Article

Toxicology and Industrial Health

2021, Vol. 37(11) 695–704
Type 2 diabetes mellitus potentiates acute © The Author(s) 2021
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acrylonitrile toxicity: Potentiation DOI: 10.1177/07482337211048583
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reduction by phenethyl isothiocyanate

Jie Zhou1,* , Xueyu Zhu1,*, Ying Dong2,*, Bobo Yang1,*, Rongzhu Lu1,*,
Guangwei Xing1,*, Suhua Wang1,* and Fang Li1,* 

Abstract
Acrylonitrile (AN) is a known animal carcinogen and suspected human carcinogen. Recently, occupational exposure
to AN has considerably increased. Previously, we demonstrated that streptozotocin-induced diabetes potentiates
AN-induced acute toxicity in rats and that the induced cytochrome P450 2E1 (CYP2E1) is responsible for this effect.
In the present study, we examined whether induction of CYP2E1 is also the underlying mechanism for the po-
tentiation of AN-induced acute toxicity in type 2 diabetes in db/db mice. The effect of phenethyl isothiocyanate
(PEITC) in reducing potentiation was also investigated. The mice were randomly divided into the normal control,
diabetic control, AN, diabetes + AN, PEITC + AN, and diabetes + PEITC + AN groups. PEITC (40 mg/kg) was orally
administered to rats for 3 days, and 1 h after the last PEITC gavage, 45 mg/kg AN was intraperitoneally injected. Time
to death was observed. The CYP2E1 level and enzymatic activity, cytochrome c oxidase (CCO) activity, and reactive
oxygen species (ROS) levels were measured. The survival rate was decreased in AN-treated db/db mice compared
with that in AN-treated wild-type mice. The hepatic CYP2E1 level and enzymatic activity remained unaltered in db/
db mice. Phenethyl isothiocyanate alleviated AN-induced acute toxicity in db/db mice as evident in the increased
survival rate, restored CCO activity, and decreased ROS level in both the liver and brain. The study results suggested
that CYP2E1 may not be responsible for the sensitivity to AN-induced acute toxicity in db/db mice and that PEITC
reduced the potentiation of AN-induced acute toxicity in db/db mice.

Keywords
Susceptibility, phenethyl isothiocyanate, cytochrome c oxidase, cytochrome P450 2E1, diabetes mellitus,
acrylonitrile

Received 8 June 2021; Revised 11 July 2021; Accepted 2 September 2021

Introduction including the lungs, liver, kidney, and nerves

The International Diabetes Federation estimated the
global prevalence of diabetes to be 463 million indi-
viduals in 2019 and projected an increase to 700
million (i.e. 10.9% of the population) in 2045 (Saeedi
et al., 2019). Similar to the general population, patients
with diabetes are often exposed to various toxic
chemicals in the occupational and living environment.
Many epidemiological and animal experimental ob-
servations have indicated that environmental pollut-
ants increase the incidence of acute cardiovascular and
cerebrovascular complications in patients with dia-
betes (Pinault et al., 2018). Diabetes potentiates the
toxicity of environmental pollutants to organ systems
(Kowalska and Kocot, 2016; Sawant et al., 2006b;
Zhang et al., 2018; Zhong et al., 2009). Furthermore,
1
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
2
Department of Clinical Laboratory, Rugao Municipal People’s
Hospital, Rugao, Jiangsu, China
*Only Jie Zhou and Xueyu Zhu were considered as cofirst authors,
need to mark *, while other authors were not considered as co-
first authors and did not require marking *.
Corresponding author:
Fang Li, School of Medicine, Jiangsu University, Xuefu road 301,
Zhenjiang 212013, Jiangsu, China.
Email: lfsjy@ujs.edu.cn
696
when exposed to environmental hazards, the immune
system is severely damaged in individuals with dia-
betes (Liu et al., 2014).
Acrylonitrile (AN) is extensively used in the
manufacture of acrylic fibers, resins, and plastic and
has been found in drinking water, food products,
cigarette smoke, and air pollutants (Koutros et al.,
2019). Globally, more than 10 billion pounds of AN
are produced annually; AN is included on the haz-
ardous air pollutant list developed by the United States
Environmental Protection Agency and was ranked 269
on the 2019 substance priority list issued by the
Agency for Toxic Substances and Disease Registry
(ATSDR, 2019). The potential health threat posed to
humans by AN exposure cannot be ignored, especially
with acute AN poisoning incidents having recently
been reported (De Smedt et al., 2014; Leng and Gries,
2014). Acrylonitrile epoxidation to cyanoethylene
oxide (CEO) via cytochrome P450 2E1 (CYP2E1) and
its subsequent metabolism to yield cyanide are re-
sponsible for AN-induced acute adverse effects in-
cluding mortality (Thier et al., 2000).
Cytochrome P450 2E1 expression is increased 3- to
8-fold in streptozotocin (STZ)-induced insulin-
dependent diabetic rats (Maksymchuk et al., 2017).
Our pervious study indicated that STZ-induced dia-
betes potentiates AN-induced acute toxicity. Increased
hepatic CYP2E1 is the main mechanism underlying
this high sensitivity (Li et al., 2021). The prevalence of
type 2 diabetes mellitus (T2DM) has increased
worldwide, both in developed and developing coun-
tries. Several studies have demonstrated significantly
heightened levels of hepatic CYP2E1 in T2DM
(Vornoli et al., 2014; Wang et al., 2018). However,
some studies have identified no difference in CYP2E1
activity in the liver when comparing between humans
(or animals) with and without T2DM (Sawant et al.,
2006a; Gravel et al., 2019). Therefore, whether T2DM
induces CYP2E1 expression remains controversial.
Although our previous study demonstrated that STZ-
induced type 1 diabetes mellitus (T1DM) increases
susceptibility to acute AN toxicity, such susceptibility
in T2DM has not been investigated. This is more
critical because T2DM accounts for 95% of all dia-
betes cases.
The relationship between consuming cruciferous
vegetables and chemoprotection has been widely
documented in epidemiological studies (Clarke et al.,
2011). The phytochemical phenethyl isothiocyanate
(PEITC) is an isothiocyanate found abundantly in
cruciferous vegetables including cabbage, broccoli,
Toxicology and Industrial Health 37(11)
and radish (Martelli et al., 2020). It displays strong
antioxidant and anti-inflammatory activities and in-
hibits CYP2E1 (Li et al., 2019; Li et al., 2021; Martelli
et al., 2020). Although our previous study showed that
PEITC significantly alleviates acute AN toxicity in
STZ-induced diabetic rats, whether the same effect
occurs in T2DM and the underlying mechanisms re-
main unknown. Further investigations on how PEITC
affects acute AN toxicity in T2DM will help reveal the
effect of PEITC on the susceptibility of patients with
diabetes mellitus to AN-induced acute toxicity.
Therefore, we used a db/db mouse genetic model of
T2DM to explore the altered susceptibility of patients
with diabetes to AN-induced acute toxicity and the role
of CYP2E1. Additionally, the protective effect of
PEITC was also examined.
Materials and methods
Chemicals and antibodies
Cytochrome C, nicotinamide adenine dinucleotide
phosphate, and PEITC were obtained from Sigma
Chemical Co (Shanghai, China). Acrylonitrile was
provided by Shanghai Petrochemical Company
(Shanghai, China). n-dodecyl-beta-D-maltoside was
purchased from Bomei BioTechnology Co, Ltd (Hefei,
China).
Antibodies against glyceraldehyde-3-phosphate de-
hydrogenase (GAPDH) and CYP2E1 were purchased
from Abcam PLC (Shanghai, China). The glutathione
(GSH) and reactive oxygen species (ROS) kits were
provided by the Nanjing Jiancheng Bioengineering
Institute (Nanjing, Jiangsu, China). Other chemicals
were of analytical grade and provided by Chemical
Reagent CO., Ltd (Zhenjiang, China).
Animals
Eight-week-old C57BL/KsJ-db/db male mice and their
littermate wild-type (WT) control mice were obtained
from the Nanjing Biomedical Research Institute of
Nanjing University, China (Accredited Number:
SCXK [SU] 2015–0001). All mice were housed at 22 ±
2°C in a controlled environment with a 12-h light/dark
cycle. Animal experimental protocols were approved
by the Animal Care and Use Committee of Jiangsu
University (Accreditation Number: SYXK [SU] 2013–
0036) and were in accordance with the guidelines of
the National Institutes of Health Guide for the Care and
Use of Laboratory Animals (Accreditation Number:
Zhou et al.
UJS-LAER-2,016,030,701). The animals were ac-
climatized to laboratory conditions for a week before
the experiments were conducted.
Chemical treatment
Acrylonitrile was dissolved in distilled water, whereas
PEITC was diluted with olive oil. PEITC was orally
administered for 3 consecutive days until the end of the
experiment. One hour after the last PEITC adminis-
tration, mice received a single intraperitoneal AN
injection at a dose of 45 mg/kg.
Lethality study
After 1 week of acclimatization, the mice were divided
into eight groups:
Group 1 (n = 10, WT + AN): WT mice were orally
treated with olive oil and received a single in-
traperitoneal injection of AN.
Groups 2–4 (n = 10, WT + PEITC at doses of 10,
20, and 40 mg/kg + AN): before AN acute ex-
posure, WT mice were pretreated with 10, 20,
and 40 mg/kg PEITC.
Group 5 (n = 11, db/db + AN): db/db mice were
pretreated with olive oil before AN acute
exposure.
Groups 6–8 (n = 10, db/db + PEITC at doses of 10,
20, and 40 mg/kg + AN): before AN acute ex-
posure, db/db mice were pretreated with 10, 20,
and 40 mg/kg PEITC.
The survival rate was constantly recorded for 4 h
after AN exposure and then every 2 h until the end-
point of the experiment (24 h after AN exposure).
Biochemical assay
Thirty-six mice were divided into the following
groups, with each group comprising six mice. Except
for the addition of the normal control group, and di-
abetic control group, the remaining groups were the
same as those described in the section of 2.4
Wild-type control: WT mice were orally treated with
olive oil before saline injection. db/db control: db/db mice
were orally treated with olive oil before saline injection.
All mice were anesthetized with 1% pentobarbital
sodium 1 h after AN injection. The livers and brains of
all mice were resected and were washed in cold saline.
The livers and brains were dissected into several parts
697
and then were immediately frozen in liquid nitrogen
for several minutes and stored at
80°C for analysis.
CYP2E1 activity assay. The preparation and storage of
hepatomicrosomes were performed according to a
previously published method (Li et al., 2021). Hepatic
CYP2E1 activity was evaluated according to a pre-
vious method described by Reinke and Moyer (1985)
with slight modification by (Li et al., 2021).
Western blot analysis. The hepatomicrosomal protein
concentration was determined using a bicinchoninic
acid (BCA) assay kit (Beyotime, Shanghai, China).
Protein samples (25 μg/lane) were separated through
10% sodium dodecyl sulfate-polyacrylamide gel
electrophoresis and transferred onto a polyvinylidene
difluoride membrane (Millipore, Merck, Germany).
After blocking with 5% skim milk in Tris-buffered
saline (Tris 10 mMTris–HCl, 120 mM NaCl, pH 7.4)
containing 0.1% Tween-20 (TBST) for 2 h at room
temperature, the membranes were incubated with anti-
CYP2E1 antibody (Abcam, dilution 1:1000) and anti-
GAPDH antibody (Santa Cruz, dilution 1:1000) at 4°C
overnight. After three washes with TBST, membranes
were further incubated with a horseradish peroxidase
(HRP)-conjugated anti-rabbit secondary antibody
(Santa Cruz, dilution 1:10,000) for 1 h at room tem-
perature. Immunoreactive protein bands were visualized
using a chemiluminescent HRP substrate (Millipore) and
scanned with the MiniChemi Mini Size Chemilumi-
nescent Imaging System (Beijing Sage Creation Science
Co Ltd, Beijing, China). Protein expression was semi-
quantified using an image analysis software, and values
were normalized to an internal control.
CCO activity assay. Cytochrome c oxidase activity was
measured using a mixture containing 0.5 mL of cyto-
chrome c (0.09 mmol/L), 2.4 mL of phosphate buffered
solution (0.03 mol/L, pH 7.4), and moderate amounts of
sodium hydrosulfite. The reaction was initiated by
adding samples of the tissue homogenates (1% for liver,
2% for brain, w/v) and 30 μL of n-dodecyl-β-d-maltoside
(0.2%, w/v) to the mixture. Changes in spectrophoto-
metric absorbance of the final mixture at 550 nm were
recorded between 0 and 1 min at intervals of 30 s. The
results were expressed as the rate of oxidation of reduced
cytochrome c per milligram wet tissue.
Measurement of ROS production. Reactive oxygen
species production was analyzed using a detection kit
according to a previous method (Li et al., 2021). 2,7-
Dichlorodihydrofluorescein diacetate is oxidized into
698
fluorescent 20,70-dichlorofluorescein (DCF) by ROS in
tissues. The oxidation of this molecule to the fluoro-
chrome DCF results in green fluorescence. The in-
tensity of this fluorescence is generally considered to
reflect ROS production. The result was expressed as
DCF fluorescence per milligram of protein.
Estimation of protein content. Protein concentration was
estimated using the BCA protein assay kit. The
standard used was bovine serum albumin.
Results
Lethality analysis
In the db/db + AN group, 82% survival was observed 1 h
after AN injection, followed by 55% at 1.3 h, and 0 at
12 h. In the WT + AN group, 80% survival was observed
at 1.6 h, followed by 60% at the endpoint of the ex-
periment (24 h after AN injection). Survival in AN-
treated db/db mice was notably lower than that in the WT
+ AN group (p = 0.0011; Figure 1(a)). Survival was
significantly increased in the WT + PEITC (10 and
40 mg/kg) + AN groups compared with that in the WT
+AN group (p = 0.0295; Figure 1 (b)). In the Kaplan–
Meier survival curves, the mean survival time was
93 min in the db/db + AN group, significantly lower than
that in the db/db + 10 and 20 mg/kg PEITC + AN groups
(388 min, p = 0.016; 505 min, p = 0.002, respectively).
At the endpoint of the experiment, 70% of AN-treated
db/db mice, which were pretreated with 40 mg/kg PEITC
survived, whereas all db/db mice treated with AN alone
died. The survival rate in the db/db + PEITC (40 mg/kg)
+ AN group was notably higher than that in the db/db +
AN group (p = 0.000). The 4-h survival rates in the db/db
+ 10, 20, and 40 mg/kg PEITC + AN groups were 80%,
80%, and 0%, respectively, and the proportions were
higher than those in the AN-treated db/db mice without
pretreatment, whose survival rate was 18% (Figure 1(c)).
Hepatic CYP2E1 protein level and
enzymatic activity
The hepatic CYP2E1 level and enzymatic activity of
WT and db/db mice with or without PEITC pre-
treatment before AN injection are indicated in Figure
2 (a) and (b). Both CYP2E1 level and enzymatic
activity in db/db mice exhibited a certain degree of
decline, but no statistically significant difference was
evident when compared with those in WT mice. AN
acute exposure also did not exhibit a significant
Toxicology and Industrial Health 37(11)
effect on the hepatic CYP2E1 level and enzyme
activity in either the db/db or WT mice compared
with the values in the corresponding control groups.
PEITC pretreatment significantly decreased
CYP2E1 activity in AN-treated db/db mice by 25%.
PEITC pretreatment also exhibited the ability to
reduce CYP2E1 expression in AN-treated db/db
mice, although the differences between the db/db
+ PEITC + AN and db/db + AN groups failed to
reach statistical significance.
Cytochrome c oxidase activity in the liver
and brain
As shown in Figure 3 (a) and (b), CCO activity in both
the brain and liver in AN-treated db/db mice was
notably lower than that in db/db control mice. Cyto-
chrome c oxidase activity in both the liver and brain
was obviously increased in db/db mice in the presence
of PEITC pretreatment before AN exposure compared
with the results for the db/db + AN mice.
Reactive oxygen species production in the liver
and brain
Reactive oxygen species production in the brain and
liver after AN exposure in WT and db/db mice is
shown in Figure 4 (a) and (b). Acrylonitrile acute
exposure significantly increased ROS production in
the liver in db/db mice compared with that in the db/db
control mice. Pretreatment with 40 mg/kg PEITC
significantly recovered ROS production both in the
liver and brain compared with the db/db + AN group.
Discussion
db/db mice are commonly used as a model of T2DM
because db/db mice have a leptin receptor defect, as a
result of which they become progressively obese and
hyperglycemic with age (Piattini et al., 2019). Leclercq
et al. (2000) found that CYP2E1 expression and en-
zymatic activity in the liver decreased in ob/ob obese
mice. When ob/ob obese mice were treated with leptin,
hepatic CYP2E1 in ob/ob mice recovered to a level
similar to that in lean mice. They proposed that leptin
may be critical for CYP2E1 induction. This study found
that hepatic CYP2E1 expression and enzyme activity
were not significantly altered in db/db mice compared
with those in WT mice. These results are consistent with
those of Ealey et al. (2008) and Lam et al. (2010), who
Zhou et al. 699

Figure 1. Kaplan–Maier survival curve of non-diabetic and diabetic rats with or without PEITC pretreatment before
acrylonitrile (AN) acute exposure. (a) wild-type + AN and db/db + AN groups; (b) wild-type + AN and wild-type + 10, 20
and 40 mg/kg PEITC + AN groups; (c) db/db + AN and db/db + 10, 20 and 40 mg/kg PEITC + AN groups. *: Significantly
different from wild-type + AN group at p < 0.05. **: Significantly different from wild-type + AN group at p < 0.01. *:
Significantly different from wild-type + AN group at p<0.05. &: Significantly different from db/db + AN group at p < 0.05.
&&: Significantly different from the db/db + AN group at p < 0.01. &&&: Significantly different from the db/db + AN group at
p < 0.001.
700
Figure 2. Hepatic CYP2E1 protein level (a) and enzymatic activity (b) in wild-type and db/db mice with or without PEITC
pretreatment before acrylonitrile (AN) acute exposure. The results are the mean ± SD. *: Significantly different from the
db/db + AN group at p < 0.05.
reported no differences in CYP2E1 level and enzymatic
activity in the liver between db/db mice and WT mice.
Wang et al. (2002) declared that CYP2E1 is the main
enzyme responsible for AN metabolism to cyanide.
Therefore, we proposed that increased CYP2E1 activity
potentiates the AN-induced acute adverse effect. Our
previous studies revealed that STZ-induced diabetic rats
and acetone-treated rats potentiate AN-induced acute
toxicity and that the primary mechanism for such
sensitivities was the induced CYP2E1 activity (Li et al.,
2019; Li et al., 2021; Suhua et al., 2010). The present
study demonstrated that db/db mice are also sensitive to
AN-induced acute adverse effects, as evident in the
higher mortality rates in the AN-treated db/db mice. The
unaltered hepatic CYP2E1 level and activity indicated
that bioactivation-mediated acute adverse effects may
not be the mechanism responsible for the potentiation of
acute toxic effects of AN in db/db mice. CYP2E1
mediates the biotransformation of carbon tetrachloride.
Additionally, T2DM and STZ-induced diabetes po-
tentiated hepatotoxicity and lethality, which were
Toxicology and Industrial Health 37(11)
induced by carbon tetrachloride (Mak and Ko, 1997;
Sawant et al., 2004). These study findings are consistent
with our findings that increased CYP2E1 activity is one
of the main mechanisms for the potentiation of carbon
tetrachloride hepatotoxicity in STZ-induced diabetic
rats, but this may not be responsible for the suscepti-
bility in T2DM rats. Absolute or relative deficiency of
insulin is a feature of different types of diabetes. Mak
and Ko (1997) reported that insulin pretreatment con-
ferred protection against carbon tetrachloride hepato-
toxicity in STZ-induced diabetic rats. We propose that
insulin deficiency may be another mechanism re-
sponsible for susceptibility to AN-related toxicity in
diabetes. The focus of our research work in the future
will be on the mechanism of specific susceptibility of
T2DM to AN-induced acute toxicity.
Both STZ-induced diabetic rats as a model of
T1DM and db/db mice as a model of T2DM exhibited
potentiated AN-induced acute adverse effects. AN is
used commonly as a monomer or comonomer to
develop elastomers, synthetic fibers, and plastics.
Zhou et al. 701

Figure 3. Cytochrome c oxidase activities in liver (a) and brain (b) in wild-type and db/db mice with or without PEITC
pretreatment before acrylonitrile (AN) acute exposure. The results are the mean ± SD. $: Significantly different from
wild-type control group at p < 0.05; &: Significantly different from wild-type + AN group at p < 0.05. #: Significantly
different from db/db control group at p < 0.05; *: Significantly different from db/db + AN group at p < 0.05.

Annually, an estimated nine billion pounds of AN are
produced worldwide (Yuanqing et al., 2013). Acci-
dents associated with acute AN toxicity often occur
(De Smedt et al., 2014; Leng and Gries, 2014). AN
exposure results from the inhalation of burning
biomass and contact with cigarette smoke or drinking
contaminated water (Marsh and Zimmerman, 2015).
AN has been detected in surgical smoke in hospital
operating rooms (Chung et al., 2010). Occupational
exposure to this compound has also sharply increased
(IARC, 1999). Globally, the prevalence of diabetes
was 451 million individuals in 2017. Those with
diabetes may have an increased risk of acute AN
toxicity in the operational space, environment, and
diet. Hence, it is necessary to develop a chemo-
preventive agent that protects against acute AN in-
toxication in those with diabetes.
Phenethyl isothiocyanate has gained attention be-
cause of its ability to inhibit CYP2E1 and activate
nuclear factor erythroid-2-related factor and its roles in
detoxification and antioxidation (Dayalan Naidu et al.,
2018). The study results indicated that pretreatment
with PEITC attenuated AN-induced acute toxicity in
db/db mice, as evident in the increased survival rates.
Because cyanide, a rapidly acting and highly toxic
chemical, is released when oxidative metabolism is
mediated by CYP2E1, the inhibition of CYP2E1 ac-
tivity alleviates acute AN toxicity. Our data demon-
strated significant inhibition of hepatic CYP2E1
activity in AN-treated db/db mice following PEITC
pretreatment. Cyanide inhibits CCO in the mito-
chondrial electron transport chain, resulting in cyto-
toxic anoxia, cellular hypoxia, and potentially death
(Bhadra et al., 2019). This suggests that reduced CCO
activity is implicated in increased cyanide levels.
Another pathway of AN elimination is GSH depletion
and manifold production of intercellular ROS, finally
resulting in oxidative damage (Guangwei et al., 2010).
PEITC decreased ROS levels in the db/db mouse brain
and liver, suggesting that PEITC has alternative
methods for attenuating the acute adverse effect that is
induced by AN via its antioxidant properties.
702 Toxicology and Industrial Health 37(11)

Figure 4. ROS production in liver (a) and brain (b) in wild-type and db/db mice with or without PEITC pretreatment before
acrylonitrile (AN) acute exposure. Each value represents the mean ± SD. &: Significantly different from wild-type + AN group at
p < 0.05; #: Significantly different from db/db control group at p < 0.05; *: Significantly different from db/db+ AN group at p < 0.05.

Our previous study showed that PEITC pre-
treatment potentiates AN-induced acute adverse
effect in STZ-induced diabetic rats due to its ability
to inhibit CYP2E1 activity and restore CCO activity
(Li et al., 2021). Given these observations, PEITC
needs to be studied further as a potential next-
generation chemopreventive agent for AN acute
toxicity in both insulin-dependent and noninsulin-
dependent diabetes.
Conclusion
By studying db/db mice, this study showed that poten-
tiation of acute AN toxicity is not due to CYP2E1 in-
duction, as evidenced by the unaltered hepatic CYP2E1
level and activity in the mice. PEITC alleviated AN-
induced acute adverse effects, increased the survival rate
of mice, and recovered the CCO activity and decreased
the ROS production in both the liver and brain of mice.
Acknowledgements
The authors acknowledge Wallace Academic Editing for
language correction.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial
support for the research, authorship, and/or publication of this
article: This work was supported in part by the Natural
Science Foundation of China (81302459), and Research
Zhou et al.
Foundation for Advanced Talents in Jiangsu University
(13JDG024).
ORCID iDs
Jie Zhou  https://orcid.org/0000-0001-5078-3136
Fang Li  https://orcid.org/0000-0002-3743-0827
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