Date on Senior Honors Thesis

5-2025

Document Type

Senior Honors Thesis

Degree Name

B.S.

Department

Biology

Author's Keywords

Cadmium; High-Fat-Diet (HFD); Normal Diet (ND); Ferroptosis; Autophagy; P38 MAPK

Abstract

Cadmium (Cd) is a non-biodegradable environmental toxin and accumulates in the body with an estimated half-life of 30-45 years. Humans can be exposed to Cd through diet, drinking water, tobacco smoking, and industrial pollution. Cd can especially accumulate in the kidney due to the release of Cd from protein-metal complexes when filtering blood in the tubules causing oxidative stress and inducing kidney injury. Obesity is another risk factor for kidney disease therefore we examined the dual effects of Cd and obesity on the accumulation of essential metals in mouse kidneys. Starting in utero and continuing until 24 weeks postweaning, male/female mice were exposed to Cd (0, 0.5, or 5 ppm) and were fed on Normal Diet (ND)/High-Fat Diet (HFD) post-weaning. ICP-MS analysis was performed to evaluate Cd and essential metals accumulation in the aforementioned mouse kidneys. ICP-MS analysis demonstrated that female mouse kidneys accumulated significantly higher amounts of Cd than male mouse kidneys with increased iron absorption in 0.5 ppm Cd/ND treated female mouse kidneys compared to 5 ppm Cd/ND treated male mouse kidneys. To understand the mechanisms underlying increased Cd and iron accumulation in the female kidneys, we evaluated the expression of ABCD3 transporter and transferrin, which are known to transport Cd and iron, respectively. ABCD3 transporter expression was significantly higher in kidneys of female mice exposed to 0.5 ppm Cd/ND as compared to mice exposed to ND or HFD. ABCD3 expression was significantly induced in male mouse kidneys exposed to 5ppm Cd/ND and may play a role in transporting Cd in male and female mice. No significant changes in transferrin expression were seen in male and female mice. Ferroptosis is an iron-mediated cell death pathway that is closely linked with the autophagy and MAPK pathways. Therefore, we examined activation of these pathways and p38 MAPK. Western blotting was performed to evaluate levels of proteins in the pathways of interest. Western blotting results demonstrated activation of p38 MAPK only in female mouse kidneys while autophagy pathways were activated in both male and female mice. Expression of ferroptosis markers CD98, FTH-1, and GPX-4 are decreased during ferroptosis. Only CD98 expression was significantly decreased in male mice treated with 0.5 ppm/ND compared to 0 ppm/ND treated mice. However, 0.5 ppm and 5 ppm cadmium exposure with HFD induced ferroptosis in female mice as demonstrated by the decrease in FTH expression. No significant difference in GPX4 expression was detected in male mice while significant decrease in female mice treated with HFD+5 ppm Cd. The increase in p38 MAPK activation may contribute to enhanced Cd accumulation and/or activation of ferroptosis/autophagy pathways in female mouse kidneys.

Lay Summary

Cadmium is a heavy metal, and its exposure can be harmful to humans. Cadmium exposure occurs from various sources, including drinking water, food, ambient air, smoking, contaminated dust, and soil. After the ingestion of cadmium-contaminated water, food, and/or cigarette smoking, cadmium can be absorbed into circulation via the gastrointestinal tract, respiratory tract, or skin. When it reaches the bloodstream, it is transported to the liver and kidney. Cadmium accumulates in the kidney and can cause kidney injury. No effective therapies exist to mitigate cadmium toxicity. In this study, we wanted to examine the effects of cadmium exposure on kidney injury. We also wanted to investigate how obesity and sex impacted the severity of kidney disease caused by cadmium exposure. Mice were used as a model organism for this study. We demonstrated that cadmium accumulates more in female mouse kidneys as compared to male mouse kidneys and this results in increased kidney damage in female mice as shown by an increase in kidney cell death. Future studies will be focused on identifying therapeutic targets to block the activation of kidney cell death pathways in the presence of cadmium to prevent kidney damage.

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