Table 4.

Summaries of the disruptive effects of BPA in in vitro studies using human cell lines ¹.

Topic	Studied Mechanism	Concentration	Type of Cells	Observed Effects	References
Ion channels and electrophysiology	Nav1.5 channels	1–100 µmol/L	HEK-transfected cell line	▪BPA blockage of the channel (Kd = 25.4 ± 1.3 µmol/L); ▪BPA-induced blockage involved the local anesthetic receptor and may have entered the closed-state pore via membrane-located side fenestrations.	[43]
	Nav1.5 channels	0.0–100 µmol/L	HEK-transfected cell line	▪BPA had a half-maximal inhibitory concentration (IC50) of 55.3 µmol/L and 23.6 µmol/L BPA for fast/peak and late Na+ channel currents	[42]
	Nav1.5 channels	1–100 µmol/L	hiPSC-CMs	▪BPA significantly inhibited Na+ current channels (IC50 = 56.5 µmol/L) ▪BPA slowed the action potential upstroke (1–100 µmol/L) ▪BPA reduced the action potential amplitude.	[41]
	Recombinant human R-type Ca2+ channels	1–100 µmol/L	HEK 293 cells	▪BPA included rapid and reversible inhibition of the channels. ▪BPA binding occured with the channel in its resting state, and in the extracellular part not involving intracellular signaling pathways.	[38]
	T-type Ca2+ channels	1–100 μmol/L	HEK 293 cells	▪BPA appeared to act as a modifier of channel gating and directly plugged the pores of the conductive channel at high concentrations.	[39]
	L-type Ca2+ channels Cav1.2	1–100 µmol/L	hiPSC-CMs	▪BPA dose-dependently inhibited Ca2+ current channels (IC50 = 6.9 µmol/L).	[41]
	Maxi-K channels	100 µmol/L	HCASMC	▪BPA increased Maxi-K currents	[35]
Ca2+ handling	Ca2+ current channels, Ca2+ transients and contraction	1–100 µmol/L	hiPSC-CMs	▪BPA in a dose-dependent manner slowed the Ca2+ transient rise time and decreased the Ca2+ transient amplitude	[41]
	Cardiac hypertrophy by disrupting Ca2+ homeostasis	8 ng/mL	Human embryonic stem-cell-derived cardiomyocytes	▪BPA induced sex-specific hypertrophic risk in terms of abnormal mitochondrial fission and ATP production by impairing CnAβ-DRP1 signaling	[86]
Vascular endothelium	Endothelial dysfunction, inflammation, and angiogenesis	0.1–1 μmol/L	HUVECs	▪BPA increased the mRNA expression of the proangiogenic genes and increased NO production ▪BPA increased the expression of phosphorylated eNOS and endothelial tube formation	[88]
	Cell division and chromosomal segregation	0.5–10 ng/mL	HUVECs	▪BPA at plasma concentrations induced aneugenic effects	[89]
	Senescence	10 ng/mL and 1 µg/mL	HUVECs	▪BPA impaired transcription and decreased viability in aging vascular EC	[90]
	Accelerating atherosclerosis	0.1–10 nmol/L	HUVECs	▪BPA appeared to be involved in accelerating atherosclerosis ▪BPA does not altered the HUVEC proliferation or migration	[59]
Pregnancy exposome	Epigenetic disruption	35.4–56.1 ng/g	Human fetal liver samples	▪Higher levels of BPA with XME genes significantly reduced expression and with increased site-specific methylation at COMT and increased average methylation at SULT2A1 promoters	[91]
		0.57 and 0.78 ng/mL	Maternal urine samples and Infant cord blood	▪BPA decreased methylation of imprinted and unprinted genes and repetitive element LINE-1	[92]
	Pregnancy physiology	1 nmol/L	BeWo trophoblast cell line, placental explant cultures, placental perfusions, and skin diffusion models	▪BPA induced cytotoxicity (EC50 = 100–125 µmol/L). ▪BPA significantly increased β-hCG secretion and caspase-3 expression in placental explants.	[95]
		0, 0.09, 0.9, and 9.0 μmol/L	BeWo trophoblast cell line	▪BPA induced trophoblast cell death under conditions of cellular stress	[96]
		1 × 10−15 to 1 × 10−7 mol/L	Human trophoblast cells HTR-8/SVneo	▪BPA altered key physiological processes in placenta development	[97]
		1 nmol/L	Human trophoblast cells HTR-8/SVneo	▪BPA induceed alterations in DNA methylation of stress response and down-regulation of angiogenic growth factors	[98]

¹ Legend: BPA—bisphenol A; CnAβ—calcineurin; DRP1—dynamin-related protein 1; HCASMC—human coronary artery smooth muscle cells; HEK—human embryonic kidney; hiPSC-CMs–human-induced pluripotent stem-cell-derived cardiomyocytes; HUVECs—human umbilical vein endothelial cells; IC50—half-maximal inhibitory concentration; LINE-1—long interspersed nuclear element-1 or L1; Maxi-K—large conductance Ca²⁺/voltage-sensitive K⁺ channel; XME—xenobiotic-metabolizing enzymes.