The Effects of Prenatal Cadmium Exposure on Maternal, Fetal, and Offspring Health

Abstract

Cadmium (Cd) is a natural heavy metal and environmental contaminant, concentrated by industrial activity. Overconsumption or inhalation of this element has been found to induce genotoxicity, ROS production, and apoptosis, leading to carcinogenesis, renal dysfunction, and cardiovascular disease (CVD). Cadmium exposure during pregnancy is particularly dangerous, as it proves to be detrimental to both the mother and developing fetus. Prenatal Cd provision in our mouse model was found to induce fetal growth restriction (FGR) in later stages of pregnancy. Within the embryo, prenatal Cd exposure significantly induced left ventricular hypertrabeculation (LVHT), which was accompanied by increased myocardial proliferation and hyperplasia. Consistently, upregulation of mRNA and protein levels of important cardiogenic factors that are imperative for myocyte proliferation and differentiation, such as p-AKT, Pten, and Gata4, were observed both in vivo and in vitro. A Gata4 germline knockdown model, exposed to the gestational Cd treatment, demonstrated a phenotypic rescue of LVHT. Maternally, Cd induced characteristics of preeclampsia (PE), as elevated systolic and diastolic blood pressure (BP) and features of proteinurea were observed during pregnancy. Additionally, significant alterations in the placental structure, such as an increased proportion of the junctional zone (Jz) and a decreased proportion of the labyrinth, were found. Cell biology and molecular experiments revealed that Cd treatment significantly altered cell differentiation, as it directed away from the invasive trophoblast cells and towards the structural cell lineages. Consequently, a significant decrease in the number of remodeled spiral arteries (SpAs) in the Cd treated placentas was observed. Furthermore, defective labyrinth (Lz) vascularization was found within the Cd treated placentas, evidenced by decreased fetal capillary (FCA) and maternal lacunae area (MLA). The interhemal membrane (IHM), which is the membrane that separates the fetal and maternal circulations, was significantly increased, further complicating the diffusion capacity. Moreover, gestational Cd treated offspring were chronically exposed to their Cd dose throughout their life and displayed developmental indications of pathological hypertrophy (PaHy) by 9 months of age, with a transition to heart failure (HF) by 18 months. This was found to be a direct consequence of the Cd treatment, as AKT/Gata4 signaling was continually activated to drive the progression of this CVD. Cd has also been found to interact with zinc (Zn), which is an important essential element for many biological processes. Prenatal Cd exposure induced a Zn deficiency within the embryonic heart ventricle and a Zn retention within the placenta. This was thought to be a synergistic consequence of decreased expression of the placental Zn transporters, ZnT1 and ZnT2, and poor vascular network and function of the Cd treated placentas. Interestingly, when Cd and Zn were co-treated, the placental defects, ventricular hypertrabeculation, Zn transport, and maternal BP were all phenotypically recovered, making Zn a possible therapeutic strategy for Cd exposed patients. In summary, this study generates compelling evidence on the harmful effects that prenatal exposure of environmental contaminants pose to both maternal and fetal health.