PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity

University of California, Berkeley, Berkeley, California, United States
Pharmacogenetics and Genomics (Impact Factor: 3.48). 04/2006; 16(3):183-90. DOI: 10.1097/01.fpc.0000189796.21770.d3
Source: PubMed
The objective was to determine PON1 status as a predictor for organophosphorus insecticide sensitivity in a cohort of Latina mothers and newborns from the Salinas Valley, California, an area with high levels of organophosphorus insecticide use. PON1 status was established for 130 pregnant Latina women and their newborns using a high-throughput two substrate activity/analysis method which plots rates of diazoxon (DZO) hydrolysis against rates of paraoxon (PO) hydrolysis. Arylesterase activity (AREase) was determined using phenylacetate as a substrate, allowing comparison of PON1 levels across PON1192 genotypes in mothers and children. Phenylacetate hydrolysis is not affected by the Q192R polymorphism. Among newborns, levels of PON1 (AREase) varied by 26-fold (4.3-110.7 U/ml) and among mothers by 14-fold (19.8-281.4 U/ml). On average, children's PON1 levels were four-fold lower than the mothers' PON1 levels (P<0.001). Average PON1 levels in newborns were comparable with reported hPON1 levels in transgenic mice expressing human PON1Q192 or PON1R192, allowing for prediction of relative sensitivity to chlorpyrifos oxon (CPO) and DZO. The predicted range of variability in sensitivity of mothers and children in the same Latino cohort was 65-fold for DZO and 131 to 164-fold for CPO. Overall, these findings indicate that many of the newborns and some of the mothers in this cohort would be more susceptible to the adverse effects of specific organophosphorus pesticide exposure due to their PON1 status. Of particular concern are exposures of pregnant mothers and newborns with low PON1 status.


Available from: Nina Holland, Jul 08, 2015
Original article 183
PON1 status of farmworker mothers and children as a
predictor of organophosphate sensitivity
Clement E. Furlong
, Nina Holland
, Rebecca J. Richter
, Asa Bradman
Alan Ho
and Brenda Eskenazi
The objective was to determine PON1 status as a predictor
for organophosphorus insecticide sensitivity in a cohort of
Latina mothers and newborns from the Salinas Valley,
California, an area with high levels of organophosphorus
insecticide use. PON1 st atus was established for 13 0
pregnant Latina women and their newborns using a high-
throughput two substrate activity/analysis method which
plots rates of diazoxon (DZO) hydrolysis against rates of
paraoxon (PO) hydrolysis. Arylesterase activity (AREase)
was determined using phenylacetate as a substrate,
allowing comparison of PON1 levels across PON1
genotypes in mothers and children. Phenylacetate hydro-
lysis is not affected by the Q192R polymorphism. Among
newborns, levels of PON1 (AREase) varied by 26-fold
(4.3–110.7 U/ml) and among mothers by 14-fold
(19.8–281.4 U/ml). On average, children’s PON1 levels
were four-fold lower than the mothers’ PON1 levels
(P < 0.001). Average PON1 levels in newborns were
comparable with reported hPON1 levels in transgenic mice
expressing human PON1
or PON1
, allowing for
prediction of relative sensitivity to chlorpyrifos oxon (CPO)
and DZO. The predicted range of variability in sensitivity of
mothers and children in the same Latino cohort was 65-
fold for DZO and 131 to 1 64-fold for CPO. Overall, these
findings indicate that many of the newborns and some of
the mothers in this cohort would be more susceptible
to the adverse effects of specific organophosphorus
pesticide exposure due to their PON1 status. Of particular
concern are exposures of pregnant mothers and newborns
with low PON1 status. Pharmacogenetics and Genomics
2006 Lippincott Williams & Wilkins.
Pharmacogenetics and Genomics 2006, 16:183–190
Keywords: children, chlorpyrifos, diazinon, Latino cohort, paraoxonase 1
(PON1), PON1 status, pregnancy
Departments of Genome Sciences and Medicine, Division of Medical Genetics,
University of Washington, Seattle, Washington and
Center for Children’s
Environmental Health, School of Public Health, University of California, Berkeley,
California, USA
Correspondence and requests for reprints to Clement Furlong, University
of Washington, Division of Medical Genetics, Box 357720, Seattle, WA
98195-7720, USA
Tel: + 1 206 543 1193; fax: + 1 206 543 3050;
e-mail: clem@u.washington.edu
Sponsorship: This study was supported by 2 P01 ES009605, ES11387,
ES09883, P30 ES01896, EPA-R82670901-5, P60 MD00222, and NIEHS
ES09601/EPA: RD-83170901. The contents of this paper are solely the
responsibility of the authors and do not necessarily represent official views of
the NIH, or the EPA.
Received 26 July 2005 Accepted 13 October 2005
Recent biological and ambient monitoring data have
indicated widespread organophosphate pesticide expo-
sures to the US population, including adults, pregnant
women, children and fetuses [1–9]. In some cases, these
exposures may exceed health-based reference levels [10–
11]. Although many uses, including residential applica-
tions, of chlorpyrifos (CPS) and diazinon (DZ) were
recently restricted by agreements with registrants
[12,13], agricultural uses are still widespread. Organophos-
phate exposures at high doses have profound effects,
primarily on the central nervous system [14], and there is
growing evidence in animals and humans to suggest that
chronic low level exposure may affect neurodevelopment
The young of many species are more susceptible to
organophosphate toxicity than adults [18–22]. For exam-
ple, the maximum tol erated dose (MTD) of CPS in
7-day-old (PND7) rats is approximately 7.7% of the MTD
in adult animals [22]. One factor contributing to the
increased sensitivity in newborns is that levels of
paraoxonase 1/arylesterase (PON1), a key organophos-
phate detoxifying enzyme, are three- to four-fold lower
than in adults [23–27]. Even among adults, the levels of
PON1 can vary by at least 13-fold [28].
Human PON1 enzyme, a high-density lipoprotein-
(HDL) associated esterase, is encoded as a 355 amino
acid protein by the PON1 gene on chromosome 7q21.3–
22.1 [29] with only its initiator methionine residue
removed before incorporation into HDL particles [30,31].
In humans, a Q192R polymorphism affects the catalytic
efficiency of hydrolysis of some organophosphate sub-
strates [28,3 2,33], including chlorpyrifos oxon (CPO),
the toxic metabolite of CPS [34]. The characterization of
all 28 TagSNPs accounts for only 28% of the variance in
PON1 levels (G.P. Jarvik, personal communicati on),
much of which is attributable to a C-108T polymorphism
in an Sp1 binding site in the 5
regulatory region [35–37].
The first two authors contributed equally to this work.
17 44-6872
2006 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 1
Simple biochemical principles dictate that rates of
detoxication of substrates are dependent on enzyme
levels. Thus, when considering the effects of genetic
variability on sensitivity to CPS/CPO exposures, both the
quantity (level) of PON1 as well as the quality (Q192
versus R192) of PON1 must be considered. In other cases
where the catalytic efficiency of hydrolysis of the two
alloforms is equivalent [e.g . for diazoxon
(DZO) hydrolysis], it is the level of PON1 that is
important [34].
Li et al. [38] introduced the term PON1 status to include
both PON1 level and functional PON1
genotype (Q/Q;
Q/R; R/R) [38]. In this method, PON1 status is
determined with a simple, high-throughput two-substrate
assay and analysis where rates of DZO hydrolysis are
plotted against rates of PO hydrolysis using serum or non-
EDTA preserved plasma samples. This method, validated
in adults, provides a functional determination of the
alloform(s) present in plasma, as well as the
level of an individual’s plasma PON1 [39–41], both
important in modulating exposures to organophosphorus
compounds as well as other risks associated with PON1
status. The lower PON1 levels associated with PON1
[42] are primarily attributable to linkage disequilibrium
with the inefficient promoter polymorphism T-108 [35].
The development of animal model systems has provided
important insights into the role of PON1 in detoxifying
specific organophosphorus compounds. Injection of puri-
fied rabbit PON1 into rats increased resistance to
paraoxon (PO) exposure [43,44] and, more significantly,
to CPO exposure [44] because rabbit PON1 hydrolyses
CPO very rapidly [45]. These observations were con-
firmed and extended using mice, which required much
less purified PON1 for injections and were more
amenable to genetic manipulation [34,38,46]. Injected
PON1 protected against CPS/CPO exposures when
injected 30 min or 24 h before exposure or up to 3 h post
exposure [47]. These experiments provided convincing
evidence that high levels of PON1 protected against
CPS/CPO exposures. The increase in resistance was most
dramatic against CPO exposures [34].
The generation of PON1 knockout mice by Shih et al. [46]
provided a model with which to examine the conse-
quence of the absence of plasma PON1 on resistance to
organophosphate exposures. The PON1 null mice were
found to have dramatically increased sensitivity to CPO
[46] and DZO exposure [34], and less noticeably
increased sensitivity to the respective parent compounds
CPS [46,47] and DZ [34]. It was surprising to find that
the PON1 null mice did not have increased sensitivity to
PO exposure [34].
Injection of purified human PO N1
or PON1
reconstituted PON1 activity in the serum of the PON1
null mice allowed for the testing of the efficiency of each
human PON1
alloform in protecting against exposure
under physiological conditions without exposing human
subjects to these toxic organophosphates [34]. Examina-
tion of the catalytic efficiencies of hydrolysis of CPO,
DZO and PO showed that it was the catalytic efficiency
that determined whether PON1 would protect against
exposures. Either hPON1
alloform protec ted equally
well against DZO exposure, in agreement with the
equivalent catalytic effic iency of each alloform for DZO
hydrolysis. However, the hPON1
alloform provided
significantly better protection against CPO exposure, in
agreement with the higher catalytic efficiency of
for CPO hydrolysis [34]. These observations
on CPO exposures have been confirmed in transgenic
mice expressing one or the other PON1
alloform at
equivalent levels [48]. The finding that PON1
not protect as well as PON1
against CPO/CPS
exposures is important because up to 50% of the general
population is homozygous for PON1
[49]. The
catalytic efficiency for PO hydrolysis was too low to
provide pro tection against PO exposures [34].
In the present study, we determined the PON1 status of
130 pregnant Latina women and their newborns living in
an agricultural community in California [7] , a region
where approximately 22 727 kg of organophosphates are
used annually [50]. We have previously reported that
maternal urinary dialkyl phosphate metabolite levels are
higher in this population relative to national reference
data [8] and were associated with a shorter gestational
age [51] and an increased frequency of abnormal reflexes
in neonates [16]. The main aims of this study were to
assess PON1 status in newborns and mothers and to
predict their relative sensitivity to specific organophos-
phorus insecticides based on recent studies with ‘PON1
humanized transgenic mice’ expressing either human
) or PON1
equivalent levels [48].
Subjects and recruitment
A subset of 130 maternal-newborn pairs were randomly
selected from the CHAMACOS cohort (Center for the
Health Assessment of Mothers and Children of Salinas),
a longitudinal birth cohort study (n = 601 enrollees, 528
live births) of the effects of environmental exposures on
the health of children living in the Salinas Valley [7].
Women were eligible for enrollment in the CHAMACOS
study if they were 18 years or older, less than 20 weeks
gestation at enrollment, English- or Spanish-speaking,
Medi-Cal eligible, and planning to deliver at the
Natividad Medical Center. All women were Latina by
ethnicity, including 87% born in Mexico, and the
remainder in the USA. Approximately 28% of the women
had worked in the fields during the pregnancy and
184 Pharmacogenetics and Genomics 2006, Vol 16 No 3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 2
another 14% had other jobs in agriculture, including
packing shed, nursery and greenhouse work. Overall, 82%
of subjects had agricultural workers living in their homes
during pregnancy. Additional information about exposure
and associations with health outcomes is reported else-
where [7,8,16,51]. All study protocols were approved by
both the University of California, Berkeley and the
University of Washington human-subject review pro-
cesses. Informed consent was obtained for all subjects.
Biological sample collection and processing
Blood was collected from mothers at the time of their
glucose tolerance test (26 ± 2.3 weeks’ gestation) and in
the hospital immediately before or after delivery.
Umbilical cord blood was collected by delivery room staff
once the baby was safely delivered. Heparinized whole
blood was centrifuged, and divided into plasma, buffy
coats and red blood cells, and stored at 801C. Processed
plasma samples were stored at 801C before being
shipped on dry ice to the University of Washington,
Seattle, where they were also stored at 801C until
analysis of enzyme activity. We first compared PON1
activities in 25 mothers at two time poi nts (26 weeks
gestation and delivery). PON1 activities were highly
correlated between the two time points for all three
measured activities of PON1 (r = 0.7, 0.8, 1.0, P < 0.0001
for AREase, CPOase and DZOase, respecti vely). The
ranges for the two measurements were comparable.
Therefore, in subsequent samples, we measured PON1
activities in blood collected at one time point only
(26 weeks’ gestation).
Determination of PON1 status
PON1 status (functional PON1
genotype and plasma
level) was determined by the method developed and
validated on adult populations by Richter and Furlong
[39]. This method provides an accurate determination of
functional PON1
genotype through the use of a two-
substrate enzyme kinetic analysis. PON1 enzyme activ-
ities in plasma of mothers and children were measured
with three different substrates, including paraoxon
(POase), diazoxon (DZOase) and phenylacetate
(AREase), according to published protocols [39–41,52].
Because phenylacetate hydrolysis is not affected by the
Q192R polymorphism and has been shown to correspond
with PON1 levels determined by immunological methods
[29,53], AREase activity was used for measurement of
PON1 levels across genotypes. For PON1 status deter-
mination, rates of DZO hydrolysis were plotted against
rates of PO hydrolysis for each mother and newborn child
(cord blood) in the study. This analysis separates the
population into three distinct groups, individuals func-
tionally homozygous for PON1
, PON1
zygotes and individuals functionally homozygous for
. The accuracy of the PON1
genotype determina tion has been verified by polymerase
chain reaction (PCR) analysis of more than 2000 adult
samples and has been shown to identify individuals with
mutations in the PON1 gene [41]. Although this plot
suggests that PON1
homozygotes have lower rates of
DZO hydrolysis than heterozygotes and PON1
homozygotes, this is not the case, as the position 192
alloforms have equivalent catalytic efficiencies for DZO
hydrolysis [34]. However, the PON1
alloform is more
sensitive to inhibition by the high salt concentration
intentionally used in this assay to resolve the three
phenotypes. The distributions and descriptive
statistics of PON1 status and enzyme levels in mothers
and their newborns were analysed by STATA 8.0 [54].
PON1 status
Figure 1 shows the PON1 status for mothers and
newborns (cord blood) as determined by the plot of
rates of hydrolysis of DZO versus PO. This plot clearly
resolves the three functional PON1
(verified by PCR analysis) for the mothers. However, a
number of data points for newborns with lower activity
values (22 out of 130 or approximately 17%) were not
resolved by this analysis and could only be accurately
assigned by genotyping the Q192R polymorphism. How-
ever, the PON1 status plot provided relative PON1 levels
for each of the 22 subjects. This analysis also shows the
effects of independent allelic expression in the hetero-
zygotes (including the newborns) with some individuals
expressing more of one PON1
alloform than the other.
Genotyping alone does not provide this information.
Several points are worth noting from this analysis: (i)
there is a large variability of PON1 activity values within
each PON1
genotype, both for mothers and newborns;
(ii) both groups of homozygotes fall closely to the trend
line; and (iii) the heterozygote values vary considerably
from the trend line (trend line not shown), consistent
with the concept of independen t cis regulation of each
PON1 allele (Fig. 1).
Range of plasma PON1 levels
Figure 2 shows PON1 levels across genotypes for mothers
and newborns estimated by the AREase activity. Figure 3
shows the effects of the PON1
polymorphism on rates
of paraoxon hydrolysis across genotypes for mothers and
newborns, and provides an excellent example of why
substrates whose rates of hydrolysis are affected by the
polymorphism should not be used to compare
levels across position 192 genotypes. Rates of paraoxon
hydrolysis are significantly lower for Q/Q homozygotes
and heterozygotes than for R/R homozygotes. The
AREase activity in mothers ranged from a low of 19.8
U/ml to a high of 281.4 U/ml (14-fold) and, in newborns,
from 4.3–110.7 U/ml (26-fold) (Fig. 2). The range of
AREase activity (PON1 levels) from the lowest newborn
to the highest mother was 4.3–281.4 U/ml (65-fold). The
mean PON1 levels, as measured by AREase, were similar
across PON1
genotypes for all mothers (Q/Q = 152
PON1 status and predicted organophosphate sensitivity Furlong et al. 185
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 3
U/ml, Q/R = 144 U/ml and R/R = 152 U/ml). The mean
PON1 levels were also similar across genotypes in
newborns (Q/Q = 31 U/ml, Q/R = 36 U/ml and R/R =
43 U/ml), with the newborn PON1
having somewhat higher average AREase activity than
the PON1
homozygotes and the newborn hetero-
zygotes expressing intermediate levels. However, these
AREase activity differences between genotype groups
were not statistically significant (P = 0.13). Although
newborns had on average four-fold less plasma PON1
than mothers, individual levels in mother-child pairs were
modestly correlated (r = 0.47, P = 0.013) (Fig. 4).
Estimation of the range of sensitivity to organophos-
phate exposure
Because both PON1
alloforms hydrolyse DZO with the
same catalytic efficiency [34], these data predict a range
of sensitivity to DZ O exposure of 26-fold in newborns
and 14-fold in mothers, with a range of 65-fold from the
most sensitive newborn to the most resistant mother. An
average four-fold difference in sensitivity to DZO
exposure is predicted betwe en mothers and newborns.
Fig. 2
QQ mother
0 100
Arylesterase, U/ml
200 30
QQ child
QR mother
QR child
Q192R genotype
RR mother
RR child
Individual data points for arylesterase activities (AREase) in mothers
(solid circles) and newborns (open circles) for each PON1
as indicated. Means are indicated by the crossbars.
Fig. 3
QQ mother
0 1000
Paraoxonase, U/l
2000 3000
QQ child
QR mother
QR child
Q192R genotype
RR mother
RR child
Individual data points for paraoxonase activities in mothers (solid
circles) and newborns (open circles) for each PON1
genotype as
indicated. Means are indicated by crossbars.
Fig. 1
0 500 1000 1500
Paraoxonase, U/l
Diazoxonase, U/l
2000 2500 3000 3500
CordQQ CordQR CordRR
MaternalQQ MaternalQR MaternalRR
PON1 status plot for mothers and newborns, determined as described
in the Methods section. Open circles, data points for PON1
homozygous mothers; closed circles, data points for PON1
homozygous newborns; closed squares, data points for heterozygous
mothers; open squares, data points for heterozygous newborns; open
triangles, data points for P ON1
homozygous mothers; closed
triangles, data points for P ON1
homozygous newborns.
Fig. 4
0 100
Arylesterase mother, U/ml
Arylesterase child, U/ml
200 300
Plot of arylesterase activities (AREase) of newborn/mother pairs
(r = 0.47, P = 0.013).
186 Pharmacogenetics and Genomics 2006, Vol 16 No 3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 4
Estimation of the range of sensitivity to CPO exposure is
more complex, due to the different catalytic efficiencies
of the two PON
alloforms for CPO hydrolysis.
However, reasonable estimates of relative sensitivity can
be made by taking advantage of data generated in the
mouse model system, where the mouse PON1 gene was
replaced with either human hPON1
or human
and colonies were established that expressed
these alloforms at the same levels in plasma. Transgenic
mice expressing hPON1
were found to be 2- to 2.5-
fold as sensitive to CPO exposure compared to mice
expressing hPON1
[48], due to the higher catalytic
efficiency of human PON1
for hydrolysis of CPO
[30]. This two- to 2.5-fold difference in sensitivity, taken
together with the 65-fold difference in plasma AREase
levels yield an estimated 131–164-fold range in CPO
sensitivity between the PON1
homozygous new-
born with the lowest PON1 level and the PON1
homozygous mother with the highest PON1 level.
To our knowledge, this is the first study where PON1
status [39,41,52] was determined for a large cohort of
mothers and their newborns using the two-substrate
assay. By plotting rates of DZO hydrolysis against rates of
PO hydrolysis, the three Q192R phenotypes were clearly
separated in the mothers and provided the relative PON1
levels for each individual in this population. However, we
found that for 17% of the newborns, with low PON1
levels, PCR analysis was required to assign position 192
genotypes, although the PON1 status analysis did provide
their cord blood PON1 levels. Although some of the
earlier studies examined only PON1 status with the two
substrate diazoxon/paraoxon assay/analysis, this study
included a measurement of rates of phenylacetate
hydrolysis (AREase), allowing comparison of PON1 levels
across PON1
genotypes. Another study examining the
relationship of PON1 levels, exposure and head circum-
ference in a large cohort of 404 births also made use of
AREase activity to determine PON1 levels [55], repre-
senting a major improvement over the many studies that
examined PON1 genotypes alone [49]. They noted a
relationship between low PON1 levels, exposure and
smaller head circumference .
The AREase values provided an estimate of the relative
sensitivity to organophosphorus com pounds whose in-vivo
catalytic efficiencies of hydrolysis are not affected by the
polymorphism (e.g. DZO). The range of AREase
values in the mothers was very similar to the range
observed in another study of Hispanic farm workers in
Washington State where a 13-fold variability was observed
[28]. The large range of AREa se values observed in thi s
study in the newborns (26-fold) predicts a broad
variability in sensitivity to organophosphate exposure
even among newborns. Surprisingly, some of the new-
borns had higher PON1 levels than some of the adults.
Thus, the individuals predicted to be highly sensitive to
organophosphate exposure include most of the newborns
as well as some of the mothers. The studies reported here
confirm earlier observations of lower PON1 activities in
neonates compared to adults [23–27,56] and are also
consistent with a recent report where neonates had 2.6–
4.6-fold lower PON1 levels, as assessed by the AREase
assay, compared to mothers, in three ethnic groups in
New York City [23].
Among the many activities of the multifuncti onal HDL-
associated enzyme PON1, hydrolysis of DZO and CPO is
important in providing protection against exposure to DZ/
DZO and CPS/CPO. Organophosphate exposures are
appropriately considered as mixed exposures to the
parent co mpounds and their oxon forms because most,
if not all, exposures include oxon residues [57,58].
Because the rate of cholinesterase inactivation by CPO
is at least three orders of magnitude higher than that of
its parent compound (CPS) [59], a very small percentage
of oxon form in an exposure is significant.
To date, most of the animal model studies with
genetically modified mice have examined CPO/CPS
exposures [34,38,46–48,60], although some recent stu-
dies were carried out on DZ/DZO exposures in PON1
null mice and PON1 null mice injected with eac h of the
purified human PON1
alloforms [34]. The results
obtained in these earlier studies have provided important
insights and predictions with respect to individual
variability in sensitivity to CPO/CPS and DZ/DZO
exposures. Li et al. [34] examined the relative in-vivo
catalytic efficiencies of hPON1
and hPON1
PON1 null mice reconstituted with purified human
or PON1
. They found that under in-vivo
physiological conditions, injection of either PON1
alloform provided equivalent protection against DZO
exposure, whereas injected human PON1
significantly better protection against CPO exposure than
did PON1
A more recent study by Cole et al. [48], using transgenic
strains of mice that expressed either PON1
at nearly equivalent levels, verified the results
of Li et al. [34] from the enzyme injection studies in the
PON1 null mice. The mice expressing PON1
approximately two- to 2.5-fold more resistant to CPO
exposure than were the PON1 null mice. Mice expressing
were nearly as sensitive as the PON1 null mice
to CPO exposures. The IC
value (exposure level for
50% inhibition) for CPO inhibition in the hPON
transgenic mice was approximately 1.1 mg/kg dermal
exposure versus approximately 2.2 mg/kg in the
mice. The levels of PON1 in the hPON1
humanized’ transgenic mice are relev ant to the studies
reported here. The transgenic mice expressed levels of
PON1 status and predicted organophosphate sensitivity Furlong et al. 187
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 5
hPON1 of 30–45 U/ml AREase (correcte d for baseline
AREase activity in PON1 null mice) [48], which are
comparable to the average levels of PON1 in the Latino
newborns described in the present study.
Cole et al. [24] examined the time course of appearance of
PON1 in the plasma of individual children and also in
mice expressing the two human PON1
alloforms under
control of the human 5
and 3
regulatory sequences. In
children, PON1 reached plateau levels at 6–24 months of
age whereas expression of human hPON1 in mice under
control of the human PON1 5
regulatory region followed
the mouse time course of PON1 appearance, peaking at
PND21. Moser et al. [62] observed that, although AREase
activity in rats peaked at 3–4 weeks of age as observed by
Li et al. [61], resistance to CPS exposure continued to
increase up to at least 90 days, corresponding to a
continued increase in plasma carboxylesterase activity.
Although there is very little carboxylesterase activity in
human serum, individual variation in carboxylesterase
levels in human liver microsomes has been reported [63].
Levels of PON1 activities reported in other studies
provide insights into the range of sensitivities expected.
The hydrolytic activities in plasma of the wild- type
C57Bl/6J mice used in our earlier studies were approxi-
mately 1800 U/l for chlorpyrifos oxonase (CPOase) and
approximately 3500 U/l for diazoxonase (DZOase) [60].
These activities are in the low range relative to those
reported for human populations. The ranges of reported
activities in another adult Hispani c population were
2145–13 540 U/l for CPOase and 2174–23 316 U/l for
DZOase [28]. It is worth noting that PON1 null mice
are approximately ten-fold more sensitive to DZO [34]
and CPO [46] exposure than wild-type mice. Based on
what is known about the catalytic efficiencies of
organophosphate hydrolysis and the large variability of
PON1 levels observed in this and other populations,
mothers and newborns homozygous for PON1
very low plasma levels of this alloform are predicted to be
a subpopulation uniquely vulnerable to adverse effects
from DZ/DZO exposures and especially CPS/CPO
exposures. One particular concern would be exposure of
a mother with very low PON1 status carrying a fetus that
had not yet developed the capacity for self-protection
against organophosphate exposure. PON1
mothers with very low PON1 status are also predicted to
be unable to pass on to their offspring a PON1 allele that
would be protective against exposure. The father of
course would contribute one PON1 allele to the child;
however, it woul d need to be a high expressing allele and
would take from 6 months to 2 years following birth to be
fully protective.
Although the usual precautions need to be observed in
extrapolating data generated in an animal model system
to predict outcomes in human exposures, genetically
manipulating a single gene in an inbred strain of mice is
nonetheless informative. PON1 appears to be the only
major enzyme in the plasma of both mice and humans
that hydrolyzes chlorpyrifos oxon and diazoxon, as can be
seen from the colinearity of the plots of rates of hydrolysis
of one substrate against others in human populations [28]
and from the dramatic consequences of deleting this gene
in mice [34,46]. Replacing the mouse PON1 gene with
each of the human PON1
alleles provides a better
means of extrapolating between the two species, even
though other pathways may contribute somewhat to the
detoxication. Even among humans, there is variability in
levels and effic iencies of other contributory detoxication
enzymes, such as carboxylesterases and cytochromes
Several factors are likely to contribute to the risk of
adverse health effects due to exposures to CPS/CPO and
DZ/DZO: (i) the level of exposure; (ii) the percentage of
oxon residue or other toxic derivatives in the exposure;
(iii) the level of enzyme (measured by AREase assay);
(iv) the catalytic efficiency of an individual’s PON1 to
detoxify organophosphate metabolites (determined by
the Q192R polymorphism); and (v) the as yet unchar-
acterized genetic variability of the cytochromes P450,
carboxylesterases and other enz ymes that participate
significantly in the detoxication of these organopho-
sphorus compounds.
Additional research is needed to determine the relative
contributions of PON1, cis- and trans-acting factors that
modulate PON1 levels, cytochrom es P450 and other
enzymes, as well as the genetic and environmental factors
that modulate the levels of enzymes involved in
detoxication of parent compounds and their respective
oxons. A recently reported method of haplotyping using
emulsion PCR should be usefu l in understanding cis
factors involved in regulation of protein levels [64].
Research is also needed to determine the exposure levels
of specific residues (trichlorophenol, CPS, CPO, diethyl-
phosphate and other toxic metabolites) required for
modelling [48,65] the effect of PON1 status on the
consequences of exposures.
Evaluation of PON1 status is not only important for
determining risk of organophosphate exposure, but also
for understanding the role of PON1 in modulating other
risks associated with the variability of normal physiologi-
cal functions of PON1, as well as the role of PON1 in the
metabolism of other xenobiotics, including drugs [66].
Multiple results indicating a prominent role for PON1
status in risk for vascular disease have been published
previously [40,46,67,68]. More recently, PON1 has been
shown to inactivate the quorum sensing signal secreted
by Pseudomonads [66,69]; however, data demonstrating the
188 Pharmacogenetics and Genomics 2006, Vol 16 No 3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 6
in-vivo importance of this activity have not yet been
In summary, the range of variability of PON1 status
observed in this study, taken together with data from
‘humanized mice’ expressing hPON1
or hPON1
in place of mouse PON1, predict a 65-fold variability in
DZO sensitivity and a 131–164-fold range in sensitivity to
CPO exposure in this population, with an average four-
fold difference in sensitivity to DZO exposure and an
average eight-to ten-fold variability in sensitivity to CPO
between groups of mothers and their newborns. These
data predict that most, if not all, newborns, as well as
a subpopulation of adults , will exhibit significantly
increased sensitivity to organophosphate exposure. These
findings highlight the significance of understanding the
susceptibility of young children to organophosphate
exposure and developing science-based risk standards
for pesticide regulation as required by the 1996 Food
Protection Act.
We gratefully acknowledge CHAMACOS staff, students
and community partners, and especially the CHAMACOS
participants and their families, without whom this study
would not have been possible. We thank Katie Kogut and
Erin Weltzien for their help with statistical analyses and
Dr Toby Cole for helpful comments and suggestions.
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    • "Several other studies demonstrate that the exposure to CP interferes with the development of mammalian nervous system (Aldridge et al. 2005; Slotkin et al. 2006). The exposure to CP had caused in utero in low birth weights and reduced head circumference of newborns especially for individuals, who have low levels of serum paraoxonase/arylesterase 1 activity (Whyatt et al. 2004; Furlong et al. 2006 ). However, no evidence of CP induced carcinogenicity had been found by the US EPA, and several human epidemiology studies have suggested possible links between CP and lungs or rectal cancers (Lee et al. 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Insecticides and their residues are known to cause several types of ailments in human body. An attempt had been made to assess digitally the geno-toxicity of methyl parathion (MP) and chlorpyrifos (CP) to in vitro grown HepG2 cell line, with Hoechst 33342 staining, comet and micronucleus assays. Additionally, 'acridine orange/ ethidium bromide' (AO/EB) staining was done for the determination of insecticideinduced cytotoxicity, in corollary. Hoechst 33342 staining of cells revealed a decrease in live-cell counts at, 8-40 mg/L MP and 15-70 mg/L CP. Moreover, nuclear fragmentations in ranges, 8 to 40 mg/L MP and 15 to 70 mg/L CP were recorded dependant on individual doses, increasingly with concomitant increases in comet tail length values. DNA fragmentation index measured in comet assays were, 94.3±0.57 at 40 mg/L MP and 93.3±2.08 at 70 mg/L CP. Average micronuclei number was 59.0±2.00 at 40 mg/L MP and 62.6±1.52 at 70 mg/L CP, per 1000 cell nuclei, in micronucleus assay. Minimum inhibitory concentration (MIC) values with AO/EB staining for monitoring cytotoxicity were 4 and 10 mg/L for MP and CP, respectively. Lethal concentration50 (LC50) values were 20.89 mg/L MP and 79.43 mg/L CP in AO/EB staining, for cytotoxicity with probit analyses. It was concluded that MP was comparatively more geno-toxic than CP to HepG2 cell. It was discernible that at lower levels of each insecticide, geno-toxicity was recorded in comparison to cytotoxicity.
    Full-text · Article · May 2016 · Environmental Science and Pollution Research
    • "Considerable residues of chlorpyrifos have been found in food chain [36]. Chlorpyrifos also adversely affects the nontarget systems including nervous system disorders, birth defects, low birth weights, immune system abnormalities, and endocrine disruption [37, 38] . Moreover , bladder cancer and chromosome damage are also found to be associated with exposure to chlorpyrifos [39]. "
    [Show abstract] [Hide abstract] ABSTRACT: Chlorpyrifos is an organophosphorus pesticide commonly used in agriculture. It is noxious to a variety of organisms that include living soil biota along with beneficial arthropods, fish, birds, humans, animals, and plants. Exposure to chlorpyrifos may cause detrimental effects as delayed seedling emergence, fruit deformities, and abnormal cell division. Contamination of chlorpyrifos has been found about 24 km from the site of its application. There are many physico-chemical and biological approaches to remove organophosphorus pesticides from the ecosystem, among them most promising is biodegradation. The 3,5,6-trichloro-2-pyridinol (TCP) and diethylthiophosphate (DETP) as primary products are made when chlorpyrifos is degraded by soil microorganisms which further break into nontoxic metabolites as CO2 , H2 O, and NH3 . Pseudomonas is a diversified genus possessing a series of catabolic pathways and enzymes involved in pesticide degradation. Pseudomonas putida MAS-1 is reported to be more efficient in chlorpyrifos degradation by a rate of 90% in 24 h among Pseudomonas genus. The current review analyzed the comparative potential of bacterial species in Pseudomonas genus for degradation of chlorpyrifos thus, expressing an ecofriendly approach for the treatment of environmental contaminants like pesticides.
    No preview · Article · Nov 2015 · Journal of Basic Microbiology
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    • "Since the polymorphism Q192R confers differential catalytic activity against these two substrates , the plot splits the population into the three functional position 192 genotype (QQ, QR, and RR). A third assay that measures rates of PA hydrolysis at low salt concentration reveals plasma PON1 activity since under these assay conditions, the PON1 Q192R polymorphism does not influence PON1 catalytic activity against PA [9] (Furlong et al.). For this assay, rates of hydrolysis of PA were measured at 270 nm for 4 min at 25 @BULLET C using 20 L of plasma diluted 1:80 in dilution buffer. "
    Full-text · Dataset · Aug 2015
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