内藤 久雄

A previous epidemiological study showed that higher total serum arsenic levels were associated with an increased risk of hypertension. However, the specific arsenic species contributing to arsenic-induced hypertension remains unknown. Speciation analysis of arsenic in serum samples is technically challenging. Therefore, this cross-sectional study investigated the associations between fasting urinary levels of total arsenic and four speciated arsenic species and the prevalence of hypertension among 2,676 Japanese residents, one of the world's leading fish-consuming populations. A follow-up animal study was conducted to corroborate these epidemiological findings. Consistent with the serum findings, total urinary arsenic levels were positively associated with the prevalence of hypertension. Unlike dimethylarsinate, monomethylarsinate, and inorganic arsenic, arsenobetaine, an organic arsenic species considered non-toxic, was consistently associated with the prevalence of hypertension independent of sodium exposure in both univariate and multivariate models. This association remained robust in a Bayesian kernel machine regression model accounting for combined exposure to the four arsenic species. Causal mediation analysis further suggested that higher fish meat consumption may promote arsenobetaine-mediated hypertension and that increased urinary arsenobetaine is associated with hypertension-mediated cardiovascular diseases. Correspondingly, a 4-week oral exposure to an estimated human-equivalent dose of arsenobetaine, but not dimethylarsinate, increased blood pressure in mice. This human and animal study is the first to suggest that increased exposure to arsenobetaine, which is linked to fish meat consumption, increases the risk of hypertension. Given the global increase in fish consumption, arsenobetaine ingestion may be an emerging international cardiovascular health concern.

Renal toxicity associated with high-level exposure to vanadium has been reported in humans. However, the association between low-level vanadium exposure and human kidney function remains unclear. A cross-sectional study was conducted among 2680 Japanese residents with low vanadium exposure. The urinary vanadium content was measured using inductively coupled plasma mass spectrometry. A multivariate logistic regression analysis was performed to examine the association between vanadium levels and abnormal estimated glomerular filtration rate (eGFR), proteinuria, and hematuria. Nagelkerke's pseudo-R2 (%) was calculated to identify the factors contributing to urinary vanadium. Stratified and mediation analyses were conducted to evaluate the mediating effects of metabolic factors on the association between vanadium and kidney function. The median urinary vanadium concentration among Japanese residents was 0.23 µg/L, which is approximately half of the Agency for Toxic Substances and Disease Registry general population reference value (0.5 µg/L) and significantly lower than those in other countries and regions. Multivariate logistic regression analysis demonstrated a significant negative association between urinary vanadium concentrations and the prevalence of abnormal eGFR and proteinuria, suggesting the potential relevance of vanadium in maintaining kidney function. The primary contributing factor to urinary vanadium levels was daily dietary intake, particularly fruit consumption. Mediation analysis indicated that lipid profiles accounted for 6.9% of the observed vanadium-eGFR association. This is the first study to demonstrate an inverse association between urinary vanadium levels and renal dysfunction, as represented by decreased eGFR. Further longitudinal and mechanistic studies are required to confirm the causal relationships.

BACKGROUND: People worldwide are routinely exposed to tellurium mainly via dietary ingestion. There has been no study to clarify the contribution of tellurium to blood pressure in humans or animals. METHODS: In this cross-sectional study conducted in a general population of 2592 residents in Japan, the associations of urinary tellurium levels with blood pressure and prevalence of hypertension were investigated. The potential sources of tellurium were also investigated. An interventional study in mice confirmed the effect of tellurium exposure on blood pressure. RESULTS: Linear and logistic regression analyses with consideration of confounders including urinary sodium-potassium ratio showed significant positive associations of urinary tellurium level with prevalence of hypertension and blood pressure. Cereals/beans and vegetables/fruits were determined to be potential dietary sources of tellurium exposure. Intermediary analysis suggested that increased intake of cereals/beans, but not that of vegetables/fruits, is positively associated with the tellurium-mediated risk of hypertension. Correspondingly, the mouse study showed that exposure to a putative human-equivalent dose of tellurium via drinking water increased blood pressure with an elevated level of urinary tellurium. The temporally increased blood pressure was decreased to the normal level by a break of tellurium exposure with a reduced level of urinary tellurium. CONCLUSIONS: The interdisciplinary approach provided the first evidence that tellurium exposure is a potential risk for increase of blood pressure. Since the human urinary tellurium level in this study is comparable with the levels in general populations in other Asian and European countries in previous studies, exposure to tellurium may be a latent universal risk for hypertension.

AIMS: There has been a shortage of human studies to elucidate the association between serum arsenic levels and the prevalence of hypertension. This study multidirectionally investigated associations among arsenic exposure, dietary ingestion, and the risk of hypertension by combined human epidemiological and mouse experimental studies. METHODS AND RESULTS: This study focused on the total arsenic level in fasting serum, a biomarker of arsenic exposure. Associations among ingestion frequencies of 54 diet items of Japanese food separated into six categories, total arsenic level in fasting serum, and the prevalence of hypertension were investigated in 2709 general people in Japan. Logistic regression analysis demonstrated a dose-dependent association between serum arsenic level and hypertension and a positive association between the ingestion of fish meat and hypertension. Further analysis showed that the latter association was fully mediated by increased fasting serum arsenic levels in humans. Similarly, oral exposure to the putative human-equivalent dose of arsenic species mixture with the same ratios in a common fish meat in Japan increased systolic blood pressure and arsenic levels in fasting serum in mice. CONCLUSION: This interdisciplinary approach suggests that fish-meat ingestion is a potential risk factor for arsenic-mediated hypertension. Because the increased consumption of fish meat is a recent global trend, health risks of the increased ingestion of arsenic via fish meat should be further investigated.