The Mechanisms of Cadmium Toxicity in Living Organisms

Abstract

Cadmium (Cd) is a toxic metal primarily found as a by-product of zinc production. Cd was a proven carcinogen, and exposure to this metal has been linked to various adverse health effects, which were first reported in the mid-19th century and thoroughly investigated by the 20th century. The toxicokinetics and dynamics of Cd reveal its propensity for long biological retention and predominant storage in soft tissues. Until the 1950s, Cd pollution was caused by industrial activities, whereas nowadays, the main source is phosphate fertilizers, which strongly contaminate soil and water and affect human health and ecosystems. Cd enters the human body mainly through ingestion and inhalation, with food and tobacco smoke being the primary sources. It accumulates in various organs, particularly the kidney and liver, and is known to cause severe health problems, including renal dysfunction, bone diseases, cardiovascular problems, and many others. On a cellular level, Cd disrupts numerous biological processes, inducing oxidative stress generation and DNA damage. This comprehensive review explores Cd pollution, accumulation, distribution, and biological impacts on bacteria, fungi, edible mushrooms, plants, animals, and humans on a molecular level. Molecular aspects of carcinogenesis, apoptosis, autophagy, specific gene expression, stress protein synthesis, and ROS formation caused by Cd were discussed as well. This paper also summarizes how Cd is removed from contaminated environments and the human body.

Keywords: Cd pollution; Cd toxicity; animals; bacteria; human; molecular mechanisms; plants.

Figure 1

Distribution of heavy metals in the environment [17].

Figure 2

Cd concentration for 2024 in Europe with the outliers overlaid as black circles. The dimension of the circle indicates the concentration for the given outlier; concentrations above 5 mg/kg⁻¹ are also indicated by their numerical value [25]. As seen from the figure, the highest Cd concentration was registered in northern Spain.

Figure 3

Czc model for Cd²⁺, Zn²⁺, and Co²⁺ efflux system functioning as proton/cation antiporter consisting of inner membrane (CzcA), outer membrane (CzcC), and membrane fusion (CzcB) proteins functioning as a dimer [45].

Figure 4

Sources of Cd and its most significant effects on different parts of the human body [90].

Figure 5

Cd exposure leads to the development of smoking-related lung diseases [90].

Figure 6

Primary outcomes in health effects following chronic Cd exposure [1].

Figure 7

General mechanisms and specific molecular pathways of Cd toxicity. The figure shows general mechanisms (gene regulation, apoptosis, autophagy, oxidative stress, and interaction with bioelements) along with the specific molecular pathways of Cd toxicity [149].

Figure 8

Interaction sites of environmental metal toxicants with the NMDA receptor are as follows: Cd²⁺ facilitates neuronal uptake after receptor stimulation. Similarly, Mn²⁺ can enter the plasma membrane through the NMDAR. Cd can directly attach to the DRPEER sequence in the extracellular domain (in the agonist binding domain (ABD)/transmembrane domain (TMD) linker) of the GluN1 subunit, inhibiting NMDA-mediated current. Pb competes with zinc for the zinc-binding site of the GluN2 subunit, thereby affecting receptor function. As for Hg, there are indications of interactions with cysteine -SH groups that regulate NMDAR activity, although this suggestion still requires experimental evidence. In most instances, metals may induce ROS, which can interact with the –SH groups of the NMDAR [150,151].

Figure 9

Cd’s effect on MAPK pathways disrupts cellular signaling and health. The figure demonstrates how Cd²⁺ disrupts the MAPK signaling pathways, highlighting direct and indirect impacts on cellular function. This leads to abnormal cell responses and an increased risk of disease. Cd’s role in activating NF-κB signaling is a pathway to increased inflammation. Cd²⁺ activates the NF-κB pathway and interacts with ROS, receptors, and kinases, resulting in heightened inflammation and potential chronic conditions. Cd²⁺ also affects the p53 pathway, which leads to DNA damage responses, including apoptosis and cell-cycle control. The role of p53 is in protecting cellular health. Cd²⁺ disrupts Ca²⁺ homeostasis by mimicking and interfering with Ca²⁺ in cells. The figure depicts the effects of Cd on calcium channels and pumps and the subsequent risks to cell function and activity. The figure also demonstrates the pathways through which Cd²⁺ influences epigenetic processes, impacting DNA methylation, histone modification, and non-coding RNA activity. These changes lead to significant alterations in gene expression, affecting cellular functions and contributing to disease progression, particularly in cancer and other severe health conditions [114].