Ecotoxicology and Environmental Safety 229 (2022) 113098

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Ecotoxicology and Environmental Safety

journal homepage: www.elsevier.com/locate/ecoenv

Review

Metabolic reprogramming in the arsenic carcinogenesis

Yihui Ruan a, Xin Fang a, Tingyue Guo a, Yiting Liu a, Yu Hu a, Xuening Wang a, Yuxin Hu c,
Lanyue Gao c, Yongfang Li b, Jingbo Pi b, d, Yuanyuan Xu a, b, *
a
Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, P.R. China
b
The Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, P.R. China
c
Experimental Teaching Center, School of Public Health, China Medical University, P.R. China
d
Program of Environmental Toxicology, School of Public Health, China Medical University, P.R. China

A R T I C L E I N F O A B S T R A C T

Edited by Professor Bing Yan Chronic exposure to arsenic has been associated with a variety of cancers with the mechanisms undefined.
Arsenic exposure causes alterations in metabolites in bio-samples. Recent research progress on cancer biology
Keywords: suggests that metabolic reprogramming contributes to tumorigenesis. Therefore, metabolic reprogramming
Arsenic provides a new clue for the mechanisms of arsenic carcinogenesis. In the present manuscript, we review the latest
Carcinogenic mechanism
findings in reprogramming of glucose, lipids, and amino acids in response to arsenic exposure. Most studies
Glucose metabolism
focused on glucose reprogramming and found that arsenic exposure enhanced glycolysis. However, in vivo studies
Lipid metabolism
Amino acid metabolism observed “reverse Warburg effect” in some cases due to the complexity of the disease evolution and microen­
Oxidative stress vironment. Arsenic exposure has been reported to disturb lipid deposition by inhibiting lipolysis, and induce
serine-glycine one-carbon pathway. As a dominant mechanism for arsenic toxicity, oxidative stress is considered
to link with metabolism reprogramming. Few studies analyzed the causal relationship between metabolic
reprogramming and arsenic-induced cancers. Metabolic alterations may vary with exposure doses and periods.
Identifying metabolic alterations common among humans and experiment models with human-relevant exposure
characteristics may guide future investigations.

1. Introduction Metabolic reprogramming is a hallmark of malignancy. It refers to

Arsenic is an element that universally exists in the environment
(ATSDR, 2015). Typically, one of the most crucial routes of human
exposure to arsenic is through drinking water (IARC, 2012). Approxi­
mately 220 million people in more than 50 countries and regions are
potentially exposed to groundwater containing arsenic levels above 10
μg/L, the guideline value set by the World Health Organization (Podg­
orski and Berg, 2020). Long-term exposure to arsenic poses a great
threat to human health. In severe cases, it leads to cancers of the skin,
lung, liver, bladder, and kidney (Chen et al., 2005; Mead, 2005; Yu et al.,
2001). Arsenic, therefore, has been categorized as a Class I human
carcinogen by the International Agency for Research on Cancer (IARC,
2012). Chromosomal aberrations, epigenetic modifications, oxidative
stress, and DNA damage have been proposed as carcinogenic modes of
this metalloid (Bjorklund et al., 2018; Cui et al., 2021; Eckstein et al.,
2017; Mandal, 2017). However, the underlying mechanisms of arsenic
carcinogenesis are not fully clear.
commonly altered metabolic pathways observed in highly proliferative
cancer cells (Faubert et al., 2020). Nobel laureate Otto Warburg first
noticed that cancer cells relied primarily on glycolysis as the primary
pathway for producing adenosine triphosphate (ATP) to support rapid
growth, even with sufficient oxygen, in a phenomenon called the
“Warburg effect” (Warburg, 1956). Over the past two decades, in-depth
research has not only confirmed that carcinogenic damage largely leads
to the Warburg effect but also suggested that the evolution of metabolic
reprogramming has far exceeded initial expectations (Pavlova and
Thompson, 2016). Currently, metabolic reprogramming refers to
changes in several metabolic pathways, such as glycolysis, gluta­
minolysis, fatty acid de novo synthesis, and fatty acid oxidation (Zhou
et al., 2019). These pathways occur collectively in cancer cells to in­
crease the acquisition of essential nutrients, prioritize the allocation of
nutrients to metabolic pathways and facilitate tumor transformation
(Pavlova and Thompson, 2016). Reprogrammed metabolic characteris­
tics may inform therapeutic approaches for selectively targeting cancer

* Correspondence to: School of Public Health, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang, Liaoning 110122, P.R. China.
E-mail addresses: yyxu@cmu.edu.cn, laurel1214@hotmail.com (Y. Xu).

https://doi.org/10.1016/j.ecoenv.2021.113098
Received 17 August 2021; Received in revised form 6 December 2021; Accepted 14 December 2021
Available online 21 December 2021
0147-6513/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Y. Ruan et al.
cells. Recently, the importance of metabolic reprogramming in the
initiation and progression of various cancers has been intensively
studied (Azoitei et al., 2016; Gu et al., 2019; Senni et al., 2019; Sun et al.,
2021). In addition, the metabolic reprogramming of immune cells is
crucial to the maintenance of the tumor microenvironment (TME) and
the fate of the tumor (Somarribas et al., 2021). While cancer cells opt for
metabolic alterations such as glycolysis to support their biosynthetic and
energetic needs for rapid proliferation and survival in hypoxic TME,
evidence suggests that the infiltrating immune cells (e.g., B cells, T cells,
myeloid-derived suppressor cells, tumor-associated macrophages, neu­
trophils, and natural killer cells) also undergo metabolic changes that
contribute to their pro- or anti-tumor functions, as reviewed by Biswas
(2015).
A number of experimental studies have demonstrated that long-term
arsenic exposure causes alterations in metabolites, such as glucose
(Garcia-Sevillano et al., 2014; Liu et al., 2014; Xu et al., 2019), lipids
(Chen et al., 2017; Rivas-Santiago et al., 2019), and amino acids (Liu
et al., 2014; Zhang et al., 2010). Research on the effect of arsenic on
glucose metabolism is the earliest and the most in-depth. In arsenic
carcinogenesis, there are also the most reports on glucose metabolism.
Current studies have found that arsenic exposure causes the Warburg
effect, which may contribute to carcinogenesis. Chronic arsenic expo­
sure enhanced glycolysis in human bronchial epithelial cells (BEAS-2B)
and human hepatic epithelial cells (L-02) (Luo et al., 2017; Zhao et al.,
2014). This metabolic pattern was required for non-anchor-dependent
growth properties, one of the typical characteristics of malignant cells.
Thus, reprogramming of glucose metabolism has been considered to
contribute to malignant cell transformation. However, it is more
complicated in vivo, as arsenic exposure was reported to reduce glyco­
lytic gene expression in the mouse liver. Moreover, arsenic exposure has
been reported to disturb lipid deposition by inhibiting lipolysis in
human renal tubular epithelial cells (HK-2) (Fang et al., 2018), and
induce the serine-glycine one-carbon (SGOC) pathway in BEAS-2B cells
(Bi et al., 2020). However, the evidence is limited. Additional studies on
metabolic alterations due to arsenic exposure are needed to verify these
findings. Of note, oxidative stress, a key mechanism underlying arsenic
toxicity, is linked to metabolic reprogramming via same key factors,
such as reduced glutathione (GSH), nicotine adenine dis­
phosphonucleotide (NADPH), nuclear factor erythroid 2-related factor 2
(NRF2), and adenosine 5’-monophosphate-activated protein kinase
(AMPK).
This paper reviews the evidence for metabolic reprogramming in
response to arsenic exposure and the probable role of metabolic
reprogramming in arsenic carcinogenesis. This information may help to
formulate better preventative and therapeutic strategies for arsenic
poisoning.
2. Metabolic reprogramming and carcinogenesis
Studies on metabolism in cancer cells have deepened our under­
standing of the functional consequences and mechanisms of metabolic
changes during carcinogenesis. Most cancer cells reprogram their
nutritional metabolism due to mutations in oncogenes and tumor sup­
pressor factors, resulting in constitutive activation of signaling pathways
involved in cell growth (Papa et al., 2019). Multiple growth signaling
nodes such as PI3K/Akt, p53, and Ras are aberrantly activated in cancer,
all of which have the ability to promote the cellular acquisition of
glucose (Ansary et al., 2019; Bravatà et al., 2021; Hoxhaj and Manning,
2020; Wang et al., 2019). The transcription factor MYC contributes to
metabolic reprogramming by shifting the uptake and metabolism of
glutamine in cancer cells (Venkateswaran et al., 2019).
Under environmental stress conditions, the metabolic reprogram­
ming of cells not only gives them a survival advantage to adapt to the
environment, but also leads to accelerated cell proliferation and
abnormal differentiation, thus promoting tumorigenesis (Lee and Kim,
2016). Utilization of pentose phosphate pathway (PPP) is frequently
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Ecotoxicology and Environmental Safety 229 (2022) 113098
elevated in tumorigenesis (Pavlova and Thompson, 2016). PPP gener­
ates various biosynthetic precursors for nucleotides and lipids using
glycolytic intermediates (Pinweha et al., 2016). SGOC pathway metab­
olites (e.g., phenylalanine and formate) contribute to a number of
cellular biosynthetic and regulatory processes (Coco et al., 2020).
Methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) was found to
be among the top three most frequently overexpressed metabolic en­
zymes in cancer, suggesting that alterations in the SGOC pathway may
be universally selected in tumorigenesis (Nilsson et al., 2014). Mutations
in metabolic enzymes leading to the accretion of specific intermediate
metabolites also drive cancer initiation (Fig. 1). Mutations of succinate
dehydrogenase and fumarate hydratase (SHDmut and FHmut) induce
elevated levels of succinate and fumarate (Eijkelenkamp et al., 2020; Ye
et al., 2013), which can activate hypoxia-inducible factor (HIF) 1
signaling via inhibition of prolyl hydroxylase domain (PHD) proteins,
demethylation of DNA via inhibition of ten-eleven translocation family
(TET), and histone demethylation via inhibition of jumonji C
domain-containing histone lysine demethylases (JMJD) (Carlson and
Van Beneden, 2014; Hawkins et al., 2016; Tannahill et al., 2013).
Similarly, mutations of isocitrate dehydrogenase (IDH1mut and IDH2mut)
lead to the generation and accumulation of the oncometabolite 2-hy­
droxyglutarate (2-HG), which results in demethylation of DNA and
histones via inhibition of JMJD and TET, respectively (Baylin and Her­
man, 2000; Ye et al., 2013). Consequently, the activation of HIF1A and
persistent histone and DNA methylation impair cellular differentiation,
contributing to cancer initiation (Baylin and Herman, 2000; Figueroa
et al., 2010; Sajnani et al., 2017) (Fig. 1).
An overarching theme in cell metabolism is improving cellular
fitness to provide a selective advantage during tumorigenesis. Thus, the
metabolites produced by oncogene-regulated metabolic pathway alter­
ations may be the basis for tumorigenesis, and some pathways might be
suitable therapeutic targets.
3. Effect of arsenic exposure on metabolism
3.1. Arsenic exposure and glucose metabolism
Glycolysis is a key pathway of glucose metabolism in cancer cells
(Liao et al., 2021). Pyruvate, as the end product of glycolysis, is con­
verted into lactate and secreted extracellularly (Liao et al., 2021; Zhu
and Thompson, 2019). Glycolysis provides the precursors for three
major classes of macromolecules (nucleic acids, lipids, and proteins),
which are required at high levels in proliferating cells (Birts et al., 2020;
Dang, 2012). Meanwhile, higher lactate levels are notably associated
with tumor recurrence and promote the emergence of an immunosup­
pressive microenvironment (Goetze et al., 2011; J. Li et al., 2021). The
currently available literature on alteration of glucose metabolism in
response to arsenic mainly focuses on glycolysis (Table 1). Long-term
arsenic exposure enhances glycolysis in cells, contributing to malig­
nant transformation. However, the effects of arsenic exposure on
glycolysis in animal models appear species specific and sometimes
opposite to the in vitro observations (Fig. 2A).
Arsenic-induced transformed cells presented with a metabolic switch
to aerobic glycolysis (Warburg effect) (He et al., 2019). Multiple studies
conducted in BEAS-2B cells have found that glycolysis and oxidative
phosphorylation (OXPHOS) in glucose homeostasis are reciprocally
regulated during the first week of arsenite exposure (Bi et al., 2020; Zhao
et al., 2013). In BEAS-2B cells treated with 1 μM arsenite, three
glycolysis-related genes were repressed during the first week, but 14
glycolysis-related genes were highly expressed by the end of the second
week, including enolase (ENO3), hexokinase (HK2), and phosphoglyc­
erate kinase (PGK2) (Zhao et al., 2013). Increased concentrations of
citrate and α-ketoglutarate (α-KG) but decreased concentrations of
fumarate and malate in a time-dependent manner were observed in
BEAS-2B cells exposed to 0.25 μM arsenite for 3 days (Bi et al., 2020).
With the prolongation of arsenic exposure, glycolysis gradually became
Y. Ruan et al. Ecotoxicology and Environmental Safety 229 (2022) 113098

Fig. 1. The role of metabolic reprogramming in

tumorigenesis. Metabolic enzyme mutations
result in the accretion of specific intermediate
metabolites that contribute to the initiation of
cancer. Blue lines represent downregulated
pathways. α-KG, α-ketoglutarate; FH, fumarate
hydratase; 2-HG, 2-hydroxyglutarate; 5hmC, 5-
hydroxymethylcytosine; IDH, isocitrate dehy­
drogenase; JMJD, jumonji C domain-containing
histone lysine demethylases; 5mC, 5-methylcy­
tosine; PHD, prolyl hydroxylase domain; TCA,
tricarboxylic acid; TET, ten-eleven trans­
location; SDH, succinate dehydrogenase.

Table 1
Effects of arsenic exposure on glucose metabolism.
Subject/model Reagent Dose Expo Metabolic changes Phenotype References
Time

in vitro
BEAS-2B NaAsO2 1 μM 4 weeks HIF1A, lactate ↑; glycolysis related genes ↑ Metabolic Zhao et al. (2013)
disruption
BEAS-2B NaAsO2 0.25 μM 3 days Citrate, isocitrate, succinate, fumarate and malate ↓; Metabolic Bi et al. (2020)
α-KG ↑ disruption
BEAS-2B NaAsO2 0.25 μM 6 months Fumarate, succinate, α-KG, isocitrate, citrate and malate Malignant Bi et al. (2020)
↓ transformation
HDF, HUC, A549, NaAsO2 0.1, 0.5, 1, 2 or 2 weeks lactate ↑ Metabolic Zhao et al. (2013)
and RWPE-1 4 μM disruption
L-02 and THLE-3 NaAsO2 2 μM 15 weeks HIF1A and MCT4↑ Malignant Luo et al. (2017)
transformation
BEAS-2B NaAsO2 1 μM 52 weeks HIF1A, 3-phosphoglycerate, isocitrate, pyruvate, G6P, Malignant Zhao et al. (2014)
and lactate ↑; glucose and α-KG ↓ transformation
in vivo
Zebrafish Na3AsO4 20 mg/L 96 hours Liver: G6P and pyruvate ↑; ursodeoxycholic acid and Liver injury Li et al. (2016)
(Aquatic chenodeoxycholic acid ↑, hypotaurine ↓
environment)
Zebrafish Na3AsO4 5 or 50 µg/L 14 days Liver: lactate, alanine, succinate, and ATP ↓; Metabolic Xu et al. (2019)
(Aquatic phosphocholine, inosine ↑ disruption
environment)
BALB/c mice NaAsO2 3 mg/kg/day 12 days Plasma: isocitrate, α-KG and citrate ↑ Metabolic Garcia-Sevillano et al.
(Gavage) disruption (2014)
C57BL/6 J mice NaAsO2 1, 2, or 4 mg/L 12 weeks Liver: glycolytic genes ↓, glycogen ↓ and Insulin resistance Gao et al. (2019)
(Drinking water) gluconeogenesis genes ↑

↑ Increase, ↓ decrease.

the main cellular energy supply pathway. Several in vitro studies of one in culture medium, including in primary human urothelial cells (HUC),
research group found that exposure to 1 μM arsenite for 2 weeks induced human prostate epithelial cells (RWPE-1), BEAS-2B cells and human
lactate accumulation in the cell accompanied by increased lactate levels dermal fibroblasts (HDF) (Zhao et al., 2013). Increased expression levels

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Y. Ruan et al. Ecotoxicology and Environmental Safety 229 (2022) 113098

Fig. 2. Metabolic reprogramming by arsenic exposure. Arsenic exposure causes metabolic reprogramming of glucose, lipid and amino acid. Part A, B, and C
correspond to glucose, lipid and amino acid metabolism, respectively. Red, black, and blue fonts indicate upregulated, sustained, and inhibited metabolic compo­
nents, respectively. CPT, carnitine palmitoyltransferase; GLUT, glucose transporter; Gly, glycine; HIF, hypoxia-inducible factor; IDH, isocitrate dehydrogenase; LDH,
lactic dehydrogenase; LXR, liver X receptor; MCT, monocarboxylate transporter; PHD, prolyl hydroxylase domain; PHGDH, phosphoglycerate dehydrogenase; PPAR,
peroxisome proliferator-activated receptor; PSAT, phosphoserine aminotransferase; Ser, serine; SHMT, serine hydroxymethyltransferase; SREBP, sterol regulatory
element-binding protein.

of the glycolysis-related genes HK2, ENO1, and glucose transporter
(GLUT4) were found in L-02 cells treated with 2 µM arsenite for
24 hours (Luo et al., 2016). At 15 weeks, a metabolic switch to glycolysis
occurred in arsenite-transformed malignant L-02 cells (Luo et al., 2017).
The same metabolic shift was observed in arsenite-transformed malig­
nant BEAS-2B cells, in which the expression levels of 45 out of 54 genes
associated with OXPHOS were downregulated, while most
glycolysis-related genes were upregulated (Bi et al., 2020). Therefore, a
key alteration of cells to adapt to long-term arsenic exposure is the
metabolic switch from the tricarboxylic acid (TCA) cycle to glycolysis.
Arsenic-induced glycolysis may promote malignant transformation.
Glycolysis is controlled by master regulatory genes, most significantly
hypoxia-responsive transcription factors of the HIF family, such as
HIF1A (Chen et al., 2019; Yeung et al., 2008). Accumulating evidence
suggests that HIF1A can be induced by arsenite (Bi et al., 2020; Zhao
et al., 2014). A marked increase in HIF1A protein levels was observed in
BEAS-2B cells exposed to 1 μM arsenite for 2 weeks (Zhao et al., 2014).
Moreover, the accumulation of HIF1A induced by arsenite is persistent,
which is different from the transient activation of HIF1A induced by
hypoxia (Ginouvès et al., 2008; He et al., 2011; Zhao et al., 2014). Under
normal conditions, HIF1A is hydroxylated at specific proline residues by
PHDs, tagging it for ubiquitination and subsequent degradation by the
proteasome pathway (Kaelin and Ratcliffe, 2008). In arsenite-exposed
BEAS-2B cells, the levels of pyruvate and isocitrate, which inhibit PHD
function, were elevated, whereas the levels of α-KG, a cofactor of PHD to
hydroxylate HIF1A, were reduced (Bi et al., 2020; Wong et al., 2013;
Zhao et al., 2014). These alterations lead to the sustained elevation of
HIF1A protein levels. In L-02 cells and non-transformed human liver
epithelial cells (THLE-3) exposed to arsenite (2 μM, 15 weeks), the
expression levels of HIF1A and lactate transporter protein mono­
carboxylate transporter (MCT) 4 coordinated by HIF1A were upregu­
lated (Luo et al., 2017). MCT4 sustains a higher level of arsenic-induced
glycolysis by exporting lactate to the extracellular environment and
maintaining the continuous pyruvate-to-lactate conversion (Pinheiro
et al., 2012). With the excretion of lactate, an acidic microenvironment
gradually develops, facilitating the generation of cytokines (e.g., IL-8
and IL-6) (Tan et al., 2015). These cytokines further promote
arsenic-induced carcinogenesis (Johnson et al., 2018). In summary,
arsenic exposure leads to aerobic glycolysis by increasing the stability of
HIF1A protein and sustains glycolysis by increasing HIF1A-induced
MCT4 levels, which contributes to malignant transformation.
In vivo studies demonstrated that arsenic-induced changes in glucose
metabolic pathways partially resemble glycolysis. Zebrafish exposed to
arsenite (20 mg/L, 96 hours) exhibited elevated expression of
glycolysis-related enzymes, such as glucokinase (GCK) and pyruvate
kinase (PK), increased levels of glycolytic intermediates (glucose-6-
phosphate (G6P) and pyruvate), and increased activity of PPP in the
liver (Li et al., 2016). The PPP is composed of nonoxidative and oxida­
tive branches, both of which promote glycolysis (Chiara et al., 2012). In
the contrast, arsenic exposure was reported to reduce the levels of

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Y. Ruan et al. Ecotoxicology and Environmental Safety 229 (2022) 113098

glycolytic products and gene transcription. In BALB/c mice gavaged
with arsenite (3 mg/kg/day, 12 days), metabolome analyses demon­
strated that plasma concentrations of lactate and alanine were signifi­
cantly decreased, while the levels of isocitrate, α-KG, glutamate, and
citrate were increased (Garcia-Sevillano et al., 2014; Garciafigueroa
et al., 2013). The expression of glycolysis genes (e.g., Gck and Pk) in the
livers of C57BL/6J mice, remained decreased after 12 weeks of arsenite
exposure (1, 2, and 4 mg/L). This may indicate a “reverse Warburg ef­
fect”. During cancer development, cancer cells induce surrounding
stromal fibroblasts to undergo aerobic glycolysis, producing large
amounts of energy metabolites such as pyruvate and lactate, which are
transported to cancer cells and then enter the mitochondria to produce
high levels of ATP through OXPHOS and fuel the TCA cycle to resist
apoptosis and promote cancer cell proliferation (Pavlides et al., 2010,
2009). Thus, a rational explanation for the role of arsenic-induced
glycolysis in carcinogenesis could be made by the Warburg effect or
the “reverse Warburg effect”.
The enhancement of glycolysis by arsenic exposure has been vali­
dated in a variety of cellular models as mentioned above. However, the
expression of glycolysis genes was inhibited by short-term arsenic
exposure, but induced by long-term exposure. Cell metabolism, as an
adaptive response to the environment, may change with exposure time.
Thus, a time-course study of metabolic reprogramming induced by
arsenic based on human internal exposure characteristics (time and
dose) is needed. The lack of a comparable time frame for the experi­
ments and complicated cell-cell interactions in the microenvironment
may help to explain these differences. As mentioned above, the "reverse
Warburg effect" observed in animal models may be caused by lactate
shuttle, transferring lactate from the stroma to cancer cells for utiliza­
tion (Whitaker-Menezes et al., 2011). Therefore, future studies consid­
ering exposure characteristics and more advanced in vitro study systems
(such as coculture and 3D culture) are critical to collect more reliable
data.
3.2. Arsenic exposure and lipid metabolism
Lipids, as important energy storage substances, play a major role in
the energy supply (Long et al., 2018). In addition to aerobic glycolysis,
lipid metabolism has become a key energy source for cancer initiation
and progression (Beloribi-Djefaflia et al., 2016; Zhu et al., 2016). Ar­
senic’s effects in adipose tissue also manifest in increased ectopic lipid
deposition in both the liver and skeletal muscle (Renu et al., 2018). The
incidence of fatty liver was significantly higher in arsenic-exposed
zebrafish (Bambino et al., 2018). Lipid deposition may be due to inhi­
bition of lipid transport and catabolism instead of enhanced lipid syn­
thesis (Table 2) (Fig. 2B).
Arsenic exposure inhibits lipid synthesis. Many lipid synthesis en­
zymes, such as liver X receptors (LXRs), fatty acid synthase (FASN), and
sterol regulatory element-binding protein (SREBP), are inhibited by
arsenic. In arsenite-exposed (5 μM, 72 hours) human hepatocellular
carcinoma cells (HepG2), the mRNA levels of LXR-β and SREBP1c were
decreased (Padovani et al., 2010). In arsenite-exposed human promye­
locytic leukemia cells (HL-60) (5 μM, 48 hours), the expression of FASN
was decreased at the protein level (Lei and Yinsheng, 2010). The protein
expression levels of FASN and SREBP1c were downregulated in the
livers of arsenic-exposed C57BKS/J (3 mg/L, 16 weeks) and C57BL/6J
(100 μg/L, 5 weeks) mice (Adebayo et al., 2015; Liu et al., 2014).
Therefore, much evidence suggests that arsenic exposure suppresses
lipid synthesis.
Arsenic exposure inhibits lipid transport. Arsenite exposure was
associated with significantly downregulated expression of carnitine
palmitoyltransferase (CPT) 1A, a fatty acid beta-oxidation (FAO) rate-
limiting enzyme, and thus accumulation of lipids, leading to malig­
nant transformation in different cell lines (Du et al., 2017; Fang et al.,
2018; Stueckle et al., 2012). CPT1A is a direct target gene of HIF2A (Du
et al., 2017). During arsenite-induced malignant transformation (5 μM,
30 weeks) of HK-2 cells, HIF2A was increased while CPT1A was
decreased at the mRNA level at 20 weeks, which led to cellular lipid
deposition. Thus, it was inferred that chronic arsenite exposure induced
abnormal lipid metabolism through HIF2A/CPT1A and resulted in the
formation of malignant cells with renal clear cell carcinoma (Fang et al.,
2018). In BEAS-2B cells exposed to arsenite (2.5 μM, 6 months),
decreased CPT1A expression at the protein level was associated with
suppression of peroxisome proliferator-activated receptor (PPAR) α,
which is crucial to the formation of tumors (Pirat et al., 2012; Stueckle
et al., 2012). There were similar situations in the low-dose arsenic
exposure in vivo experiments. Under low-dose arsenic exposure (0.5 or
2 mg/L), serum carnitine levels increased in Sprague-Dawley rats (Wang
et al., 2015). However, when the arsenic exposure dose reached
10 mg/L, the opposite results appeared in Sprague-Dawley rats. The
expression level of Cpt2 in the liver was increased, and serum carnitine
levels were decreased (Wang et al., 2015).
The limited existing evidence suggests that arsenic exposure induces
lipid accumulation in some target cells. However, the conclusions are
dramatically different among reports with varied study designs,
including the applied experimental models and treatment protocols.
3.3. Arsenic exposure and amino acid metabolism
Disorders in amino acid metabolism appear to be a general reaction
to a variety of poisons in mammals (Connor et al., 2004). However, there
are few reports on the topic of arsenic and amino acid metabolism.
Experimental investigations concerning the impacts of arsenic exposure
on amino acid metabolism are summarized in Table 3. Arsenic exposure
leads to enhancement of the SGOC pathway and depletion of S-adeno­
sylmethionine (SAM) (Fig. 2C).

Table 2
Effects of arsenic exposure on lipid metabolism.
Subject/model Reagent Dose Expo time Metabolic changes Phenotype References

in vitro
HK-2 NaAsO2 2 or 5 μM 30 weeks Fatty acid ↑, HIF2A ↑, CPT1A ↓ Malignant transformation Fang et al. (2018)
BEAS-2B NaAsO2 2.5 μM 6 months PPARα/δ ↓ Malignant transformation Stueckle et al. (2012)
HepG2 NaAsO2 1, 3 or 5 μM 72 hours LXR-β and SREBP1c ↓ Cholesterol efflux attenuation Padovani et al. (2010)
HL-60 NaAsO2 5 μM 48 hours FASN ↓ Growth inhibition Lei and Yinsheng (2010)
in vivo
C57BL/6 J mice NaAsO2 100 μg/L 5 weeks Liver: SREBP1c, FASN, and LDL receptor↓ Atherosclerosis Adebayo et al. (2015)
(Drinking water)
C57BKS/J mice NaAsO2 3 mg/L 16 weeks Liver: PPARγ ↑; FASN and CD36 ↓ Type 2 diabetes Liu et al. (2014)
(Drinking water) Adipose: CD36, FASN and PPARγ ↑
Sprague-Dawley rats NaAsO2 10 mg/L 3 months Liver: Cpt2 ↑ Metabolic disruption (Wang et al., 2015)
(Drinking water) Serum: carnitine ↓
Sprague-Dawley rats NaAsO2 0.5 or 2 mg/L 3 months Serum: carnitine ↑ Metabolic disruption (Wang et al., 2015)
(Drinking water)

↑ Increase, ↓ decrease.

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Y. Ruan et al. Ecotoxicology and Environmental Safety 229 (2022) 113098

Table 3
Effects of arsenic exposure on amino acid metabolism.
Subject/ Reagent Dose Expo time Metabolic changes Phenotype References
model

in vitro
BEAS-2B NaAsO2 0, 0.25, 0.5,1 or 6 months Serine, glycine and methionine ↑ Malignant Bi et al. (2020)
2 μM transformation
in vivo
Sprague- NaAsO2 0.5, 2, or 10 mg/L 3 months Serum: methionine and SAM ↓ Metabolic Wang et al. (2015)
Dawley rats (Drinking water) disruption
BALB/c mice NaAsO2 3 mg/kg/day 12 days Liver: arginine and tryptophan ↓; cysteine, glutamate, and Metabolic Garcia-Sevillano et al.
(Drinking water) methionine ↑ disruption (2014)
Kidney: arginine ↓
Plasma: arginine ↓; cysteine, glutamate ↑
Wistar rats NaAsO2 10 or 50 mg/L 6 months Serum: L-palmitoylcarnitine ↓ Metabolic Wang et al. (2014)
(Drinking water) disruption
ICR mice NaAsO2 5, 10, or 20 mg/ 24, Serum: valine, leucine, proline, phenylalanine, tryptophan, Metabolic Chen et al. (2017)
kg 48 hours tyrosine, asparagine, glutamate, and arginine ↑ disruption
(Gavage)
Zebrafish Na3AsO4 20 mg/L 96 hours Liver: threonine, glycine, and 2-aminobutanoate ↓ Early liver damages Liu et al. (2014)
(Aquatic
environment)

↑ Increase, ↓ decrease.

Synthetic serine is a vital precursor for the composite of lipids,
proteins and nucleic acids and is essential for cancer proliferation.
Glycine supplies methyls for the one-carbon metabolism that is used in
synthetic lipids, nucleic acids, and proteins, as well as DNA methylation
(Labuschagne et al., 2014). Glycine can be further converted from newly
synthesized serine from 3-phosphoglycerate and imported serine cata­
lyzed by serine hydroxymethyltransferases (SHMTs) (Nikiforov et al.,
2002). The bioactivities of glycine and serine and their associated
metabolic pathways are integral to malignant transformation and rapid
cell proliferation, and play an important role as drivers of cancer initi­
ation and migration (Jain et al., 2012; Locasale, 2013). The SGOC
pathway partially intersects with the glycolysis pathway (Fig. 2). In
arsenite-transformed malignant BEAS-2B cells, the major metabolic in­
termediates in the glycolytic pathway were diverted to glycolytic sub­
pathways, most significantly, the serine-glycine pathway (Bi et al.,
2020). The levels of the metabolites in the SGOC pathway were signif­
icantly upregulated due to increased expression of the metabolic en­
zymes SHMT, phosphoserine aminotransferase (PSAT),
phosphoglycerate dehydrogenase (PHGDH), and glycolate oxidase
(GOX) (Bi et al., 2020). Arsenic-exposed cells seem to prefer enhancing
the uptake and synthesis of growth-essential amino acids (e.g., glycine
and serine) for proliferation (Fig. 2). Variations in the contents of amino
acids, including glycine and serine, in response to arsenic have been
observed in in vivo studies. However, due to the differences in experi­
mental animal species, arsenic concentrations, administration routes,
and exposure times, the reported results are inconsistent and even
contradictory.
SAM is an essential methyl donor for many methyltransferases
(Goering et al., 1999). The biometabolism of arsenic shares SAM with
the DNA methylation process (Goering et al., 1999). The level of SAM in
serum was decreased in arsenite-exposed (10 mg/L, 3 months)
Sprague-Dawley rats (Wang et al., 2015). Therefore, arsenic exposure is
suspected to cause DNA hypomethylation. Hypomethylation of the
promoter regions of the oncogenes c-Myc and c-Hras has been observed
under arsenic-exposed conditions (Takahashi et al., 2002). DNA hypo­
methylation enhances gene expression while hypermethylation sup­
presses it (Zong et al., 2019). Global hypomethylation, which induces
genomic instability, also contributes to cell transformation (Klutstein
et al., 2016). Thus, DNA hypomethylation by depletion of SAM may
contribute to arsenic carcinogenesis under some circumstances.
Activation of SGOC pathway activation and reduced SAM levels have
been found in many cancers. These particular pathways or amino acids
were first studied in response to arsenic exposure probably because they
had been predicted to be changed. SGOC pathway activation is a
considerable part of cancer metabolism (Zhao et al., 2020) and SAM is
the key methyl donor for arsenic biometabolism (Tellez-Plaza et al.,
2014). Available studies on arsenic and amino acids are relatively
limited. In addition, no systematic profile study has been conducted.
4. Link between oxidative stress and metabolic reprogramming
in response to arsenic exposure
Oxidative stress is defined as a disproportionate increase in reactive
oxygen species (ROS) in relation to antioxidant capacity (Hayes et al.,
2020). Excess ROS damage biomolecules including lipids, proteins and
nucleic acids, causing malfunction of the enzymes involved in meta­
bolism, and even cellular injury and cell death (B. Li et al., 2021).
Typically, glucose utilization, fatty acid metabolism, and one-carbon
metabolism are affected by oxidative stress (Assies et al., 2014; Butter­
field and Halliwell, 2019). Oxidative stress caused by arsenic exposure is
suggested as the primary mechanism behind increased cancer risks
(Ganyc et al., 2007). Therefore, it is reasonable to conceive that oxida­
tive modification of enzymes in metabolism gives rise to metabolic
reprograming in arsenic-induced malignancies. However, emerging ev­
idence suggests that exposure to arsenic at human-relevant doses causes
no obvious elevation in intracellular ROS levels (Dodson et al., 2018;
Lau et al., 2013; Wu et al., 2019). Despite these controversial reports, it
is well accepted that oxidative stress occurs in response to arsenic
exposure. On the other hand, certain metabolic pathways or metabolites
are anti-oxidative or pro-oxidative. Up to now, few studies have been
devoted to providing direct links between oxidative stress and metabolic
reprogramming under arsenic-exposed conditions (Hu et al., 2020). To
maintain stable control over ROS production, organisms have evolved a
complex array of defense systems, typically transcriptionally regulated
by NRF2, composed of antioxidants such as GSH and NADPH, and
facilitated by key signaling pathway nodes such as AMPK (Filomeni
et al., 2015; Hayes et al., 2020; Panieri and Santoro, 2016). Meanwhile,
these factors are key to maintaining cell metabolism.
4.1. NADPH and GSH
NADPH and GSH serve as the bridge between oxidative stress and
metabolism (Cioffi et al., 2019). NADPH is a reducing equivalent, which
is utilized by hundreds of reductive enzymes such as glutathione
reductase (GR) as an electron donor to maintain the reduced form
(Miller et al., 2018; Zhang et al., 2019). GSH, one of the prime antiox­
idants, is reversibly oxidized to glutathione disulfide (GSSG) during the
scavenging of ROS. The link between energy production and oxidative

6
Y. Ruan et al. Ecotoxicology and Environmental Safety 229 (2022) 113098

stress becomes evident because GSH is regenerated from GSSG as an 4.1.3. FAO
NADPH-dependent process. NADPH is mainly derived from PPP, FAO is an important source of NADPH. A consistent fraction of the
glycolysis, SGOC, and FAO pathways (Cioffi et al., 2019; Lotocki and acetyl-CoA produced by FAO enters the TCA cycle and generates citrate,
Kakkar, 2020; Meister and Tate, 1976; Panieri and Santoro, 2016). GSH which is therefore exported into the cytosol and funneled into metabolic
maintenance is also closely related to the above four pathways (Fig. 3). reactions catalyzed by malic enzyme (ME) 1 and IDH1, ultimately pro­
ducing large amounts of NADPH (Carracedo et al., 2013). Arsenic was
4.1.1. PPP and glycolysis reported to inhibit the key FAO enzyme CPT1A in HK2 cells, leading to
Arsenic activates the PPP and enhances glycolysis in a variety of cells malignant transformation (Fang et al., 2018). However, more evidence
(Bi et al., 2020; Luo et al., 2017, 2016; Zhao et al., 2013). Glycolytic is needed for the effect of arsenic exposure on FAO regulation and the
intermediates can be shuttled into metabolic pathways that directly or involvement of FAO in arsenic carcinogenesis.
indirectly contribute to the generation of reducing equivalents, mainly
PPP-derived NADPH or glutaminolysis-derived GSH (Panieri and San­
4.2. NRF2
toro, 2016). PPP is a major catabolic pathway of glucose through which
cancer cells produce large amounts of ribose-5-phosphate, a precursor of
NRF2 is a well-known transcription factor regulating antioxidant
nucleotide synthesis and NADPH (Chiara et al., 2012). Thus, NADPH
defense. It is held in the cytoplasm under physiological conditions by
generated by PPP is found at the crossroad between unrestricted pro­
interacting with Kelch-like ECH-associated protein (KEAP) 1 and is
liferation and scavenging of excessive ROS (Patra and Hay, 2014).
subsequently degraded via the ubiquitin–proteasome pathway (Ville­
neuve et al., 2010). Arsenic was found to inhibit the Keap1-dependent
4.1.2. SGOC pathway
E3 ubiquitin ligase by augmenting the association of Keap1 with Cul3,
The SGOC pathway integrates inputs from amino acids (mainly
resulting in NRF2 nuclear translocation and accumulation (Wang et al.,
serine and glycine) and generates multiple carbon units (tetrahy­
2008). Recently, it was indicated that NRF2 activation by a
drofolate (THF) and its derivatives) (Panieri and Santoro, 2016). This
human-relevant dose of arsenic is p62-dependent due to blockade of
pathway has traditionally been associated with cancer cells due to its
autophagic flux (Lau et al., 2013; Wu et al., 2019).
importance in the synthesis of nucleic acids, lipids and proteins in
Once activated, NRF2 transcriptionally regulates genes involved in
proliferating cells. Serine-derived one-carbon units are primarily used
antioxidation (Mitsuishi et al., 2012). With respect to GSH and NADPH,
for nucleotide synthesis (Ducker and Rabinowitz, 2017), while serine is
NRF2 promotes GSH production and regeneration by activating genes
predominantly utilized in the mitochondria of mammalian cells to
encoding glutamate-cysteine ligase catalytic subunit (GCLC),
generate NADPH and stimulate GSH synthesis (Fan et al., 2014). In
glutamate-cysteine ligase modifier subunit (GCLM) and solute carrier
arsenite-transformed malignant BEAS-2B cells, the levels of metabolites,
family 7 member 11 (SLC7A11) (Habib et al., 2015; Shanmugam et al.,
including serine, glycine, and methionine in SGOC pathway were
2016; Yamamoto et al., 2018), and regulates the expression of enzymes
significantly upregulated (Bi et al., 2020). Given the emerging roles of
that synthesize NADPH, such as IDH1, ME1, 6-phosphogluconate de­
metabolic alterations in cancer cells and the intimate connection be­
hydrogenase (PGD), and glucose6-phosphate dehydrogenase (G6PD)
tween the SGOC pathway and redox homeostasis of human tumors, key
(He et al., 2020; Heiss et al., 2013). In addition, NRF2 transcriptionally
nodes in one-carbon metabolism might represent potential preventive
regulates enzymes that catalyze rate-limiting steps or are situated at
targets of carcinogenesis.
branching points in major metabolic pathways, such as G6PD, PGD,
transaldolase (TALDO) 1, and transketolase (TKT) in PPP, MTHFD2 and

Fig. 3. The link between oxidative stress and

metabolic reprogramming in response to
arsenic exposure. GSH, NADPH, NRF2, and
AMPK mediate metabolic reprogramming to
accommodate the disturbed redox status
induced by arsenic. Red lines represent upre­
gulated pathways. Blue lines represent down­
regulated pathways. ACC, acetyl-CoA
carboxylase; AMPK, adenosine 5’-mono­
phosphate-activated protein kinase; ENO,
enolase; GCLC, glutamate-cysteine ligase cata­
lytic subunit; GCLM, glutamate-cysteine ligase
modifier subunit; G6PD, glucose6-phosphate
dehydrogenase; GSH, glutathione; GSSG,
glutathione disulfide; HK, hexokinase; IDH,
isocitrate dehydrogenase; ME, malic enzyme;
MTHFD, methylenetetrahydrofolate dehydro­
genase; NADPH, nicotine adenine dis­
phosphonucleotide; NRF2, nuclear factor
erythroid 2-related factor 2; PGD, 6-phospho­
gluconate dehydrogenase; PGK, phosphoglyc­
erate kinase; PPAT, phosphoribosyl
pyrophosphate amidotransferase; PPP, pentose
phosphate pathway; SGOC, serine-glycine one-
carbon; TALDO, transaldolase; TKT,
transketolase.

7
Y. Ruan et al.
phosphoribosyl pyrophosphate amidotransferase (PPAT) in nucleotide
synthesis, and FASN, acetyl-CoA carboxylase (ACC) 1, stearoyl CoA
desaturase (SCD) 1, and ATP-citrate lyase (ACL) in lipid metabolism (He
et al., 2020; Heiss et al., 2013) (Fig. 3). In the malignant transformation
of BEAS-2B cells, arsenic induced NRF2-dependent activation of HIF1A,
which in turn coordinated with NRF2 for the transcription of genes in
the PPP, glycolysis, and SGOC pathways, enhancing glucose uptake and
NADPH production (Bi et al., 2020; Heiss et al., 2013; Macleod et al.,
2009; Malhotra et al., 2010) (Fig. 3). NRF2 is considered to play a dual
role in cancers. How NRF2 is activated and how NRF2 activation is
involved in arsenic carcinogenesis are still debated. The evolution of
redox status and metabolism in chronic arsenic exposure is probably
coordinated by this particular transcription factor.
4.3. AMPK
Previous examinations have shown that arsenic causes activation of
the cellular energy sensor AMPK (Chanda et al., 2008; Lee et al., 2006).
AMPK maintains NADPH levels by decreasing fatty acid synthesis and
increasing FAO through the inhibition of ACC1/2 (Jeon et al., 2012)
(Fig. 3). Fatty acid synthesis is a major NADPH-consuming process
(Walsh et al., 2018). In contrast, FAO produces NADPH (Carracedo
et al., 2013). FAO activation and FAS inhibition can prevent early stages
but promote late stages of carcinogenesis (Jeon, 2016). This suggests
that AMPK activation is beneficial for cancer prevention. Moreover,
AMPK plays a determinant role in maintaining NADPH homeostasis in
cancer cells upon energy stress, which is critical for cancer cell survival
(Jeon et al., 2012). Thus, caution is needed when considering the role of
AMPK in cancer because it performs both anti- and pro-tumorigenic
roles, depending in part on the regulation of lipid metabolism.
In summary, oxidative stress or redox disturbance induced by long-
term arsenic exposure may participate in metabolic reprogramming
directly or indirectly and may subsequently be involved in carcinogen­
esis. This reminds us of the reciprocal crosstalk between redox homeo­
stasis and metabolism, which requires further study.
5. Conclusion and future perspectives
Metabolic reprogramming is a hallmark of cancer, providing energy
and metabolites to support the rapid growth and proliferation of cancer
cells. Chronic exposure of the cells to arsenic induces malignant trans­
formation. Similar to other cancer cells, arsenic-transformed cells have
an increased need for nutrients, energy, and biosynthetic activities to
produce all macromolecular components. The mechanism of arsenic
carcinogenesis has been a focus of decades. However, little has been
done to determine how changes in metabolism are related to arsenic
carcinogenesis. Arsenic exposure interferes with metabolic transduction
pathways at different levels, including the gene expression, intracellular
protein, protein function, and metabolite levels (Bi et al., 2020; Fang
et al., 2018; Luo et al., 2016; Wu et al., 2019).
Although the role of metabolic reprogramming in arsenic carcino­
genesis has been studied, the full range of influences has yet to be
elucidated and requires further investigation. An in vivo experimental
model for arsenic carcinogenesis has not been well established to date,
and many mechanistic studies have been conducted in vitro. Cell culture
models facilitate the characterization of malignant transformation by
arsenic. However, they have failed to provide information on metabolic
reprogramming with the microenvironment. Therefore, it is imperative
to develop more advanced in vitro study system or appropriate in vivo
models for study. The wide variations in applied concentration, treat­
ment duration, and cell types/tissues have led to inconsistent results and
conclusions. Arsenic-induced tumorigenesis is a chronic process. Only a
small proportion of studies have investigated the metabolic activities
after long-term exposure to arsenic. Studies mimicking the characteris­
tics of arsenic exposure in humans (long-term and internal exposure
doses) should be fully considered in the future. Such studies will provide
8
Ecotoxicology and Environmental Safety 229 (2022) 113098
more reliable information on how metabolism alters and thereby con­
tributes to arsenic carcinogenesis. Moreover, no consistent metabolic
profile for arsenic-induced cancers has been reported because most
previous studies analyzed particular metabolites or metabolic pathways.
The evaluation of globally altered metabolites will help to identify new
candidates and comprehensively target the key metabolic changes in
response to arsenic exposure.
Perhaps by solving the above issues, we will gain insight into the
carcinogenic mechanisms of arsenic and identify the best way to
perform prompt prevention to protect the population exposed to arsenic.
Funding
This work was supported by National Natural Science Foundation of
China (82022063 and 81573187), National Key R&D Program of China
(2018YFC1311600), and Key R&D Plan Guidance Project (2018225098)
from Department of Science and Technology of Liaoning Province,
China.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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