Aristolochic
acids (AAs) have been known as potent nephrotoxins
since the use of AA-containing herbal medicines was linked with a
series of sporadic renal fibrotic nephropathy cases, and yet an estimated
100 million people worldwide are still at risk today because of continued
use of similar medicines. However, a similar nephropathic condition
is endemic in the rural Balkan regions (e.g., Serbian farming villages)
and AAs were again found to be the causative agents. In the case of
this Balkan endemic nephropathy, AAs were found to have originated
from a widespread local weed Aristolochia clematitis L. In this study, we tested the hypothesis that AAs released from
decomposition of A. clematitis were
also being leached into groundwater, thus polluting the drinking water
of local residents. We initiated the study by developing a dispersive
solid-phase extraction-based sample preparation method for water samples
suspected of AA contamination. The validated method was then coupled
with a liquid chromatography-tandem mass spectrometric method to measure
AAs in groundwater samples collected from Serbia. Our study revealed
for the first time that groundwater in Serbia is extensively contaminated
with AA-I, at ng/L levels. Results also showed that AAs are long-lived
water contaminants, with no observable concentration changes over
a 2-month period of sample storage.
Balkan endemic nephropathy (BEN)
is a multifactorial environmental
disease, with chronic exposure to aristolochic acids (AAs) through
AA-contaminated food being one of the major etiological mechanisms.
However, the bulk of previous research has only focused on investigating
the possible roles of individual pollutants in disease development
and the etiological mechanism of BEN remains controversial. In this
study, we investigated the exposure concentration and duration dependence
of coexposure to phthalate esters and lignite coal-derived phenol
and polycyclic aromatic hydrocarbons (PAHs) on the metabolism and
DNA adduct formation of aristolochic acid I (AAI). Results showed
that both the metabolic activation and DNA adduct formation of AAI
in cultured human kidney cells were affected by their coexposure to
the above-mentioned environmental pollutants. Furthermore, our results
suggest that chemicals leached from lignite coal likely played a role
by triggering AA-activating enzymes to produce more of the promutagenic
DNA adducts, thus further elevating the nephrotoxicity and carcinogenicity
of AAs and increasing the risk of BEN. It is believed that the results
of this study provide a better understanding of the etiological mechanism
of BEN and offer insights into methods and policies to lower the risk
of this devastating disease.
Emerging
evidence suggests that chronic exposure to aristolochic
acids (AAs) is one of the etiological pathways leading to chronic
kidney disease (CKD). Due to the traditional practice of herbal medicine
and AA-containing plants being used extensively as medicinal herbs,
over 100 million East Asians are estimated to be at risk of AA poisoning.
Given that the chronic nephrotoxicity of AAs only manifests itself
after decades of exposure, early diagnosis of AA exposure could allow
for timely intervention and disease risk reduction. However, an early
detection method is not yet available, and diagnosis can only be established
at the end stage of CKD. The goal of this study was to develop a highly
sensitive and selective method to quantitate protein adducts of aristolochic
acid I (AAI) as a biomarker of AA exposure. The method entails the
release of protein-bound aristolactam I (ALI) by heat-assisted alkaline
hydrolysis, extraction of ALI, addition of internal standard, and
quantitation by liquid chromatography–tandem mass spectrometric
analysis. Accuracy and precision of the method were critically evaluated
using a synthetic ALI-containing glutathione adduct. The validated
method was subsequently used to detect dose-dependent formation of
ALI–protein adducts in human serum albumin exposed to AAI and
in proteins isolated from the tissues and sera of AAI-exposed rats.
Our time-dependent study showed that ALI–protein adducts remained
detectable in rats even at 28 days postdosing. It is anticipated that
the developed method will fill the technical gap in diagnosing AA
intoxication and facilitate the biomonitoring of human exposures to
AAs.
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