Cadmium exposure inhibits MMP2 and MMP9 activities in the prostate and testis.

Matrix metalloproteinases (MMPs) are zinc (Zn(2+)) and calcium (Ca(2+)) dependant endopeptidases, capable of degradation of numerous components of the extracellular matrix. Cadmium (Cd(2+)) is a well known environmental contaminant which could impair the activity of MMPs. In this sense, this study was conducted to evaluate if Cd(2+) intake inhibits these endopeptidases activities at the rat prostate and testicles and if it directly inhibits the activity of MMP2 and MMP9 at gelatinolytic assays when present in the incubation buffer. To investigate this hypothesis, Wistar rats (5 weeks old), were given tap water (untreated, n = 9), or 15 ppm CdCl2 diluted in drinking water, during 10 weeks (n = 9) and 20 weeks (n = 9). The animals were euthanized and their ventral prostate, dorsal prostate, and testicles were removed. These tissue samples were processed for protein extraction and subjected to gelatin zymography evaluation. Additionally, we performed an experiment of gelatin zymography in which 5 μM or 2 mM cadmium chloride (CdCl2) was directly dissolved at the incubation buffer, using the prostatic tissue samples from untreated animals that exhibited the highest MMP2 and MMP9 activities in the previous experiment. We have found that CdCl2 intake in the drinking water led to the inhibition of 35% and 30% of MMP2 and MMP9 (p < 0.05) at the ventral prostate and testis, respectively, in Cd(2+) treated animals when compared to controls. Moreover, the activities of the referred enzymes were 80% and 100% inhibited by 5 μM and 2 mM of CdCl2, respectively, even in the presence of 10 mM of CaCl2 within the incubation buffer solution. These important findings demonstrate that environmental cadmium contamination may deregulate the natural balance in the extracellular matrix turnover, through MMPs downregulation, which could contribute to the toxic effects observed in prostatic and testicular tissue after its exposure.

[1]  R. F. Gerlach,et al.  Inhibition of human gingival gelatinases (MMP-2 and MMP-9) by metal salts. , 2000, Dental materials : official publication of the Academy of Dental Materials.

[2]  S. Álvarez,et al.  Morphological changes and oxidative stress in rat prostate exposed to a non-carcinogenic dose of cadmium. , 2004, Toxicology letters.

[3]  R. Visse,et al.  This Review Is Part of a Thematic Series on Matrix Metalloproteinases, Which Includes the following Articles: Matrix Metalloproteinase Inhibition after Myocardial Infarction: a New Approach to Prevent Heart Failure? Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: the Good, the Ba , 2022 .

[4]  W. Fávaro,et al.  Caffeine reduces cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis. , 2013, Reproductive toxicology.

[5]  M. Beasley,et al.  Short-term inhalation of cadmium oxide nanoparticles alters pulmonary dynamics associated with lung injury, inflammation, and repair in a mouse model , 2014, Inhalation toxicology.

[6]  Gillian Murphy,et al.  Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair? , 2008, Nature Clinical Practice Rheumatology.

[7]  W. Fávaro,et al.  Finasteride Inhibits Human Prostate Cancer Cell Invasion through MMP2 and MMP9 Downregulation , 2013, PloS one.

[8]  S. Taboga,et al.  Matrix metalloproteinase (MMP)-2 and MMP-9 activity and localization during ventral prostate atrophy and regrowth. , 2010, International journal of andrology.

[9]  Z. Werb,et al.  How matrix metalloproteinases regulate cell behavior. , 2001, Annual review of cell and developmental biology.

[10]  M. Waalkes,et al.  Cadmium carcinogenesis. , 2003, Mutation research.

[11]  P. Gustin,et al.  Anti-inflammatory effects of formoterol and ipratropium bromide against acute cadmium-induced pulmonary inflammation in rats. , 2010, European journal of pharmacology.

[12]  J. Cury,et al.  Effect of lead, cadmium and zinc on the activity of enamel matrix proteinases in vitro. , 2000, European journal of oral sciences.

[13]  E. Crawford,et al.  Characterising the castration‐resistant prostate cancer population: a systematic review , 2011, International journal of clinical practice.

[14]  J. W. Von den Hoff,et al.  Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. , 2005, BioTechniques.

[15]  S. Felisbino,et al.  Early changes induced by short‐term low‐dose cadmium exposure in rat ventral and dorsolateral prostates , 2011, Microscopy research and technique.

[16]  S. Felisbino,et al.  Finasteride treatment alters MMP-2 and -9 gene expression and activity in the rat ventral prostate. , 2010, International journal of andrology.

[17]  S. Lanone,et al.  Interaction of matrix metalloproteinases with pulmonary pollutants , 2012, European Respiratory Journal.

[18]  I. Stamenkovic Matrix metalloproteinases in tumor invasion and metastasis. , 2000, Seminars in cancer biology.

[19]  L. Matrisian,et al.  Metalloproteinases and their inhibitors in matrix remodeling. , 1990, Trends in genetics : TIG.

[20]  M. Wilson,et al.  Metalloproteinase activities expressed during development and maturation of the rat prostatic complex and seminal vesicles. , 1992, Biology of reproduction.

[21]  M Hutton,et al.  Sources of cadmium in the environment. , 1983, Ecotoxicology and environmental safety.

[22]  S. Garrett,et al.  Cadmium, environmental exposure, and health outcomes. , 2011, Ciencia & saude coletiva.

[23]  R. Visse,et al.  Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases : Structure , 2003 .

[24]  M. Lindsey,et al.  Inhibiting metalloproteases with PD 166793 in heart failure: impact on cardiac remodeling and beyond. , 2008, Cardiovascular therapeutics.

[25]  D. Auld Removal and replacement of metal ions in metallopeptidases. , 1995, Methods in enzymology.

[26]  S. Felisbino,et al.  Fibronectin induces MMP2 expression in human prostate cancer cells. , 2013, Biochemical and biophysical research communications.