Ameliorative Mechanism of Dietary Vitamin D and Magnesium on Newborn’s Pulmonary Toxicity Induced by Cadmium

Cadmium (Cd) exposure in mothers can cause respiratory issues in newborns, but the exact toxicity mechanisms are not fully understood. Vitamin D deficiency in Cd-exposed rats is associated with increased cadmium accumulation in tissues. Finding a cost-effective medication that is vital for the body while also reducing the effects of poisoning is crucial in treating poisonings. To investigate the mechanisms of Cd-induced lung toxicity, we examined the impact of prolonged Cd exposure in female rats before pregnancy on newborn lung health, focusing on sera TNF-α level, lung P53, Foxo1 mRNA, and lung VEGF, and BMP-4 protein level. A total of 50 rats were divided into control, Cd, Cd+Vitamin D, Cd+Mg, and Cd + Vitamin D+Mg groups. Cd exposure resulted in higher serum TNF-α levels and a significant rise in P53 mRNA levels. Additionally, the occurrence of hemorrhage, inflammatory cell infiltration, and thickening of alveolar walls decreased following treatment with vitamin D + Mg. Although Cd did not affect the newborns' body weight, it did impair their lung function. These findings suggest that the Cd-induced increase in the P53 gene expression could be alleviated by vitamin D and Mg, along with the elevation of VEGF and BMP-4 proteins and Foxo1 gene expression. The study revealed that environmental toxins can sometimes harm molecules and proteins, leading to damage in critical fetal tissues. However, these issues can be mitigated through essential supplements. Structured Abstract The increasing role of Cd in the erratic behavior of numerous biological and molecular entities, notably the development of fetal lung tissue, has made it beneficial to investigate the possible adverse effects of Cd exposure in pregnant mothers and fetal organ development, where instinctive molecular events occur. Researchers are encouraged to create new aspects of medications to reduce clinical symptoms and improve the quality of life due to exposure to metal toxins, particularly in industrialized countries. The present study aimed to evaluate histopathological and molecular modifications of fetal lungs caused by maternal Cd toxicosis and evaluate the possible ameliorating effects of vitamin D and Mg alone and in combination with fetal lung developmental abnormalities, followed by maternal toxin induction, which can be generalized to humans.Fifty female Wistar rats were purchased from the Pasteur Institute of Iran. To induce the model, cadmium at a dose of 2mg/kg body weight was injected intraperitoneally into the female rats over 28 days before mating (5 days after injection in a week). Afterward, the female rats were randomly divided into type IV polycarbonate cages and mated with healthy male rats. The pregnancy was confirmed by observation of the vaginal plaque, which was subsequently observed, and the number of days of embryo formation was calculated. Subsequently, the pregnant rats were assigned to the following groups and received PBS, vitamin D, Mg, or vitamin D + Mg. At the end of the nine-day treatment period (the 6th day of pregnancy to the 14th day), the neonates were born vaginally, and their body weight and mortality were recorded. The P53 and Foxo1 gene expression levels in the left and right lobes of the homogenized lungs of the newborns in each group were assessed. TNF-alpha was detected in the sera collected from the newborns by ELISA. The isolated left and right lung tissues were homogenized in radioimmunoprecipitation assay (RIPA) buffer and the superior phase was collected to determine the total protein content by Lowry's method and VEGF and BMP-4 protein levels. The obtained lung samples from newborn rats were fixed in a 10% formalin solution for tissue processing. The fixed samples were embedded in paraffin, and serial paraffin sections were prepared for hematoxylin and eosin staining. This study is the first to examine how maternal Cd exposure affects fetal lung development and to estimate the impact of prescribing Mg and vitamin D during pregnancy. The present study assessed the effects of a repeated dose of Cd for 4 weeks before pregnancy on the lung development of newborn rats born to mothers treated with vitamin D and Mg. The results showed that the P53 gene was overexpressed in the model group, while Foxo1 gene expression was downregulated, negatively impacting the lung structure and developmental indices of the fetuses. Therefore, the intake of vitamin D and Mg may contribute to improving the various stages of Cd-induced lung injury by modulating lung inflammation and mucosal secretion while also positively influencing the number of surviving offspring.