Table 4.

Summary of laboratory-based studies reporting the relationship between nonessential trace element exposure and CHDs.

Element	Animal model	Function	Potential mechanism	Reference
Cd	Zebrafish (Danio rerio) embryos cultured in Cd-containing media	Cu exposure led to hypertrophy of ventricle and pericardium; reduced heart rate; and abnormally elevated heart contractility	NA	(132)
Cd	Fertilized eggs injected with CdCl2 solutions	Cd exposure increased myocardial tissue area of the right ventricle	Cd exposure increased cell proliferation and upregulated expression of cell circle related genes in right ventricle	(133)
As	Zebrafish (Danio rerio) embryos cultured in As-containing media	As exposure decreased the amount of myocardium in ventricle, delayed cardiac looping, and dampened heart rate	NA
As	Zebrafish (Danio rerio) embryos cultured in As-containing media	As exposure increased pericardial cavity as well as elongated atrium and ventricle	As exposure suppressed Dvr1 expression	(83)
As	Embryos from pregnant rats fed with As	As exposure increased risks of CHDs in offspring	As exposure increased Mef2C expression and H3K9 acetylation in fetal rat hearts	(84)
As	AV canal explants from chicken embryos were incubated on the collagen gel pretreated with sodium arsenite	As exposure perturbed EMT duringcardiac development	As suppressed TGF-β/Smad signaling	(86)
Ni	Marine medaka (Oryzias melastigma) embryos cultured in Ni-containing media	Ni exposure induced cardiovascular anomalies	Ni exposure led to dysregulated expression of cardiac development-related genes including ATPase, smyd1, cox2, and bmp4	(94)

ATPase, adenosine triphosphatases; As, arsenic; AV, atrioventricular; bmp4, bone morphogenetic protein 4; Cd, cadmium; cox2, cyclooxygenase 2; EMT, epithelial-mesenchymal transition; Ni, nickel; smyd1, SET And MYND domain containing 1; TGF-β, transforming growth factor β.