Table 1.

Summary of studies analyzing effects of Cd on microRNAs (miRNAs).

Type of Study	Cell Culture/Species	Treatment Doses and Duration	Effects on miRNAs	Ref.
In vitro	Murine ovarian granulosa cells	10, 20 and 40 µM 2, 4, 6, and 8 h	Target gene function of 29 miRNAs mainly consisted of cell metabolism regulation, mRNA post-transcriptional regulation, IL-6-mediated signal transduction, cell cycle, proliferation, differentiation, migration. These miRNAs are associated with target genes associated with the signaling of Ras, Rap1, Foxo, Hippo, MAPK and carcinogenic pathway, actin cytoskeleton regulation, stem cell signaling pathway polymorphism and local adhesion resulting in cell division and tumorigenesis.	[56]
In vitro	Primary human proximal tubular epithelial cells (HPTECs)	25 µM CdCl2 6 and 24 h	Increased expression of miR-132-3p after 6 h. Increased expression of miR-132-3p after 24 h. 10-fold increase in miR-34a-5p and miR-224-5p expression; decreased miR-455-3p expression. Decreased expression of miR-18a-5p and miR-146b-5p after 24 h. Temporally increased miR-132-3 and changes in other miRNA expression may be useful in assessing renal damage.	[58,59]
In vitro	Cd-transformed prostate epithelial cells (CTPE) developed from immortalized nontumorigenic human prostate epithelial cells (RWPE-1)	10 µM 8 weeks	12 miRNAs were downregulated; three miRNAs were upregulated. Increased oncogene mRNA expression (KRAS by 2000%; RAB22A by 48%). Increased cell signaling E2F1 mRNA by 52%. Decreased cell-adhesion-related genes CADM1 mRNA by 65% and CTNNA1 mRNA by 25%. Increased cell survival and apoptosis-related genes BCL2L1 mRNA by 25%; decreased p27Kip1 protein by 49% and FOXO4 mRNA by 61%. Increased expression of RAS/ERK pathway activation. Following exposure to Cd, transformation of epithelial cells resulted in increased tumorigenic cell formation.	[68]
In vitro	Hepatoma cell line (HepG2)	0.1–10 µM CdCl2 24, 48, and 72 h	No cell cycle arrest was observed. The distribution of cell population among the cell cycle phases (G1, S, G2/M) did not change. KEGG mapping demonstrated that the p53 gene was not regulated at the transcriptional level, nor was there clear evidence of an upregulation of this transcription factor. The p53 was translocated into the nucleus, yet p21Cip1/WAF-1 was not activated. Mir-372 able to affect p21Cip1/WAF-1 was upregulated. Changes in p21 activity will alter p53 activity, and p53 is critical for maintenance of normal cell function.	[69]
In vivo	Male Sprague-Dawley rats	s.c. 0.6 mg/kg CdCl2 12 weeks	Expression levels of 44 miRNAs were significantly increased (miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, miR-3084c-3p). Expression levels of 54 miRNAs were significantly decreased (miR-193b-3p, miR-455-3p, miR-342-3p).	[58]