blood and islet Cd content in mice in vivo and ex vivo.
(a) Blood Cd concentration in mice exposed to either Veh or 1mM CdCl2 for 4 weeks (n=5/group). (b) Islet Cd content (normalized to total islet protein) in mice exposed to either Veh or 1mM CdCl2 for 4 weeks (n=4/group) and in islet culture exposed to either Veh or 0.5μM CdCl2 for 72 hours (n=6/group). #Interquartile range of islet Cd and ∞highest islet Cd value found in humans (data from Wong et al. (2017)). Data are expressed as mean ± SEM. ***p<0.001.
Fig. 1.
Fig. 1.. Blood and islet Cd content in mice in vivo and ex vivo.
(a) Blood Cd concentration in mice exposed to either Veh or 1mM CdCl2 for 4 weeks (n=5/group). (b) Islet Cd content (normalized to total islet protein) in mice exposed to either Veh or 1mM CdCl2 for 4 weeks (n=4/group) and in islet culture exposed to either Veh or 0.5μM CdCl2 for 72 hours (n=6/group). #Interquartile range of islet Cd and ∞highest islet Cd value found in humans (data from Wong et al. (2017)). Data are expressed as mean ± SEM. ***p<0.001.
Fig. 2.
Fig. 2.. Islet transcription profile of Veh and Cd-exposed mice following 6 weeks of exposure.
(a) Volcano plot of islet transcriptome in mice exposed to either Veh (n=5) or Cd (n=4) for 6 weeks. Data are expressed as mean ± SEM.
Fig. 3.
Fig. 3.. Islet transcriptome profile of Veh and Cd-exposed mice following 18 weeks of exposure.
(a) Volcano plot of islet transcriptome and (b) Bar graph of pathway enrichment analysis of differentially expressed genes (as defined by FDR-adjusted p<0.05) in Veh (n=6) and Cd-exposed (n=5) mice following 18 weeks of Cd exposure.
Fig. 3.
Fig. 3.. Islet transcriptome profile of Veh and Cd-exposed mice following 18 weeks of exposure.
(a) Volcano plot of islet transcriptome and (b) Bar graph of pathway enrichment analysis of differentially expressed genes (as defined by FDR-adjusted p<0.05) in Veh (n=6) and Cd-exposed (n=5) mice following 18 weeks of Cd exposure.
Fig. 4.
Fig. 4.. Transcriptome profile of Veh and Cd-exposed islets ex vivo.
Volcano plot of islet transcriptome following 96 hours exposure of either Veh or 0.5μM CdCl2 in mouse pancreatic islet culture (n=5/group).
See this image and copyright information in PMC

References

    1. Afridi HI, Kazi TG, Kazi N, Jamali MK, Arain MB, Jalbani N, Baig JA and Sarfraz RA (2008). “Evaluation of Status of Toxic Metals in Biological Samples of Diabetes Mellitus Patients.” Diabetes Research and Clinical Practice 80(2): 280–288. - PubMed
    1. Anders S, Pyl PT and Huber W (2015). “HTSeq-A Python Framework to Work with High-Throughput Sequencing Data.” Bioinformatics 31(2): 166–169. - PMC - PubMed
    1. Andrew AS, Warren AJ, Barchowsky A, Temple KA, Klei L, Soucy NV, O’Hara KA and Hamilton JW (2003). “Genomic and proteomic profiling of responses to toxic metals in human lung cells.” Environ Health Perspect 111(6): 825–835. - PMC - PubMed
    1. Barregard L, Bergstrom G and Fagerberg B (2013). “Cadmium exposure in relation to insulin production, insulin sensitivity and type 2 diabetes: a cross-sectional and prospective study in women.” Environ Res 121: 104–109. - PubMed
    1. Beck R, Chandi M, Kanke M, Styblo M and Sethupathy P (2019). “Arsenic is more potent than cadmium or manganese in disrupting the INS-1 beta cell microRNA landscape.” Arch Toxicol 93(11): 3099–3109. - PMC - PubMed

Publication types

Substances