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.

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.

Cardiovascular responses to lead are biphasic, while methylmercury, but not inorganic mercury, monotonically increases blood pressure in rats.

Cardiovascular diseases, such as heart attack and stroke, are the major cause of death worldwide. It is well known that a high number of environmental and physiological risk factors contribute to the development of cardiovascular diseases. Although risk factors are additive, increased blood pressure (hypertension) is the greatest risk factor. Over the last two decades, a growing number of epidemiological studies associate environmental exposure to lead or mercury species with hypertension. However, cardiovascular effects beyond blood pressure are rarely studied and thresholds for effect are not yet clear. To explore effects of lead or mercury species on the cardiovascular system, normal male Wistar rats were exposed to a range of doses of lead, inorganic mercury or methylmercury through the drinking water for four weeks. High-resolution ultrasound was used to measure heart and vascular function (carotid artery blood flow) at baseline and at the end of the exposure, while blood pressure was measured directly in the femoral artery at the end of the 4-week exposure. After 4 weeks, blood pressure responses to lead were biphasic. Low lead levels decreased blood pressure, dilated the carotid artery and increased cardiac output. At higher lead doses, rats had increased blood pressure. In contrast, methylmercury-exposed rats had increased blood pressure at all doses despite dilated carotid arteries. Inorganic mercury did not show any significant cardiovascular effects. Based on the current study, the benchmark dose level 10% (BMDL10s) for systolic blood pressure for lead, inorganic mercury and methylmercury are 1.1, 1.3 and 1.0 µg/kg-bw/d, respectively. However, similar total mercury blood levels attributed to inorganic mercury or methylmercury produced strikingly different results with inorganic mercury having no observable effect on the cardiovascular system but methylmercury increasing systolic and pulse pressures. Therefore, adverse cardiovascular effects cannot be predicted by total blood mercury level alone and the mercury species of exposure must be taken into account.

Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats.

Environmental exposure to metal mixtures in the human population is common. Mixture risk assessments are often challenging because of a lack of suitable data on the relevant mixture. A growing number of studies show an association between lead or mercury exposure and cardiovascular effects. We investigated the cardiovascular effects of single metal exposure or co-exposure to methylmercury [MeHg(I)], inorganic mercury [Hg(II)] and lead [Pb(II)]. Male Wistar rats received four different metal mixtures for 28 days through the drinking water. The ratios of the metals were based on reference and environmental exposure values. Blood and pulse pressure, cardiac output and electrical activity of the heart were selected as end-points. While exposure to only MeHg(I) increased the systolic blood pressure and decreased cardiac output, the effects were reversed with combined exposures (antagonism). In contrast to these effects, combined exposures negatively affected the electrical activity of the heart (synergism). Thus, it appears that estimates of blood total Hg levels need to be paired with estimates of what species of mercury dominate exposure as well as whether lead co-exposure is present to link total blood Hg levels to cardiovascular effects. Based on current human exposure data and our results, there may be an increased risk of cardiac events as a result of combined exposures to Hg(II), MeHg(I) and Pb(II). This increased risk needs to be clarified by analyzing lead and Hg exposure data in relation to cardiac electrical activity in epidemiological studies.