title: The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio.
abstract: Hypertension is considered to be the most important risk factor for the development of cardiovascular diseases. Beside life-style risk factors, exposure to lead and mercury species are increasingly discussed as potential risk factors. Although there are a few previous studies, the underlying mechanism by which exposure to lead and mercury disturb blood pressure regulation is not currently understood. Potential mechanisms are oxidative stress production, kidney damage and activation of the renin-angiotensin system (RAS), all of which can interact to cause dysregulation of blood pressure. Male rats (Wistar) were exposed to lead, inorganic mercury, methylmercury or two mixtures of all three metals for four weeks through the drinking water. The two mixture ratios were based on ratios of known reference values or environmental exposure from the literature. To investigate the potential mechanism of actions, blood pressure was measured after four weeks and compared to plasma nitrotyrosine or reduced/oxidized glutathione levels in liver as markers for oxidative stress. Plasma renin and angiotensin II levels were used as markers for RAS activation. Finally, kidney function and injury were assessed via urinary and plasma creatinine levels, creatinine clearance and urinary kidney-injury molecule (KIM-1). While exposure to lead by itself increased oxidative stress and kidney damage along with blood pressure, inorganic mercury did not affect blood pressure or any end-point examined. Conversely, methylmercury instead increased RAS activation along with blood pressure. Surprisingly, when administered as mixtures, lead no longer increased oxidative stress or altered kidney function. Moreover, the mixture based on an environmental ratio no longer had an effect on blood pressure, while the reference value ratio still retained an increase in blood pressure. Based on our results, the prominent mechanism of action associated with the development of hypertension seems to be oxidative stress and kidney damage for lead, while increased RAS activation links methylmercury to hypertension, but these mechanisms along with hypertension disappear when metals are present in some mixtures.
authors.affiliation: Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada; Department of Soil Science, University of Saskatchewan, 51 Campus Drive, Saskatoon, SK S7N 5A8, Canada. Electronic address: tanja.wildemann@usask.ca.
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Wildemann
authors.affiliation: Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada; Department of Soil Science, University of Saskatchewan, 51 Campus Drive, Saskatoon, SK S7N 5A8, Canada. Electronic address: steven.siciliano@usask.ca.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Siciliano
authors.affiliation: Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada; Department of Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK S7N 5B4, Canada. Electronic address: lynn.weber@usask.ca.
authors.forename: Lynn P
authors.initials: LP
authors.lastname: Weber
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D060766:Drinking Water; D005978:Glutathione / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007854:Lead / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008628:Mercury / Q000633:toxicity*; D008767:Methylmercury Compounds / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D060766:Drinking Water; D008767:Methylmercury Compounds; D007854:Lead; C002744:3-nitrotyrosine; D014443:Tyrosine; D008628:Mercury; D005978:Glutathione
keywords: Blood pressure; Kidney; Lead acetate; Mechanism of action; Mercury chloride; Mono-methylmercury chloride; Oxidative stress; Renin–angiotensin