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ROS and ERK Pathway Mechanistic Approach on Hepatic Insulin Resistance After Chronic Oral Exposure to Cadmium NOAEL Dose

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Abstract

Cadmium is a critical toxic agent in occupational and non-occupational settings and acute and chronic environmental exposure situations that have recently been associated with metabolic disease development. Until now, the no observed adverse effect level (NOAEL) of cadmium has not been studied regarding insulin resistance development. Therefore, we aimed to monitor whether chronic oral exposure to cadmium NOAEL dose induces insulin resistance in Wistar rats and investigate if oxidative stress and/or inflammation are related. Male Wistar rats were separated into control (standard normocalorie diet + water free of cadmium) and cadmium groups (standard normocalorie diet + drinking water with 15 ppm CdCl2). At 15, 30, and 60 days, oral glucose tolerance, insulin response, and insulin resistance were analyzed using mathematical models. In the liver glycogen, triglyceride, pro- and anti-inflammatory cytokines, cadmium, zinc, metallothioneins, and redox balance were quantified. Immunoreactivity analysis of proteins involved in metabolic and mitogenic insulin signaling was performed. The results showed that a cadmium NOAEL dose after 15 days of exposure causes ROS and mitogenic arm of insulin signaling to increase while hepatic glycogen diminishes. At 30 days, Cd accumulation accentuated ROS production, hepatic triglyceride overaccumulation, and mitogenic signals that develop insulin resistance. Finally, inflammation and lipid peroxidation appear after 60 days of Cd exposure, while lipids and carbohydrate homeostasis deteriorate. In conclusion, environmental exposure to cadmium NAOEL dose causes hepatic Cd accumulation and ROS overproduction that chronically declines the antioxidant defense, deteriorates metabolic homeostasis associated with the mitogenic pathway of insulin signaling, and induces insulin resistance.

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Acknowledgements

The authors thank Vicerrectoria de Investigación y Posgrado [VIEP; TRMS-NAT21] through Ygnacio Martínez Laguna, CONACyT, and the “Sistema Nacional de Investigadores” of Mexico for the financial support of this research project [VESO, 533291] and Dr. Francisco Ramos Collazo (Bioterio “Claude Bernard”, BUAP) for his assistance and the donation of the animals used in this work. We also express our gratitude to Dra. Yhisell Domínguez Alonso of the Clinical Laboratory “CAISS S.A de C.V” for providing the facilities to carry out this study. We thank Professor Robert Simpson for editing the English language text.

Funding

CONACyT and the “Sistema Nacional de Investigadores” of Mexico for the financial support of this research project [VESO, 533291].

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Authors and Affiliations

  1. Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, Chemistry Department, Meritorious Autonomous University of Puebla, 14 South, FCQ1, Ciudad Universitaria, C.P. 72560, Puebla, Mexico

    Victor Enrique Sarmiento-Ortega, Diana Moroni-González, Eduardo Brambila & Samuel Treviño

  2. Department of Pharmacy, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, 22 South, FCQ9, Ciudad Universitaria, C.P. 72560, Puebla, Mexico

    Alfonso Diaz

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  1. Victor Enrique Sarmiento-Ortega
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  2. Diana Moroni-González
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  3. Alfonso Diaz
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  4. Eduardo Brambila
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  5. Samuel Treviño
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Contributions

Victor Enrique Sarmiento-Ortega, Eduardo Brambila, and Samuel Treviño designed the study and wrote the protocol. Victor Enrique Sarmiento-Ortega, Alfonso Díaz, Diana Moroni-González, and Samuel Treviño performed the experiments. Victor Enrique Sarmiento-Ortega, Eduardo Brambila, and Samuel Treviño managed the literature searches and analysis. Eduardo Brambila and Diana Moroni-González undertook the statistical analysis. Alfonso Díaz, Victor Enrique Sarmiento-Ortega, Eduardo Brambila, and Samuel Treviño wrote the first draft of the manuscript. All contributing authors have approved the final manuscript.

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Correspondence to Samuel Treviño.

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Sarmiento-Ortega, V.E., Moroni-González, D., Diaz, A. et al. ROS and ERK Pathway Mechanistic Approach on Hepatic Insulin Resistance After Chronic Oral Exposure to Cadmium NOAEL Dose. Biol Trace Elem Res 201, 3903–3918 (2023). https://doi.org/10.1007/s12011-022-03471-5

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