Cd is found in the nature as a compound in association with different elements e.g., oxygen (CdO), chlorine (CdCl₂), sulfur (CdSO₄·xH₂O). Cadmium oxide (CdO) is the most common form found in the environment. A higher transformation rate of Cd to the plants from the soil was reported previously than other heavy metals like Pb and Hg (Satarug, 2018[123]; Zhang and Reynolds, 2019[160]). Humans are exposed to dietary Cd mainly through vegetables and grains (Fagerberg et al., 2015[36]). Consumption of liver and kidney of animal origin represent the major sources of Cd accumulation in human body (Mahurpawar, 2015[85]). Heavy metal exposure can be high in specific areas either geographically or through human actions. For example, vegetable items from South Asian regions, such as potato, onion, bitter gourd, spinach, chili, and tomato, have been shown to accumulate more Cd than the safe limits in different published studies (Nawab et al., 2018[99]; Salhotra and Verma, 2017). The Cd concentration has also been reported to be alarming in fish (Ali et al., 2020[4]; Arulkumar et al., 2017[11]) and meat items in different regions (González-Weller et al., 2006[45]; Jamil et al., 2015[61]). Tobacco is another source of Cd for not only people who actively smoke but also those who are indirectly exposed to smoking. Even people who are rarely exposed to smoke may experience a twofold increase in the lifetime Cd burden (Morrow, 2001[97]). In addition to being ingested and inhaled, Cd can also be exposed to the human body via skin absorption, as our skin is the easiest means of contact with this metal. Cd-rich environments, such as industrial or mining areas, can be sources of exposure through our skins (Wang J et al., 2022[148]). The different sources of Cd via which the maternal body is exposed to this metal are illustrated in Figure 2(Fig. 2).

Cd is generally taken up by humans as Cd-glutathione (Cd-GSH) or Cd-metallothionein (Cd-MT) or in complex with phytochelatins by vegetables or animal body parts. Cd seems to be absorbed in the intestine by enterocytes, mainly in the duodenum and proximal jejunum (Sabolić et al., 2010[117]). Physiological processes in females, such as menstruation and pregnancy, induce a low iron (Fe) status in the body and subsequently increase dietary Cd uptake through gastrointestinal absorption (Fagerberg et al., 2012[37]). The ability of Cd to share physicochemical features such as Ca and zinc (Zn) helps its absorption by competing with these divalent metallic ions (Martelli et al., 2006[86]).

After intake, Cd binds with intestinal metallothionein (MT), and then, Cd-MT is reinternalized, possibly by endocytosis, followed by degradation in lysosomes (Sabolić et al., 2010[117]). When dissociated from complex forms, Cd may exist in the blood in the form of Cd²⁺ or Cd-albumin (Cd-alb).

The Cd-alb complex enters the liver via endocytosis and dissociates into Cd²⁺ and albumin via the lysosome.

Cd²⁺ can cross the sinusoidal membrane via divalent metal transporter-1 (DMT-1), Zrt-Irt-like protein-8 or Ca-channels, induce the nucleus to produce MT and can be stored in hepatocytes as a nontoxic Cd-MT complex (Fagerberg et al., 2012[37]). Although some Cd-MT is released into the blood and others into the bile, chronic exposure to low doses of Cd (a few micromoles in the murine model) has been shown to deplete the GSH level by vacuolizing Cd-GSH (Mezynska and Brzóska, 2018[88]). However, short term exposure to a higher dose of Cd might result an elevated Cd²⁺ in the bloodstream which induce ROS in hepatocytes (Sabolić et al., 2010[117]).

The portion of Cd that is not received by hepatocytes is taken up by different tissues (such as the kidney and ovary) after it reaches the systemic circulation (El Muayed et al., 2012[32]; Varga et al., 1993[142]). DMT-1 and, to some extent, transient receptor potential cation channel subfamily V member 6 (TRPV6) play key roles in transporting Cd²⁺ from the systemic circulation to the fetal circulation by crossing the placenta (Dwivedi et al., 2013[31]; Somsuan et al., 2019[129]; Storm et al., 2016[131]).

The redistribution of Cd from the liver occurs in the kidney as Cd-MT (Jarup et al., 1983[62]). This Cd-MT is then excreted in the urine (Fagerberg et al., 2012[37]) or can be redeposited in the kidney if the Cd level reaches the critical concentration (150 µg/g), causing several defects (Fagerberg et al., 2015[36]). The pathway of Cd transportation from the diet state to the bloodstream state is presented in Figure 3(Fig. 3).

A highly specialized fetal organ, placenta that starts to form approximately 5 days after conception (Turco and Moffett, 2019[140]). The placenta is responsible for the passage of nutrients like Zn and Fe through maternal circulation into the fetal circulation. It also synthesizes important pregnancy hormones such as estrogen, progesterone and other necessarypeptides after the first trimester (Somsuan et al., 2019[129]; Wong et al., 2015[153]). A reduction in the biosynthesis of progesterone from the placenta was noted due to gestational exposure to Cd (Miceli et al., 2005[89]).

Pregnancy-related exposure to Cd may have an impact on the fetus's vascular system, which results in a decrease in placental blood flow and in the region where the mother and fetus exchange gases and nutrients. This raises the possibility of intrauterine growth retardation (Larsen et al., 2002[75]). As a divalent cation, Cd²⁺ can be transported into fetal circulation in a similar way to that of Fe. In maternal circulation, Cd²⁺ and Fe²⁺ attach to transferrin (Tf) and then contact placental syncytiotrophoblast (STB) cells with the help of transferrin receptor (TfR) (Somsuan et al., 2019[129]). Through endocytosis, they then move toward the endosome. DMT-1, which is located on the surface of the endosomal membrane, predominantly transports Fe²⁺ and Cd²⁺ into the STB cytoplasm. A portion of the Cd²⁺ conjugates with MT, and some Fe²⁺ is stored in the cytoplasm by forming a bond with ferritin. When Cd²⁺ crosses the threshold level in STB cells, it competes with Fe²⁺ to reach fetal circulation with the help of DMT-1 (Somsuan et al., 2019[129]). The transportation of Cd from maternal circulation to fetal circulation is shown in Figure 4(Fig. 4).

To preserve brain homeostasis and safeguard the central nervous system (CNS), the blood‒brain barrier (BBB) is formed by brain capillaries in vertebrates and functions as a selective barrier (Tjakra et al., 2020[135]). In fetuses, the formation of the BBB starts at the 8^th week of gestation (Virgintino et al., 2000[144]). The transportation of nutrients and waste material as well as the development of adherens junctions (AJs) and tight junctions (TJs) are performed by the endothelial capillary cells of the BBB. These two junctions are responsible for limiting the paracellular diffusion of water-soluble particles (Abbott et al., 2010[1]).

Owing to the sophisticated structure of mammalian capillaries in brain tissues, it is not easy to display the toxic nature of Cd in the BBB. However, several studies have been performed on animal models to visualize this trait. A study revealed that when the embryos of zebrafish were treated with CdCl₂, the cerebral hemorrhage rate increased, which indicates BBB dysfunction (Zhang T et al., 2021[162]). Zonula occludens-1 (ZO-1), claudin-5 and occludin are three important proteins that play key roles in maintaining the integrity of junctions. When two groups of chickens were fed a Cd-rich diet at different concentrations (70 mg/kg CdCl₂ and 140 mg/kg CdCl₂), the first group prevented the perturbation of Cd toxicity by upregulating ZO-1 and Occludin slightly, whereas the other group failed to do so. This occurred because of the decrease of these proteins in the presence of a high dose of Cd. Consequently, this leads to damage to these two junctions, TJs and AJs, which are responsible for developing defects in the BBB. This experiment confirmed that Cd can surpass the BBB of the fetus (Li et al., 2023[77]).

Besides, studies have demonstrated that Cd induces the elevation of ROS generation which leads to BBB disruption, tubulin modifications, and disturbances in synaptic transmission. Cd-induced oxidative stress has been strongly linked to the development and progression of Parkinson's disease and Alzheimer's disease, contributing to neuronal damage and dysfunction (Okuda et al., 1997[102]; Panayi et al., 2002[103]). This ROS generation plays a key role in activating the mitogen-activated protein kinase (MAPK) pathway, contributing to neuronal apoptosis (Pearson et al., 2001[106]). The MAPK family, including extracellular signal-regulated protein kinases (Erk1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK, regulates various cellular processes (Rockwell et al., 2004[113]). These MAPKs become activated during Cd-induced ROS generation (Chen, Luo, et al., 2008[19]). A proposed model for the signaling pathway involved in Cd²⁺-induced oxidative stress in HT4 neuronal cells suggests that ROS production, driven by PI3-K and a NADPH oxidase-like flavoprotein, initiates the activation of stress kinases (JNK and p38 MAPK) and their downstream transcription factors (c-Jun, ATF-2, and CREB). In this pathway, p38 MAPK (but not JNK) acts as a key signaling molecule responsible for the upregulation of COX-2 and HO-1, phosphorylation of ATF-2 and CREB, and the activation of caspase-dependent PARP cleavage and caspase-independent mechanisms, which ultimately contribute to neuronal cell death as shown in Figure 5(Fig. 5) (Rockwell et al., 2004[113]).

The perinatal and postnatal stages are the two consecutive stages of a newborn. According to the WHO, the perinatal period begins just after the 22^nd week of gestation and ends on the 7^th day after birth (Cioni et al., 2011[21]). On the other hand, the postnatal period starts just after the birth of a newborn and lasts till 6^th to 8^th week of life (Lopez-Gonzalez and Kopparapu, 2024[83]). As the perinatal stage consists of both the gestational period and the post-life period, Cd exposure occurs in this case first via cord blood (Li et al., 2019[76]; Zhang M et al., 2021[161]) and secondarily via breastmilk (Samiee et al., 2019[120]). On the other hand, the potential sources of Cd exposure during the postnatal period are thought to be breastmilk (Dabeka et al., 2011[25]), formula milk (Winiarska-Mieczan, 2014[152]) and tobacco smoke (Sanders et al., 2015[121]). Therefore, in both cases, breastmilk has been found to be one of the most common crucial factors.

The mammary glands that produce breastmilk, separate maternal blood and breastmilk, similar to the placenta (Rossipal, 2000[116]). Although essential nutrients are transported via this gland, it cannot prevent all toxic elements like Cd from entering the breastmilk (Cousins et al., 2006[23]; Nakamura, Ohba, and Ohta, 2012[98]). Postnatal exposure to Cd via breastmilk was confirmed by research on rat offspring, where Cd was found in the stomachs of offspring at post-natal day (PND) 2, PND6 and PND14 before weaning (Jacquillet et al., 2007[60]). Although breastmilk exposure to Cd has been confirmed, the mechanism of this exposure is still unclear. Owing to its similar physical and ionic properties, Cd mimics the transportation pathway of some divalent ions, such as Fe, Mn, and Ca (Bridges and Zalups, 2005[13]). Cellular TfRs are responsible for the transportation of Fe from blood plasma to mammary epithelial cells when they are bound to Tf. (Lönnerdal, 2007[82]). Cd binds with TfR along with Fe when there is a decreased amount of Fe²⁺ and when TfR is upregulated. This affects the transfer of Cd into breastmilk via the Fe transportation pathway (Harris and Madsen, 1988[50]). On the other hand, a positive association was found between Cd²⁺ and Mn^2+, where Mn first binds with Tf. Then, it is received by the TfR and transported to the mammary gland via DMT1 (Gunshin et al., 1997[47]). Another experiment revealed that the expression of the milk protein β-casein was reduced as the Ca concentration in the mammary gland was reduced due to the high dose of Cd (Öhrvik et al., 2006[101]). Even a low dose of Cd can inhibit the transportation of Ca via Ca transporters such as CaT1 (Peng et al., 2000[107]). Cd²⁺ also disturbs the function of the mammary gland by downregulating the expression of secretory pathway calcium-ATPase (SPCA). SPCA transports Ca²⁺ into the Golgi apparatus of the mammary gland, which facilitates milk protein phosphorylation (Faddy et al., 2008[35]; Öhrvik et al., 2011[100]). The mechanism of Cd exposure via breastmilk is depicted in Figure 6(Fig. 6).

The prenatal period is the timeframe before the birth of infants, during which the developing embryo or fetus remains distinctly sensitive to maternal behavior and exposure. In humans, the prenatal stage is categorized as 0-2 weeks as the germinal stage, 3-8 weeks as the embryonic stage, and 9 weeks until birth as the fetal stage. Among these, the fetal stage is critical for migration, maturation, and networking of neurons, and maternal exposure to teratogens poses a high risk to these processes (Ptak and Petronis, 2010[109]). One of the earliest studies showed that prenatal exposure to Cd at gestational day 20 (GD20) created vacuolated endothelial cells in the rat fetal brain, indicating the susceptibility of the CNS to this toxic heavy metal (Rohrer et al., 1978[114]). Gestational Cd exposure at the prenatal stage has been shown to disturb motor coordination and the sensorimotor reflex, causing a delay in the development of the righting reflex and cliff aversion at 0.6 mg/kg Cd exposure in pregnant Wister rats (GD7to GD15) (Minetti and Reale, 2006[92]). A South Asian study assessing urinary Cd levels during pregnancy revealed an inverse association not only with the full-scale intellectual quotient (FSIQ) but also with verbal IQ (VIQ) and performance IQ (PIQ) at the age of 5 years (Kippler, Tofail, Hamadani, et al., 2012[73]). Exencephaly was identified in the fetuses of C57 and SWV mice at GD18, as pregnant mothers were injected with 4 mg/kg CdCl₂ on GD8 (Robinson et al., 2009[111]). One of the earliest studies on rats exposed to 3.5 mg/kg Cd from GD5 to 15 revealed a significant dose-dependent decrease in vertical and horizontal explorative action among pups due to altered bioelectric and higher-order functions of the CNS (Dési et al., 1998[28]).

In humans, prenatal Cd exposure was shown to be inversely associated with children's adaptive and social skills. Maternal health and behavior also play a role in infants' neurodevelopment due to the high level of susceptibility to toxicants during the gestational period. A negative correlation was observed between prenatal Cd exposure and neurodevelopment in offspring born to diabetic and smoking mothers (Ma et al., 2021[84]). The study considered 300 mothers in 2010 and 2011 in Shandong, China, and measured the infants' developmental quotients (DQs) based on gross and fine motor, adaptivity, linguistic and social traits at one year of age and the level of brain-derived neurotrophic factor (BDNF), an important regulator of synaptic plasticity. They reported that a 10-fold increase in Cd in mothers' blood is associated with 5.7- and 4.31-point decreases in DQ and cord serum BDNF levels, respectively (Wang Y et al., 2016[149]). Studies performed in other countries have also revealed a correlation between maternal Cd levels and impaired cognitive development (Kippler et al., 2016[69]) and lower PIQ (Jeong et al., 2015[63]) among offspring.

The perinatal period starts at later stages of gestation and ends after the first week of childbirth in humans. Synaptic action during the perinatal period is also recognized as a decisive period in neurodevelopment since the synaptic maturation and apoptosis of inactive neurons occur predominantly at perinatal age (Cioni et al., 2011[21]).

A separate cohort revealed an inverse association between the Cd level in cord blood and the FSIQ of offspring at the age of 4.5 years (Tian et al., 2009[134]). Studies have been conducted on rodents and murine models exposed to Cd at late gestational and early-life nursing ages, which exhibit abnormal behavioral patterns. A murine model study with perinatal Cd exposure revealed that perinatal Cd exposure downregulates the expression of specific hormones in the brain at low doses (Ishitobi et al., 2007[57]). An important regulator of early brain development is thyroid hormone. It has been observed that perinatal Cd exposure in mice caused a significant decrease in serum thyroxine levels in MT-I/II-null mice (Mori et al., 2006[96]). A study conducted in 2004 in Taiwan revealed that high cord blood Cd levels (mean 0.31 µg/L) were associated with significant decreases in head circumference and decreases in height, weight, and head size up to 3 years of age (Lin et al., 2011[79]).

Treatment with Cd or 'Cd and Pb' significantly decreased the levels of the CNS maturating enzyme alkaline phosphatase (ALP) on PND0 in Cd‒Pb-co-exposed pups. Another enzyme important for synaptic function, acetylcholinesterase (AChE), has been shown to be decreased at PND21 in the Cd-exposed group (Antonio et al., 2003[7]). Low explorative skills among the pups were identified in an experiment performed on Wister rats. The mother rats were fed with 7 mg/kg Cd from gestational day (GD) 5 to GD 15 and 4 lactation weeks, and it was assumed that the abnormalities occurred due to altered bioelectric and higher-order functions of the CNS (Dési et al., 1998[28]).

An overall presentation of neuro-related disorders caused by different stages of Cd exposure and their molecular events are presented in Table 1(Tab. 1) (References in Table 1: Antonio et al., 2003[7]; Dési et al., 1998[28]; Feng et al., 2019[39]; Ishitobi et al., 2007[57]; Jeong et al., 2015[63]; Kippler et al., 2012[72], 2016[69]; Lin et al., 2011[79]; Ma et al., 2021[84]; Minetti & Reale, 2006[92]; Mori et al., 2006[96]; Rohrer et al., 1978[114]; Tehrani et al., 2023[133]; Tian et al., 2009[134]; Wang et al., 2016[146]; Zhang et al., 2016[159]; Zhou et al., 2020[165]).

By studying epigenetics, we understand how gene expression is regulated in response to environmental factors without altering the sequence of genes (Abdi et al., 2018[3]; Iridoy Zulet et al., 2017[56]). Among all other epigenetic modifications, DNA methylation is the most well-known mechanism that explains the emergence of certain diseases (Iridoy Zulet et al., 2017[56]). DNAmethylation has been used as a biomarker to identify the epigenetic alterations that lead to different neurological diseases (Jin and Liu, 2018[65]). Cd exposure has been shown to have detrimental epigenetic effects on different human tissues that can cause abnormalities in fetal circulation and neurodevelopment. The effects of epigenetic changes caused by Cd exposure on placental and fetal development are well known and generally involve DNA methylation (Castillo et al., 2012[16]; Kippler et al., 2013[70]; Sanders et al., 2014[122]; Vaiserman and Lushchak, 2021[141]; Vidal et al., 2015[143]).

Protocadherins like PCDHAC1 expression in the placenta may inversely be affected by maternal Cd exposure, potentially making fetal development more susceptible to epigenetic changes. The Pcdh-αC1 gene family encodes a wide range of transmembrane proteins that are expressed in distinct patterns across individual neurons in the vertebrates. Lower DNA methylation in the Pcdh-αC1's promoter and 5'- region appears to increase vulnerability to Cd-related repression of PCDH, which is linked to the impairment of CNS (Kawaguchi et al., 2008[67]). It was also reported that Cd-mediated suppression of Pcdh-αC1 gene in placenta caused preeclampsia in expecting mothers. Reduced expression of this gene can result in neuronal impairment and weight loss in fetuses (Everson et al., 2016[34]). The placenta is the most vital intermediary organ during pregnancy and is involved in the organization and maturation of the hypothalamic-pituitary-adrenal (HPA) axis as well as cortisol homeostasis in the fetus. The actions of the placenta in this pathway rely on the glucocorticoid receptor gene (NR3C1) and its downstream signaling (Seckl, 1997[126]). A growing body of evidence indicates that alterations in the DNA methylation pattern of the NR3C1 gene's promoter can result in neurobehavioral complications in neonates at an early age (Bromer et al., 2013[14]; Monk et al., 2016[94]). According to multivariate regression analysis, prenatal Cd exposure alone or in combination with other heavy metals, such as As, Pb, Mn, Hg and Zn, leads to increased NR3C1 methylation in the placenta. These findings suggest that fetal HPA axis development is disrupted after NR3C1 hypermethylation, which contributes to the risk of reduced neuromuscular activity and abnormal cognitive behavior (Appleton et al., 2017[9]; Bromer et al., 2013[14]).

miRNAs are among the leading posttranscriptional regulators. The development and functionality of the brain are highly dependent on the proper expression of miRNAs (Wang Z et al., 2022[150]). miRNAs regulate the major number of mRNAs that are expressed in the CNS (Tonacci et al., 2019[137]). The adverse effects of Cd during pregnancy include regulation of the expression of miRNAs like miR-26a. It was found that Cd leads to the inhibition of miR-26a which is responsible for the increased expression of SMAD1 gene, resulting in preeclamptic placenta (Brooks et al., 2016[15]). However, the impact of Cd exposure on the altered expression of miRNAs are responsible for neurodevelopmental disorders, is still under investigation.

A very recent population-based miRNA-seq study revealed an association between altered placental miRNA expression and gestational Cd exposure. They concluded that prenatal Cd exposure markedly increased placental miR-509-3p and miR-193b-5p expression, which corresponds to abnormal placental function and CNS development in fetuses. They predicted 44 target genes (ADAM10, CRK, OTX2 etc.) for miR-509-3p and 47 target genes (ABL2, CIC, SYN6 etc.) for miR-193b-5p, that are involved in CNS development and maturation. The dysregulation of these genes results in atypical neurobehavioral performance of the newborn (Tehrani et al., 2023[133]). Another finding suggests that prenatal Cd and polychlorinated biphenyls exposure alters miRNA expression in the placenta, which may impact fetal development. According to this study, Cd exposure affects miR-1537, a gene linked to high-risk neuroblastoma (Fieuw et al., 2011[42]; Q. Li et al., 2015[78]).

Another epigenetic mechanism through which Cd generates neurotoxicity is histone modification (Ijomone et al., 2020[54]). Among the 16 diverse types of histone modifications, the acetylation and deacetylation of histones are the major factors involved in the emergence of different types of diseases (Chen et al., 2006[18]; Ijomone et al., 2020[54]). In the case of Cd exposure in the fetus, neurotoxicity generated by histone modification seems very rare. In addition to other histone modifications, an interaction between histone deacetylation and Cd-induced neurotoxicity in the fetus has been identified. Histone deacetylases (HDACs) are enzymes that regulate chromatin structure via the deacetylation of histone proteins (Montgomery et al., 2009[95]). HDAC2 (a class of HDACs) has a negative effect on the plasticity of synapses and the formation of memory (Guan et al., 2009[46]). Therefore, psychiatric disorders may occur due to the abnormal upregulation of this enzyme (Datta et al., 2018[27]). When SD rats and their pups were fed water containing Pb acetate and CdCl₂ (150 ppm and 5 ppm, respectively), an increase in HDAC2 due to the effect of Cd was detected in the hippocampal tissues of the pups (Zhou et al., 2020[165]). A negative relation was found between HDAC2 and some synaptic genes (Bdnf promoter I/II, Egr1, Fos, Cpg15) where these genes' expression was downregulated and was found to be responsible for hampering synaptic plasticity and formation of memory (Guan et al., 2009[46]).

A particular study on the strain-specific effects of Cd exposure on neuronal development reported that C57BL/6 mouse pups are more vulnerable than the SWV strain to Cd exposure. Prenatal exposure to Cd markedly upregulated p53 signalling pathway as well as its downstream mediators, Ccng1 and Pmaip1 in C57BL/6 mice. The upregulation of these two genes is associated with NTD. Moreover, several other genes important in CNS development, such as Nr2f1, Nr2f2, Elavl4, Zic1, Neurog1, En2 and Metrn, are reportedly downregulated in C57BL/6 mouse embryos compared with SWV mice (Robinson et al., 2009[111]). Though it can be assumed that there might be some epigenetic alterations for these kind of regulatory changes in gene related to CNS, we couldn't conclude about this because of the lack of study. All these epigenetic modifications with their resulting neuronal diseases are illustrated in Figure 8(Fig. 8).

This work was partially supported by the Grant funded by Research and Innovation Center (RIC), Khulna University under grant number KU/RC-04/2000-44 to Dr. Chanchal Mandal.

The authors declare that they have no conflict of interest.

CM, SSP and FRT conceived and designed the content. SSP and FRT constructed all the figures and wrote the manuscript. FY, AS and DH contributed to drafting the article and revising it critically. CM made the final approval of the version to be published.

We have not used any artificial intelligence (AI)-assisted technologies in the production of submitted work.