Kang et al.

Genes and Environment (2021) 43:13

https://doi.org/10.1186/s41021-021-00183-5

REVIEW Open Access

Formaldehyde exposure and leukemia risk:

a comprehensive review and network-
based toxicogenomic approach
Doo Seok Kang1, Hyun Soo Kim1, Jong-Hyeon Jung2, Cheol Min Lee3, Yeon-Soon Ahn4 and Young Rok Seo1*

Abstract
Formaldehyde is a widely used but highly reactive and toxic chemical. The International Agency for Research on
Cancer classifies formaldehyde as a Group 1 carcinogen, based on nasopharyngeal cancer and leukemia studies.
However, the correlation between formaldehyde exposure and leukemia incidence is a controversial issue. To
understand the association between formaldehyde exposure and leukemia, we explored biological networks based
on formaldehyde-related genes retrieved from public and commercial databases. Through the literature-based
network approach, we summarized qualitative associations between formaldehyde exposure and leukemia. Our
results indicate that oxidative stress-mediated genetic changes induced by formaldehyde could disturb the
hematopoietic system, possibly leading to leukemia. Furthermore, we suggested major genes that are thought to
be affected by formaldehyde exposure and associated with leukemia development. Our suggestions can be used to
complement experimental data for understanding and identifying the leukemogenic mechanism of formaldehyde.
Keywords: Formaldehyde, Leukemia, Toxicogenomics, Biological network analysis, Carcinogenicity

Background outdoors due to the widespread use of products contain-

Formaldehyde is a colorless, pungent-smelling, and ing formaldehyde [3]. The World Health Organization
highly reactive chemical with toxic properties. As the recommends an indoor limit of formaldehyde of 0.1 mg/
simplest aldehyde form (H-CHO), formaldehyde is syn- m3 (0.08 ppm) [4]. Occupational exposure to formalde-
thesized by the catalytic oxidation of methanol. It is also hyde is variable and occurs in numerous industries, in-
easily dissolved in water; a 37% formaldehyde solution is cluding manufacturing [5]. Small amounts of
used as a preservative, pesticide, and disinfectant. For- formaldehyde are naturally generated in living organisms
maldehyde is manufactured commercially and used ex- through normal metabolic processes, such as DNA/
tensively in many products, such as resins, plastics, RNA/histone demethylation and oxidative deamination
textiles, wood products, adhesives, medicines, and cos- [6]. The concentration of endogenous formaldehyde in
metics [1]. The predominant route of formaldehyde ex- the blood of humans is approximately 2–3 mg/L (0.1
posure is inhalation occurring during environmental and mM) [7]. Therefore, many people are constantly exposed
occupational exposure [2]. Environmental exposure to to formaldehyde, in large or small quantities, in their
formaldehyde occurs more frequently indoors than daily lives because of its ubiquitous nature.
Exogenous formaldehyde exposure is commonly asso-
ciated with eye and upper respiratory tract irritation.
* Correspondence: seoyr@dongguk.edu
1
Department of Life Science, Institute of Environmental Medicine for Green
Formaldehyde is genotoxic and cytotoxic, inducing DNA
Chemistry, Dongguk University Biomedi Campus, 32 Dongguk-ro, damage and chromosomal changes [8]. Increased gen-
Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Republic of Korea omic instability from genotoxic chemicals can increase
Full list of author information is available at the end of the article

© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
Kang et al. Genes and Environment (2021) 43:13 Page 2 of 10

the risk of cancer [9–12]. Formaldehyde is classified as a micronucleus formation, sister chromatid exchanges,
human carcinogen (Group 1) by the International and chromosome aberrations in peripheral lymphocytes
Agency for Research on Cancer (IARC), based on studies and nasal mucosa were observed during human occupa-
of nasopharyngeal cancer and leukemia [13]. However, tional studies on formaldehyde exposure [30–32]. Sig-
studies on the causal relationship between formaldehyde nificant changes in the percentage of B cells, cytotoxic T
exposure and leukemia development are controversial, cells, and natural killer cells were found, and genetic
with conflicting results [14]. polymorphisms in metabolic and DNA repair genes were
Advances in molecular biology and bioinformatics associated with increased genetic damages in subjects
have led to the development of disciplines that focus on exposed to formaldehyde [33–35]. Exogenous and en-
the organization and analysis of large-scale biological dogenous formaldehyde can induce N2-hydroxymethyl-
data [15, 16]. Toxicogenomics (a combination of toxicol- dG adducts [36]. In vitro studies showed induction of
ogy and genomics) is a field that studies genomic re- DNA–protein crosslinks (DPCs) by formaldehyde expos-
sponses to xenobiotic exposures [17, 18]. ure in white blood and nasal epithelial cells [37, 38]. In
Toxicogenomics provides information on the effects of addition, DPCs in white blood cells were higher in
toxicant exposure on humans, ranging from genetic al- workers exposed to formaldehyde than in non-exposed
terations to disease, based on a genetic profile, with the workers [37, 39]. As the early lesions in the process of
goal of identifying biomarkers and toxicity mechanisms carcinogenesis, the level of DPCs is considered a bio-
using high-throughput technologies [19–21]. Many pub- marker of formaldehyde exposure [37, 39]. These geno-
lic resources on chemical–gene–disease interactions and toxic effects are the potential carcinogenic mode of
other toxicogenomic information can be easily accessed action for formaldehyde [5, 27].
[22]. The macroscopic integration of existing knowledge
can result from big data utilization, leading to new per- Association between formaldehyde exposure and leukemia
spectives on intricate biological interactions. In this re- incidence
view, we discuss the carcinogenicity of formaldehyde in Although the carcinogenicity of formaldehyde as a con-
relation to leukemia through a toxicogenomic approach. sequence of chronic exposure has been indicated [13],
Using public and commercial databases, we explore bio- the biological mechanisms by which formaldehyde in-
logical networks to better understand the association be- duces cancer are not completely understood. The associ-
tween formaldehyde exposure and leukemia ation between formaldehyde exposure and the
development. occurrence of leukemia is especially disputable. After
examining the data from various epidemiological and
Review animal studies, the IARC concluded that there is “strong
Carcinogenicity of formaldehyde but not sufficient evidence” that formaldehyde causes
In the early 1980s, findings from studies on nasal tumors leukemia [13]. Three large industrial cohort studies [40–
in rats exposed to formaldehyde provoked concern 42] notably influenced the interpretation of other studies
about its carcinogenicity [23–25]. Diverse chronic and on formaldehyde exposure and leukemia, and positive
sub-chronic rodent studies provided sufficient evidence associations were observed in the two cohort studies [41,
that inhalation and oral administration routes of formal- 42]. Coggon et al. investigated a cohort of 14,014
dehyde exposure induce cancer [13]. Furthermore, workers at six British factories where formaldehyde was
concentration-dependent increases of formaldehyde on produced or used, and they observed no association [40].
tumor incidence and cell proliferation were demon- Hauptmann et al. retrospectively analyzed the data from
strated [26, 27]. The association between formaldehyde a study undertaken by the NCI that included 25,619
and the development of cancers was also reported in workers at 10 U.S. industrial plants that used or pro-
many epidemiological studies [13]. At the National Can- duced formaldehyde [41]. Pinkerton et al. conducted a
cer Institute (NCI), Hauptmann et al. conducted the lar- study for the National Institute for Occupational Safety
gest epidemiological study on occupational exposure to and Health that included 11,039 workers in three gar-
formaldehyde and found a statistically significant in- ment plants where formaldehyde resins were used in
crease in death from nasopharyngeal cancer [28]. Based fabric processing [42]. These three original studies and
on the comprehensive results of large-scale human and their updated versions are summarized in Table 1 [40–
animal studies, the IARC concluded that formaldehyde 45]. A review of the recent study findings that included
causes nasopharyngeal cancer and leukemia and is posi- an extended follow-up period after 10 years or more
tively associated with sinonasal cancer [13]. showed that the risk of leukemia tended to decrease.
Formaldehyde can react with DNA, and in the major- Some case-control studies evaluated the risk of lympho-
ity of studies, it displays genotoxicity during mutation hematopoietic malignancies, but no significant elevations
tests in vitro and in vivo [29]. Increased DNA damage, of leukemia risk were found [46–49]. Among these
Kang et al. Genes and Environment (2021) 43:13 Page 3 of 10

Table 1 Summary of large cohort studies about formaldehyde and leukemia

Author Cohort descriptions Results (95% CI) Comments
Coggon et al. [40] 14,014 workers at factories Leukemia: 31 deaths All subjects
1941–2000 SMR 0.91 (0.62–1.29) High exposure ≥2.0 ppm group
Leukemia: 8 deaths
SMR 0.71 (0.31–1.39)
Coggon et al. [43] Update of Coggon et al. Leukemia: 54 deaths All subjects
1941–2012 SMR 1.02 (0.77–1.33) High exposure ≥2.0 ppm group
Myeloid Leukemia: 36 deaths
SMR 1.20 (0.84–1.66)
Leukemia: 13 deaths
SMR 0.82 (0.44–1.41)
Myeloid Leukemia: 8 deaths
SMR 0.93 (0.40–1.82)
Hauptmann et al. [41] 25,619 workers at factories Leukemia: 29 deaths Peak exposure ≥4.0 ppm group
1966–1994 RR 2.46 (1.31–4.62) Compared low peak exposure
Myeloid Leukemia: 14 deaths (0.1–1.9 ppm)
RR 3.46 (1.27–9.43) 35 years of median length of
follow-up
Beane Freeman et al. [44] Update of Hauptmann et al. Leukemia: 48 deaths Peak exposure ≥4.0 ppm group
1966–2004 RR 1.42 (0.92–2.18) 42 years of median length of
Myeloid Leukemia: 19 deaths follow-up
RR 1.78 (0.87–3.64)
Pinkerton et al. [34] 11,039 garment workers Leukemia: 15 deaths The mean TWA exposure 0.15 ppm
1955–1998 SMR 1.92 (1.08–3.17) Multiple cause mortality from
Myeloid Leukemia: 8 deaths leukemia and myeloid leukemia
SMR 2.55 (1.10–5.03) 10+ years exposure and 20+ years
since the first exposure
Meyers et al. [45] Update of Pinkerton et al. Leukemia: 23 deaths Multiple cause mortality from
1955–2008 SMR 1.74 (1.10–2.60) leukemia and myeloid leukemia
Myeloid Leukemia: 10 deaths 10+ years exposure and 20+
SMR 1.90 (0.91–3.50) years since the first exposure
CI Confidence interval, SMR Standardized mortality ratio, RR Relative risk, TWA Time-weighted average

studies, Linos et al. showed a significantly elevated risk potential mechanisms for formaldehyde-induced
for acute myeloid leukemia (AML) among employees in leukemia: direct damage to stem cells in the bone mar-
funeral homes and crematories when age and state of row through the blood, damage to hematopoietic stem/
residence were adjusted (three exposed cases, odds ra- progenitor cells circulating in the blood, and damage to
tio = 6.7, 95% confidence interval = 1.2–36.2) [47]. primitive pluripotent stem cells present within nasal or
Hauptmann et al. also reported a significantly increased oral passages [8]. Considering that formaldehyde and its
risk for myeloid leukemia among funeral industry metabolic pathway exist naturally in all cells, it is likely
workers who performed embalming for more than 34 that formaldehyde toxicity occurs as a result of high
years compared to subjects who performed embalming concentration exposure that overwhelms normal meta-
less than 500 times (14 exposed cases, odds ratio = 3.9, bolic capacities [29]. As a basis for the occurrence of
95% confidence interval = 1.2–12.5, p = 0.024) [50]. distant-site toxicity, several studies were undertaken to
Other epidemiological studies, meta-analyses, and re- estimate increased formaldehyde concentrations in the
evaluations of previous studies showed inconsistent find- blood due to formaldehyde exposure. Significant effects
ings on the association between formaldehyde and of formaldehyde exposure were not observed in the
leukemia [2, 8, 13, 51–53]. blood of humans exposed to 1.9 ppm for 40 min, rats ex-
There is debate on the biological plausibility of posed to 14.4 ppm for 2 h [7], or in rhesus monkeys ex-
whether formaldehyde can induce distant-site toxicity, as posed to 6 ppm for 6 h/day, 5 days/week for 4 weeks
formaldehyde is rapidly metabolized and highly reactive, [55]. The failure of exogenous formaldehyde to increase
and its toxicity is generally limited to the local exposure formaldehyde levels in the blood decreases the likelihood
site [5, 54]. Therefore, it would be valuable to demon- that formaldehyde directly affects the bone marrow.
strate the formaldehyde-induced leukemogenic traits, Other studies used radiolabeled formaldehyde to exam-
such as 1) exogenous formaldehyde can reach the bone ine its systemic toxicity in distant sites. Rats exposed to
marrow, 2) formaldehyde can induce hematopoietic tox- up to 15 ppm of 14C- and 3H-formaldehyde for 6 h did
icity, and 3) leukemia occurs in animal models exposed not show an increase in covalent adducts in the bone
to formaldehyde [29]. Zhang et al. suggested three marrow [56]. Rats lacking glutathione, required for
Kang et al. Genes and Environment (2021) 43:13 Page 4 of 10

formaldehyde oxidation, also did not show an increase results, indirect or unknown effects of formaldehyde may
in covalent adducts in bone marrow following formalde- cause toxicity at the distant site, including bone marrow.
hyde inhalation [57]. In rats and non-human primates, Alterations in the genes related to leukemia development
exogenous DNA adducts formed by inhaled 13CD2-for- caused by formaldehyde exposure would be key events in
maldehyde were found only in the nasal epithelium and converting a hematopoietic stem cell into a leukemic stem
not in the bone marrow and peripheral blood cells (rats: cell and subsequent disease development [8, 73].
10 ppm, 1 or 5 days; 2 ppm, 7–28 days; 15 ppm, 1–4 days; Inconsistency of results from numerous studies about
monkeys: 6 ppm, 2 days) [36, 58–60]. These studies con- formaldehyde exposure and leukemia demonstrates the
cluded that exogenous formaldehyde does not cause need to consider the effects of individual genetic back-
distant-site toxicity beyond the portal of entry. Although grounds, interspecies differences, and exposure concen-
the exposure periods tend to be short, these results show tration and duration, as the expression of a phenotype
that Zhang et al.’s hypothesized modes of action of can differ between individuals equally exposed to a toxi-
formaldehyde-induced leukemia might be unlikely [14]. cant [74–77]. In this regard, to help better understand
In contrast, some animal studies reported an increased this complexity, we applied a novel approach that uti-
incidence of hematological malignancies or toxicity in lizes genomic data in order to summarize the association
bone marrow following formaldehyde exposure. The in- between formaldehyde and leukemia. In the summariz-
cidence of lymphoma in mice exposed to 14.3 ppm for 2 ing process, we additionally suggest specific genes as po-
years was slightly increased (p = 0.06), and survival- tential biomarker candidates with strong links to
adjusted undifferentiated leukemia in rats was increased formaldehyde exposure and leukemia development.
(p < 0.0167) [24]. Hematopoietic tumors in high-dose
oral-exposed rats [61] and clastogenic and cytogenetic Formaldehyde-related genomic resources
effects on the bone marrow in rats exposed to low con- With the development of bioinformatics, approaches
centrations of formaldehyde (0.5 or 1.5 mg/m3) were ob- that utilize existing data to elucidate biological phenom-
served [62]. However, there were questions regarding ena are widely used. Biological databases manage diverse
the data reliability of these studies, and other studies data types, such as DNA, RNA, proteins, diseases, path-
contradicted the results [29, 54]. Recent animal studies ways, and literature studies [78]. The active use of data-
designed to simulate human occupational exposures re- bases can provide new perspectives on human-related
ported bone marrow toxicities induced by formaldehyde, studies, such as biomarker identification, prediction of
suggesting potential toxic mechanisms via oxidative human health effects, early diagnosis of disease, and
stress. Mice exposed to up to 3 mg/m3 formaldehyde (8 drug development [79, 80]. To explore the association
h/day for 7 days) by nose-only inhalation exhibited a sig- between formaldehyde exposure and leukemia through
nificant dose-dependent increase in reactive oxygen spe- molecular network analysis, we searched formaldehyde-
cies and DPCs and a decrease of glutathione in distant related genes from public and commercial databases.
organs, including bone marrow [63]. Under a similar ex- The Comparative Toxicogenomics Database (CTD) is
posure condition for 2 weeks, there was a significant de- a publicly available database that provides information
crease in the counts of leucocytes, erythrocytes, and about the human health effects of chemicals (http://
lymphocytes and bone marrow toxicity induced via oxi- ctdbase.org/). Its core contents include various chem-
dative stress, inflammation, and apoptosis [64, 65]. Fur- ical–gene–disease interactions manually curated from
thermore, whole-body inhalation of 3 mg/m3 in mice the literature [22]. These data are not only internally in-
decreased nucleated bone marrow cells and colony for- tegrated with each other but also with external datasets
mation from bone marrow stem/progenitor cells, in- in order to expand networks and predict novel infer-
creasing oxidative stress [66, 67]. In mice exposed to ences. Pathway Studio (version 12.3; Elsevier,
formaldehyde (20, 40, and 80 mg/m3) for 15 days (2 h/ Netherlands) is a commercially available text mining-
day), bone marrow toxicities (pathological changes, de- based biological network analysis software that enables
creased activity of antioxidants, increased micronucleus, researchers to explore molecular interactions of diverse
DNA damage, and malondialdehyde) and expression biological processes and visualize this information by in-
changes in Prx, Mpo, Bax, Bcl-2, and Cycs protein were tegrating knowledge from millions of scientific publica-
observed [68, 69]. Deficiencies of the genes Aldh2, Adh5, tions [81]. Through the keyword search in CTD and the
and Fancd2, which detoxify endogenous formaldehyde, Pathway Studio database, we retrieved 3927 and 416
led to hematotoxicity and leukemia in mice [70, 71]. formaldehyde-related genes, respectively (accessed 1 Oct
Interestingly, studies showing bone marrow toxicity 2020). We then identified 122 common genes affected
caused by formaldehyde were mainly conducted in mice, by exogenous formaldehyde exposure in both databases
an important consideration in light of the interspecies through the examination of the original papers (Supple-
differences in exposure effects [72]. Based on these mentary materials).
Kang et al. Genes and Environment (2021) 43:13 Page 5 of 10

Possibility of oxidative stress-mediated leukemia exposure and other entities to distinguish any inaccurate
development reference information that the text mining technique
Network-based approaches are widely used to elucidate could have produced; for example, are the associations
dynamic biological interactions [82, 83]. The greatest ad- negative or positive simply based on the number of ref-
vantage of molecular network analysis is that it can be erences? Do the studies come primarily from one re-
used to determine interactions among multiple factors search group? However, our current analysis could not
that affect a correlation, based on a vast scientific litera- distinguish conflicting interests among research groups.
ture, instead of focusing on one-dimensional relation- As a result of this detailed literature-based prediction,
ships among a small number of factors. To infer the we hypothesize that formaldehyde can induce the devel-
association between formaldehyde exposure and opment of leukemia by disturbing the normal differenti-
leukemia incidence, we explored key molecular networks ation process of hematopoietic stem cells through the
for the 122 common genes using the Pathway Studio induction of dysfunctions in major genes via oxidative
software. Pathway Studio presents biological relations stress. Furthermore, it is predicted that formaldehyde
through the connectivity (edge) among the entities could interfere with the function of antioxidant enzymes
(nodes), such as genes, cell processes, diseases, or chemi- in the bone marrow and lymphocytes. Alterations of
cals. The relation is determined using reference sen- genes GSTT1 and GSTP1 that inhibit oxidative stress
tences extracted from the scientific literature and the [84] were associated with leukemia, especially AML. The
number of references [81]. Therefore, our network ap- expression changes in these genes were also identified in
proach sums up the existing knowledge known between the bone marrow of mice that inhaled formaldehyde and
formaldehyde and leukemia. rats’ white blood cells, respectively [64, 85]. Abnormal
The biological interactions of the 122 genes associated lymphocytes are a major feature of lymphohematopoietic
with hematological malignancies and cell processes were malignancies [86, 87]. To support the reliability of the
initially predicted (Fig. 1, Supplementary materials). For networks, we categorized the top diseases and biological
the minimal academic credibility, only relations con- functions of selected genes in Fig. 1 using Ingenuity
firmed by more than three references were considered. Pathway Analysis (Qiagen, Germany), a popular bio-
Subsequently, the criteria of the number of references informatics analysis software (Supplementary Table 1).
were adjusted, considering the total connectivity on each Selected formaldehyde-related genes were associated
entity (i.e., the total amount of relations) in the Pathway with cancer and hematological system development and
Studio database (1 reference per 1000 connectivity) to function. Especially, we suggest major genes that are
reduce the bias of analysis from interactions that have worth considering when attempting to identify the links
been more intensively studied. We selected between formaldehyde exposure and leukemia (Table 2).
formaldehyde-related hematological malignancies by re- Several studies reported that formaldehyde induces ex-
ferring to epidemiological data in the IARC report pub- pression changes in TP53 and BCL2, responsible for
lished in 2012 [13]. The relation types of “Quantitative regulating apoptotic mechanisms [88–90]. Abnormal
Change,” “Genetic Change,” and “Regulation” between apoptosis due to formaldehyde exposure may lead to un-
genes and diseases were analyzed (Fig. 1a). These genes regulated self-renewal of hematopoietic stem/progenitor
were associated with many subtypes of leukemia, lymph- cells [66, 91]. The BAX/BCL2 ratio has clinical signifi-
oma, and myeloma (AML, chronic myeloid leukemia, cance in leukemias [92]. Furthermore, DNMT3A, which
acute lymphoblastic leukemia, chronic lymphocytic is regulated by TP53, is frequently mutated in AML and
leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, other hematological malignancies [93], and a decrease in
myelodysplastic syndrome, etc.). Figure 1b shows that DNMT3A expression by formaldehyde exposure sug-
these genes regulate the cell processes associated with gested that formaldehyde has hypomethylation effects
the genotoxic and cytotoxic effects of formaldehyde. Our [94, 95]. In various leukemic disease studies, TNF ex-
prediction suggests that exposure to formaldehyde in- pression was increased and associated with poor progno-
creases the generation of reactive oxygen species and in- sis [96–98]. Therefore, identifying the changes in major
duces oxidative stress and DNA damage, resulting in genes in the hematopoietic system caused by prolonged
cytotoxicity and an increased cancer risk caused by ab- exposure to formaldehyde will be valuable in under-
normal cell proliferation and differentiation. Addition- standing the leukemogenic mechanism.
ally, a detailed review summarized in Fig. 2 was Utilizing a literature-based network approach, we ex-
conducted by screening major genes, cell processes, and plored qualitative associations between formaldehyde
leukemic diseases with many interactions in the network and comprehensive leukemia. It was also predicted that
to determine their influence on the hematopoietic sys- altered gene expression or mutation triggered by oxida-
tem. We carefully examined the reliability of references tive stress because of formaldehyde exposure could dis-
regarding the correlation between formaldehyde turb the hematopoietic system and lead to an increased
Kang et al. Genes and Environment (2021) 43:13 Page 6 of 10

Fig. 1 Biological interactions among the formaldehyde-related genes, a hematological malignancies, and b cell processes. The molecular network
analysis was conducted using Pathway Studio software (version 12.3). The relations between genes/proteins and other entities (disease and cell
process) were analyzed. The schematic legend is located to the left

risk of malignant hematopoietic diseases. Given that the Epo, Cyp1a1, and Gstt1) and protein expression changes
biological plausibility of distant-site toxicity by formalde- (Csf2ra, Epo, Epor, Bax, Bcl2, Mpo, and Prx2) in the bone
hyde inhalation is a key point in elucidating the possibility marrow of mice that inhaled formaldehyde [64, 66–69].
of leukemogenesis [14], we also examined our toxicoge- The cytokine levels of TNF-α and IL-1β were increased in
nomic data for genes/proteins that showed activity the bone marrow of formaldehyde-exposed mice [64]. The
changes at distant sites following formaldehyde inhalation. polymorphisms in GSTP1 and PARP1 genes were related
Low concentrations of inhaled formaldehyde increased to increased genetic damage in peripheral blood lympho-
PDGFRA and MDM2 gene expressions in human periph- cytes of formaldehyde-exposed subjects [34]. Although
eral lymphocytes of the residents of new apartments [99]. not all genes in our toxicogenomic data reflect distant-site
It was also shown that TXN gene expression decreased in toxicity, some genes associated with leukemic diseases
human blood for subjects under controlled conditions showed altered expression at distant sites following for-
[100]. Gene expression changes in Gpx3, Gstp1, Odc1, maldehyde exposure. Based on these findings, indirect or
Polr2a, Ptgs1, and Rps6ka5 were identified in white blood unknown leukemia-inducing mechanisms caused by for-
cells of rats exposed to 2 ppm formaldehyde [85]. In maldehyde on the hematopoietic system cannot be ruled
addition, we identified gene expression changes (Atm, out.
Kang et al. Genes and Environment (2021) 43:13 Page 7 of 10

Fig. 2 The summarized network of the potential leukemogenic mechanism via oxidative stress. The interactions between selected entities with
many associations in previous network analyses and leukemia-related entities were analyzed

Conclusions formaldehyde-related genes retrieved from public and

In this review, we explored the controversial association commercial databases to help understand the association
between exposure to the carcinogen formaldehyde and between formaldehyde and leukemia. Our literature-
the incidence of leukemia. Although there are inconsist- based prediction suggests a potential leukemia-inducing
ent results on this topic, recent studies reported the mechanism of formaldehyde via oxidative stress, as well
bone marrow or hematopoietic toxicity by formaldehyde as major genes associated with formaldehyde and
[65–67]. We analyzed biological networks among leukemia. Validation of these genes should be performed

Table 2 Formaldehyde and leukemia related major gene descriptions

Gene Functional Cell process Disease
class
BCL2 SOD Angiogenesis, Apoptosis, DNA damage, ALL, AML, CLL, CML, Hematologic neoplasm, Hematopoietic system
Hemopoiesis, Inflammatory response, Oxidative malignancy, Hodgkin’s disease, Leukemia, Lymphoma, Multiple
stress myeloma, Myelodysplastic syndrome, Myeloid leukemia, non-
Hodgkin’s lymphoma
DNMT3A Apoptosis, DNA methylation, Hemopoiesis, ALL, AML, CLL, CML, Hematologic neoplasm, Hematopoietic system
Inflammatory response malignancy, Leukemia, Lymphoma, Myelodysplastic syndrome,
Myeloid leukemia, Myeloproliferative disorder
TNF GPx, SOD Angiogenesis, Apoptosis, DNA damage, ALL, AML, CLL, CML, Hodgkin’s disease, Leukemia, Lymphoma, Multiple
Hemopoiesis, Inflammatory response, Oxidative myeloma, Myelodysplastic syndrome, non-Hodgkin’s lymphoma
stress
TP53 SOD Angiogenesis, Apoptosis, DNA damage, DNA ALL, AML, Bone marrow failure, CLL, CML, Hematologic neoplasm,
methylation, Hemopoiesis, Inflammatory response, Hematopoietic system malignancy, Hodgkin’s disease, Leukemia,
Oxidative stress Lymphoid leukemia, Lymphoma, Multiple myeloma, Myelodysplastic
syndrome, Myeloid leukemia, Myeloproliferative disorder, non-
Hodgkin’s lymphoma
SOD Superoxide dismutase, ALL Acute lymphoblastic leukemia, AML Acute myeloid leukemia, CLL Chronic lymphocytic leukemia, CML Chronic myeloid leukemia,
GPx Glutathione peroxidase
Kang et al. Genes and Environment (2021) 43:13 Page 8 of 10

in further studies. To better understand the leukemo- Republic of Korea. 3Department of Chemical and Biological Engineering,
genicity of formaldehyde, reproducible experiments that College of Natural Science and Engineering, Seokyeong University, Seoul
02173, Republic of Korea. 4Department of Preventive Medicine and Institute
determine the causality are needed. Important factors, of Occupational and Environmental Medicine, Wonju College of Medicine,
such as individual genetic backgrounds, interspecies dif- Yonsei University, Wonju, Gangwon 26426, Republic of Korea.
ferences, and exposure degree, should be considered.
Received: 16 August 2020 Accepted: 19 March 2021
Further studies that correctly evaluate the distant-site
toxicity utilizing well-designed genomic data to simulate
prolonged occupational exposure will also be needed. References
Nevertheless, the possibility of other perspectives, such 1. Agency for Toxic Substances and Disease Registry. Toxicological Profile for
as aberrant activation of major genes and signaling path- Formaldehyde. https://www.atsdr.cdc.gov/toxprofiles/tp111.pdf. Accessed 1
June 2020.
ways, is also worth considering. Our approach can be 2. Checkoway H, Boffetta P, Mundt DJ, Mundt KA. Critical review and synthesis
used to complement experimental data for elucidating of the epidemiologic evidence on formaldehyde exposure and risk of
the effects of genetic factors and can be applied in the leukemia and other lymphohematopoietic malignancies. Cancer Causes
Control. 2012;23(11):1747–66. https://doi.org/10.1007/s10552-012-0055-2.
identification of new mechanisms and biomarkers. 3. Kim KH, Jahan SA, Lee JT. Exposure to formaldehyde and its potential
human health hazards. J Environ Sci Health C Environ Carcinog Ecotoxicol
Abbreviations Rev. 2011;29:277–99.
ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; 4. World Health Organization. WHO Guidelines for Indoor Air Quality: Selected
CI: Confidence interval; CLL: Chronic lymphocytic leukemia; CML: Chronic pollutants. Copenhagen: World Health Organization, Regional Office for
myeloid leukemia; CTD: Comparative Toxicogenomics Database; Europe; 2010. p. 103–56. ISBN 9789289002134
GPx: Glutathione peroxidase; IARC: International Agency for Research on 5. National Toxicology Program. Final report on carcinogens background
Cancer; IPA: Ingenuity Pathway Analysis; NCI: National Cancer Institute; document for formaldehyde. Rep Carcinog Backgr Doc. 2010;10:i–512.
OR: Odds ratio; RR: Relative risk; SMR: Standardized mortality ratio; 6. Reingruber H, Pontel LB. Formaldehyde metabolism and its impact on
SOD: Superoxide dismutase; TWA: Time-weighted average human health. Curr Opinion Toxicol. 2018;9:28–34. https://doi.org/10.1016/j.
cotox.2018.07.001.
Supplementary Information 7. Heck HD, Casanova-Schmitz M, Dodd PB, Schachter EN, Witek TJ, Tosun T.
The online version contains supplementary material available at https://doi. Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-
org/10.1186/s41021-021-00183-5. 344 rats exposed to CH2O under controlled conditions. Am Ind Hyg Assoc
J. 1985;46(1):1–3. https://doi.org/10.1080/15298668591394275.
8. Zhang L, Steinmaus C, Eastmond DA, Xin XK, Smith MT. Formaldehyde
Additional file 1. exposure and leukemia: a new meta-analysis and potential mechanisms.
Additional file 2. Mutat Res. 2009;681(2-3):150–68. https://doi.org/10.1016/j.mrrev.2008.07.002.
9. Miller EC, Miller JA. Mechanisms of chemical carcinogenesis. Cancer. 1981;
47(S5):1055–64. https://doi.org/10.1002/1097-0142(19810301)47:5+<1055:A
Acknowledgements ID-CNCR2820471302>3.0.CO;2-3.
Not applicable. 10. Oliveira PA, Colaco A, Chaves R, Guedes-Pinto H, De-La-Cruz PL, Lopes C.
Chemical carcinogenesis. An Acad Bras Cienc. 2007;79(4):593–616. https://
Authors’ contributions doi.org/10.1590/S0001-37652007000400004.
DSK and HSK collected and analyzed data. DSK wrote the manuscript. JHJ, 11. Cohen SM, Arnold LL. Chemical Carcinogenesis. Toxicol Sci. 2010;120:S76–
CML, and YSA reviewed and revised the manuscript. YRS supervised the 92.
entire processes. All authors read and approved the final manuscript. 12. Kang DS, Yang JH, Kim HS, Koo BK, Lee CM, Ahn YS, et al. Application of the
adverse outcome pathway framework to risk assessment for predicting
Funding carcinogenicity of chemicals. J Cancer Prev. 2018;23(3):126–33. https://doi.
This study was supported Korea Environment Industry & Technology Institute org/10.15430/JCP.2018.23.3.126.
(KEITI) through The Chemical Accident Prevention Technology Development 13. International Agency for Research on Cancer. Chemical agents and related
Program, funded by Korea Ministry of Environment (MOE) (2017001970001) occupations. IARC Monogr Eval Carcinog Risks Hum. 2012;100:9–562.
and (2018001350006). 14. Andersen ME, Gentry PR, Swenberg JA, Mundt KA, White KW, Thompson C,
et al. Considerations for refining the risk assessment process for
Availability of data and materials formaldehyde: results from an interdisciplinary workshop. Regul Toxicol
Not applicable. Pharmacol. 2019;106:210–23. https://doi.org/10.1016/j.yrtph.2019.04.015.
15. Rim KT. Adverse outcome pathways for chemical toxicity and their
Declarations applications to workers’ health: a literature review. Toxicol Environ Health
Sci. 2020;12(2):99–108. https://doi.org/10.1007/s13530-020-00053-7.
Ethics approval and consent to participate 16. Rim KT. In silico prediction of toxicity and its applications for chemicals at
Not applicable. work. Toxicol Environ Health Sci. 2020;12(3):191–202. https://doi.org/10.1
007/s13530-020-00056-4.
Consent for publication 17. Koedrith P, Kim H, Weon JI, Seo YR. Toxicogenomic approaches for
All authors have read the manuscript and approved its submission and understanding molecular mechanisms of heavy metal mutagenicity and
publication. carcinogenicity. Int J Hyg Environ Health. 2013;216(5):587–98. https://doi.
org/10.1016/j.ijheh.2013.02.010.
Competing interests 18. Rim K-T, Kim S-J. A toxicogenomics study of two chemicals in coffee roasting process.
The authors declare that they have no competing interests. Mol Cell Toxicol. 2020;16(1):25–38. https://doi.org/10.1007/s13273-019-00055-8.
19. Ancizar-Aristizábal F, Castiblanco-Rodríguez AL, Márquez DC, Rodríguez AI.
Author details Approaches and perspectives to toxicogenetics and toxicogenomics. Revista
1
Department of Life Science, Institute of Environmental Medicine for Green de la Facultad de Medicina. 2014;62:605–15.
Chemistry, Dongguk University Biomedi Campus, 32 Dongguk-ro, 20. Koh EJ, Hwang SY. Multi-omics approaches for understanding
Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Republic of Korea. 2Faculty of environmental exposure and human health. Mol Cell Toxicol. 2019;15(1):1–7.
Health Science, Daegu Haany University, Gyeongsan, Gyeongbuk 38610, https://doi.org/10.1007/s13273-019-0001-4.
Kang et al. Genes and Environment (2021) 43:13 Page 9 of 10

21. Kang M-J, Lee M-Y. Toxicoproteomic analysis of deltamethrin exposure in industries. J Natl Cancer Inst. 2003;95(21):1615–23. https://doi.org/10.1093/
neuroblastoma cell lines. Mol Cell Toxicol. 2020;16(1):93–101. https://doi. jnci/djg083.
org/10.1007/s13273-019-00064-7. 42. Pinkerton LE, Hein MJ, Stayner LT. Mortality among a cohort of garment
22. Davis AP, Grondin CJ, Johnson RJ, Sciaky D, King BL, McMorran R, et al. The workers exposed to formaldehyde: an update. Occup Environ Med. 2004;
comparative Toxicogenomics database: update 2017. Nucleic Acids Res. 61(3):193–200. https://doi.org/10.1136/oem.2003.007476.
2017;45(D1):D972–8. https://doi.org/10.1093/nar/gkw838. 43. Coggon D, Ntani G, Harris EC, Palmer KT. Upper airway cancer, myeloid
23. Swenberg JA, Kerns WD, Mitchell RI, Gralla EJ, Pavkov KL. Induction of leukemia, and other cancers in a cohort of British chemical workers exposed
squamous cell carcinomas of the rat nasal cavity by inhalation exposure to to formaldehyde. Am J Epidemiol. 2014;179(11):1301–11. https://doi.org/10.1
formaldehyde vapor. Cancer Res. 1980;40(9):3398–402. 093/aje/kwu049.
24. Battelle Columbus Laboratories. Final report on a chronic inhalation 44. Beane Freeman LE, Blair A, Lubin JH, Stewart PA, Hayes RB, Hoover RN, et al.
toxicology study in rats and mice exposed to formaldehyde. Research Mortality from lymphohematopoietic malignancies among workers in
Triangle Park: Chemical Industry Institute of Toxicology; 1981. formaldehyde industries: the National Cancer Institute cohort. J Natl Cancer
25. Kerns WD, Pavkov KL, Donofrio DJ, Gralla EJ, Swenberg JA. Carcinogenicity Inst. 2009;101(10):751–61. https://doi.org/10.1093/jnci/djp096.
of formaldehyde in rats and mice after long-term inhalation exposure. 45. Meyers AR, Pinkerton LE, Hein MJ. Cohort mortality study of garment
Cancer Res. 1983;43(9):4382–92. industry workers exposed to formaldehyde: update and internal
26. Monticello TM, Swenberg JA, Gross EA, Leininger JR, Kimbell JS, Seilkop S, comparisons. Am J Ind Med. 2013;56(9):1027–39. https://doi.org/10.1002/a
et al. Correlation of regional and nonlinear formaldehyde-induced nasal jim.22199.
cancer with proliferating populations of cells. Cancer Res. 1996;56(5):1012– 46. Ott MG, Teta MJ, Greenberg HL. Lymphatic and hematopoietic tissue cancer
22. in a chemical manufacturing environment. Am J Ind Med. 1989;16(6):631–
27. Swenberg JA, Moeller BC, Lu K, Rager JE, Fry RC, Starr TB. Formaldehyde 43. https://doi.org/10.1002/ajim.4700160603.
carcinogenicity research: 30 years and counting for mode of action, 47. Linos A, Blair A, Cantor KP, Burmeister L, VanLier S, Gibson RW, et al.
epidemiology, and cancer risk assessment. Toxicol Pathol. 2013;41(2):181–9. Leukemia and non-Hodgkin's lymphoma among embalmers and funeral
https://doi.org/10.1177/0192623312466459. directors. J Natl Cancer Inst. 1990;82(1):66. https://doi.org/10.1093/jnci/82.1.
28. Hauptmann M, Lubin JH, Stewart PA, Hayes RB, Blair A. Mortality from solid 66.
cancers among workers in formaldehyde industries. Am J Epidemiol. 2004; 48. Partanen T, Kauppinen T, Luukkonen R, Hakulinen T, Pukkala E. Malignant
159(12):1117–30. https://doi.org/10.1093/aje/kwh174. lymphomas and leukemias, and exposures in the wood industry: an
29. Golden R, Pyatt D, Shields PG. Formaldehyde as a potential human industry-based case-referent study. Int Arch Occup Environ Health. 1993;
leukemogen. An assessment of biological plausibility. Crit Rev Toxicol. 2006; 64(8):593–6. https://doi.org/10.1007/BF00517706.
36(2):135–53. https://doi.org/10.1080/10408440500533208. 49. Blair A, Zheng T, Linos A, Stewart PA, Zhang YW, Cantor KP. Occupation and
30. He JL, Jin LF, Jin HY. Detection of cytogenetic effects in peripheral leukemia: a population-based case-control study in Iowa and Minnesota.
lymphocytes of students exposed to formaldehyde with cytokinesis-blocked Am J Ind Med. 2001;40(1):3–14. https://doi.org/10.1002/ajim.1066.
micronucleus assay. Biomed Environ Sci. 1998;11(1):87–92. 50. Hauptmann M, Stewart PA, Lubin JH, Beane Freeman LE, Hornung RW,
31. Ye X, Yan W, Xie H, Zhao M, Ying C. Cytogenetic analysis of nasal mucosa Herrick RF, et al. Mortality from lymphohematopoietic malignancies and
cells and lymphocytes from high-level long-term formaldehyde exposed brain cancer among embalmers exposed to formaldehyde. J Natl Cancer
workers and low-level short-term exposed waiters. Mutat Res. 2005;588(1): Inst. 2009;101(24):1696–708. https://doi.org/10.1093/jnci/djp416.
22–7. https://doi.org/10.1016/j.mrgentox.2005.08.005. 51. Gentry PR, Rodricks JV, Turnbull D, Bachand A, Van Landingham C, Shipp
32. Costa S, Coelho P, Costa C, Silva S, Mayan O, Santos LS, et al. Genotoxic AM, et al. Formaldehyde exposure and leukemia: critical review and
damage in pathology anatomy laboratory workers exposed to reevaluation of the results from a study that is the focus for evidence of
formaldehyde. Toxicology. 2008;252(1-3):40–8. https://doi.org/10.1016/j.tox.2 biological plausibility. Crit Rev Toxicol. 2013;43(8):661–70. https://doi.org/1
008.07.056. 0.3109/10408444.2013.818618.
33. Costa S, Garcia-Leston J, Coelho M, Coelho P, Costa C, Silva S, et al. 52. Checkoway H, Dell LD, Boffetta P, Gallagher AE, Crawford L, Lees PS, et al.
Cytogenetic and immunological effects associated with occupational Formaldehyde exposure and mortality risks from acute myeloid leukemia
formaldehyde exposure. J Toxicol Environ Health A. 2013;76(4-5):217–29. and other Lymphohematopoietic malignancies in the US National Cancer
https://doi.org/10.1080/15287394.2013.757212. Institute cohort study of Workers in Formaldehyde Industries. J Occup
34. Costa S, Carvalho S, Costa C, Coelho P, Silva S, Santos LS, et al. Increased Environ Med. 2015;57(7):785–94. https://doi.org/10.1097/JOM.
levels of chromosomal aberrations and DNA damage in a group of workers 0000000000000466.
exposed to formaldehyde. Mutagenesis. 2015;30(4):463–73. https://doi.org/1 53. Kwon SC, Kim I, Song J, Park J. Does formaldehyde have a causal association
0.1093/mutage/gev002. with nasopharyngeal cancer and leukaemia? Ann Occup Environ Med. 2018;
35. Costa S, Costa C, Madureira J, Valdiglesias V, Teixeira-Gomes A. Guedes de 30(1):5. https://doi.org/10.1186/s40557-018-0218-z.
Pinho P, et al. occupational exposure to formaldehyde and early biomarkers 54. Heck H, Casanova M. The implausibility of leukemia induction by
of cancer risk, immunotoxicity and susceptibility. Environ Res. 2019;179(Pt formaldehyde: a critical review of the biological evidence on distant-site
A):108740. https://doi.org/10.1016/j.envres.2019.108740. toxicity. Regul Toxicol Pharmacol. 2004;40(2):92–106. https://doi.org/10.1016/
36. Lu K, Collins LB, Ru H, Bermudez E, Swenberg JA. Distribution of DNA j.yrtph.2004.05.001.
adducts caused by inhaled formaldehyde is consistent with induction of 55. Casanova M, Heck HD, Everitt JI, Harrington WW Jr, Popp JA. Formaldehyde
nasal carcinoma but not leukemia. Toxicol Sci. 2010;116(2):441–51. https:// concentrations in the blood of rhesus monkeys after inhalation exposure.
doi.org/10.1093/toxsci/kfq061. Food Chem Toxicol. 1988;26(8):715–6. https://doi.org/10.1016/0278-691
37. Shaham J, Bomstein Y, Meltzer A, Kaufman Z, Palma E, Ribak J. DNA--protein 5(88)90071-3.
crosslinks, a biomarker of exposure to formaldehyde--in vitro and in vivo studies. 56. Casanova-Schmitz M, Starr TB, Heck HD. Differentiation between metabolic
Carcinogenesis. 1996;17(1):121–5. https://doi.org/10.1093/carcin/17.1.121. incorporation and covalent binding in the labeling of macromolecules in
38. Neuss S, Holzmann K, Speit G. Gene expression changes in primary human the rat nasal mucosa and bone marrow by inhaled [14C]- and
nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010; [3H]formaldehyde. Toxicol Appl Pharmacol. 1984;76(1):26–44. https://doi.
198(2):289–95. https://doi.org/10.1016/j.toxlet.2010.07.010. org/10.1016/0041-008X(84)90026-7.
39. Shaham J, Bomstein Y, Gurvich R, Rashkovsky M, Kaufman Z. DNA-protein 57. Casanova M, Heck HA. Further studies of the metabolic incorporation and
crosslinks and p53 protein expression in relation to occupational exposure covalent binding of inhaled [3H]- and [14C] formaldehyde in Fischer-344
to formaldehyde. Occup Environ Med. 2003;60(6):403–9. https://doi.org/1 rats: effects of glutathione depletion. Toxicol Appl Pharmacol. 1987;89(1):
0.1136/oem.60.6.403. 105–21. https://doi.org/10.1016/0041-008X(87)90181-5.
40. Coggon D, Harris EC, Poole J, Palmer KT. Extended follow-up of a cohort of 58. Moeller BC, Lu K, Doyle-Eisele M, McDonald J, Gigliotti A, Swenberg JA.
british chemical workers exposed to formaldehyde. J Natl Cancer Inst. 2003; Determination of N2-hydroxymethyl-dG adducts in the nasal epithelium
95(21):1608–15. https://doi.org/10.1093/jnci/djg046. and bone marrow of nonhuman primates following 13CD2-formaldehyde
41. Hauptmann M, Lubin JH, Stewart PA, Hayes RB, Blair A. Mortality from inhalation exposure. Chem Res Toxicol. 2011;24(2):162–4. https://doi.org/10.1
lymphohematopoietic malignancies among workers in formaldehyde 021/tx1004166.
Kang et al. Genes and Environment (2021) 43:13 Page 10 of 10

59. Yu R, Lai Y, Hartwell HJ, Moeller BC, Doyle-Eisele M, Kracko D, et al. 81. Nikitin A, Egorov S, Daraselia N, Mazo I. Pathway studio—the analysis and
Formation, accumulation, and hydrolysis of endogenous and exogenous navigation of molecular networks. Bioinformatics. 2003;19(16):2155–7.
formaldehyde-induced DNA damage. Toxicol Sci. 2015;146(1):170–82. https://doi.org/10.1093/bioinformatics/btg290.
https://doi.org/10.1093/toxsci/kfv079. 82. Gao X, Petricoin EF 3rd, Ward KR, Goldberg SR, Duane TM, Bonchev D, et al.
60. Lai Y, Yu R, Hartwell HJ, Moeller BC, Bodnar WM, Swenberg JA. Network proteomics of human dermal wound healing. Physiol Meas. 2018;
Measurement of endogenous versus exogenous formaldehyde-induced 39(12):124002. https://doi.org/10.1088/1361-6579/aaee19.
DNA-protein crosslinks in animal tissues by stable isotope labeling and 83. Xu C, Cao H, Zhang F, Cheadle C. Comprehensive literature data-mining analysis
ultrasensitive mass spectrometry. Cancer Res. 2016;76(9):2652–61. https:// reveals a broad genetic network functionally associated with autism spectrum
doi.org/10.1158/0008-5472.CAN-15-2527. disorder. Int J Mol Med. 2018;42(5):2353–62. https://doi.org/10.3892/ijmm.2018.3845.
61. Soffritti M, Maltoni C, Maffei F, Biagi R. Formaldehyde: an experimental 84. Dutta T, Nayak C, Bhattacharjee S. Acetylcholinesterase, Butyrylcholinesterase
multipotential carcinogen. Toxicol Ind Health. 1989;5(5):699–730. https://doi. and glutathione S-Transferase enzyme activities and their correlation with
org/10.1177/074823378900500510. genotypic variations based on GST M1 and GST T1 loci in long term-pesticide-
62. Kitaeva LV, Kitaev EM, Pimenova MN. The cytopathic and cytogenetic exposed tea garden workers of sub-Himalayan West Bengal. Toxicol Environ
sequelae of chronic inhalational exposure to formaldehyde on female germ Health Sci. 2019;11(1):63–72. https://doi.org/10.1007/s13530-019-0389-1.
cells and bone marrow cells in rats. Tsitologiia. 1990;32(12):1212–6. 85. Rager JE, Moeller BC, Miller SK, Kracko D, Doyle-Eisele M, Swenberg JA, et al.
63. Ye X, Ji Z, Wei C, McHale CM, Ding S, Thomas R, et al. Inhaled formaldehyde Formaldehyde-associated changes in microRNAs: tissue and temporal
induces DNA-protein crosslinks and oxidative stress in bone marrow and specificity in the rat nose, white blood cells, and bone marrow. Toxicol Sci.
other distant organs of exposed mice. Environ Mol Mutagen. 2013;54(9): 2014;138(1):36–46. https://doi.org/10.1093/toxsci/kft267.
705–18. https://doi.org/10.1002/em.21821. 86. Batty N, Ghonimi E, Feng L, Fayad L, Younes A, Rodriguez MA, et al. The
64. Zhang Y, Liu X, McHale C, Li R, Zhang L, Wu Y, et al. Bone marrow injury absolute monocyte and lymphocyte prognostic index for patients with
induced via oxidative stress in mice by inhalation exposure to formaldehyde. diffuse large B-cell lymphoma who receive R-CHOP. Clin Lymphoma
PLoS One. 2013;8(9):e74974. https://doi.org/10.1371/journal.pone.0074974. Myeloma Leuk. 2013;13(1):15–8. https://doi.org/10.1016/j.clml.2012.09.009.
65. Zhang Y, McHale CM, Liu X, Yang X, Ding S, Zhang L. Data on 87. Scarfo L, Ferreri AJ, Ghia P. Chronic lymphocytic leukaemia. Crit Rev Oncol
megakaryocytes in the bone marrow of mice exposed to formaldehyde. Hematol. 2016;104:169–82. https://doi.org/10.1016/j.critrevonc.2016.06.003.
Data Brief. 2016;6:948–52. https://doi.org/10.1016/j.dib.2015.12.058. 88. Zhao Y, Wei C, Wu Y, Ma P, Ding S, Yuan J, et al. Formaldehyde-induced paxillin-
66. Wei C, Wen H, Yuan L, McHale CM, Li H, Wang K, et al. Formaldehyde tyrosine phosphorylation and paxillin and P53 downexpression in Hela cells. Toxicol
induces toxicity in mouse bone marrow and hematopoietic stem/ Mech Methods. 2016;26(2):75–81. https://doi.org/10.3109/15376516.2015.1082001.
progenitor cells and enhances benzene-induced adverse effects. Arch 89. Tang XQ, Ren YK, Zhou CF, Yang CT, Gu HF, He JQ, et al. Hydrogen sulfide
Toxicol. 2017;91(2):921–33. https://doi.org/10.1007/s00204-016-1760-5. prevents formaldehyde-induced neurotoxicity to PC12 cells by attenuation
67. Ge J, Yang H, Lu X, Wang S, Zhao Y, Huang J, et al. Combined exposure to of mitochondrial dysfunction and pro-apoptotic potential. Neurochem Int.
formaldehyde and PM2.5: Hematopoietic toxicity and molecular mechanism 2012;61(1):16–24. https://doi.org/10.1016/j.neuint.2012.04.011.
in mice. Environ Int. 2020;144:106050. 90. Tsukahara S, Yamamoto S, Win-Shwe T-T, Ahmed S, Kunugita N, Arashidani K,
68. Yu G, Chen Q, Liu X, Guo C, Du H, Sun Z. Formaldehyde induces bone et al. Inhalation of low-level formaldehyde increases the Bcl-2/Bax expression
marrow toxicity in mice by inhibiting peroxiredoxin 2 expression. Mol Med ratio in the hippocampus of immunologically sensitized mice.
Rep. 2014;10(4):1915–20. https://doi.org/10.3892/mmr.2014.2473. Neuroimmunomodulation. 2006;13(2):63–8. https://doi.org/10.1159/000094829.
69. Yu GY, Song XF, Liu Y, Sun ZW. Inhaled formaldehyde induces bone 91. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer
marrow toxicity via oxidative stress in exposed mice. Asian Pac J Cancer stem cells. Nature. 2001;414(6859):105–11. https://doi.org/10.1038/35102167.
Prev. 2014;15(13):5253–7. https://doi.org/10.7314/APJCP.2014.15.13.5253. 92. Del Principe MI, Dal Bo M, Bittolo T, Buccisano F, Rossi FM, Zucchetto A, et al.
70. Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia.
Genotoxic consequences of endogenous aldehydes on mouse Haematologica. 2016;101(1):77–85. https://doi.org/10.3324/haematol.2015.131854.
haematopoietic stem cell function. Nature. 2012;489(7417):571–5. https:// 93. Yang L, Rau R, Goodell MA. DNMT3A in haematological malignancies. Nat
doi.org/10.1038/nature11368. Rev Cancer. 2015;15(3):152–65. https://doi.org/10.1038/nrc3895.
71. Pontel LB, Rosado IV, Burgos-Barragan G, Garaycoechea JI, Yu R, Arends MJ, 94. Liu Q, Yang L, Gong C, Tao G, Huang H, Liu J, et al. Effects of long-term low-dose
et al. Endogenous formaldehyde is a hematopoietic stem cell Genotoxin formaldehyde exposure on global genomic hypomethylation in 16HBE cells. Toxicol
and metabolic carcinogen. Mol Cell. 2015;60(1):177–88. https://doi.org/10.1 Lett. 2011;205(3):235–40. https://doi.org/10.1016/j.toxlet.2011.05.1039.
016/j.molcel.2015.08.020. 95. Tong Z, Han C, Qiang M, Wang W, Lv J, Zhang S, et al. Age-related
72. Klaunig JE, Xu Y, Isenberg JS, Bachowski S, Kolaja KL, Jiang J, et al. The role formaldehyde interferes with DNA methyltransferase function, causing
of oxidative stress in chemical carcinogenesis. Environ Health Perspect. memory loss in Alzheimer's disease. Neurobiol Aging. 2015;36(1):100–10.
1998;106(Suppl 1):289–95. https://doi.org/10.1016/j.neurobiolaging.2014.07.018.
96. Baseggio L, Bienvenu J, Charlot C, Picollet J, Felman P, Coiffier B, et al.
73. Pedersen-Bjergaard J, Christiansen DH, Desta F, Andersen MK. Alternative
Higher LPS-stimulated TNF-alpha mRNA levels in peripheral blood
genetic pathways and cooperating genetic abnormalities in the pathogenesis
mononuclear cells from non-Hodgkin’s lymphoma patients. Exp Hematol.
of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia.
2001;29(3):330–8. https://doi.org/10.1016/S0301-472X(00)00672-X.
2006;20(11):1943–9. https://doi.org/10.1038/sj.leu.2404381.
97. Stifter G, Heiss S, Gastl G, Tzankov A, Stauder R. Over-expression of tumor
74. Montagutelli X. Effect of the genetic background on the phenotype of
necrosis factor-alpha in bone marrow biopsies from patients with
mouse mutations. J Am Soc Nephrol. 2000;11(Suppl 16):S101–5.
myelodysplastic syndromes: relationship to anemia and prognosis. Eur J
75. Yasuda SP, Yuki M, Yoshiaki K. Effects of genetic background on
Haematol. 2005;75(6):485–91. https://doi.org/10.1111/j.1600-0609.2005.00551.x.
susceptibility and the acceleration of hearing loss in mice. In An Excursus
98. Hoermann G, Greiner G, Valent P. Cytokine regulation of microenvironmental
into Hearing Loss. IntechOpen. 2018.
cells in Myeloproliferative neoplasms. Mediat Inflamm. 2015;2015:17.
76. Shin JY, Jung HJ, Moon A. Molecular markers in sex differences in Cancer.
99. Lee MH, Lee BH, Shin HS, Lee MO. Elevated levels of PDGF receptor and
Toxicol Res. 2019;35(4):331–41. https://doi.org/10.5487/TR.2019.35.4.331.
MDM2 as potential biomarkers for formaldehyde intoxication. Toxicol Res.
77. Park J, Kwon SO, Kim S-H, Kim SJ, Koh EJ, Won S, et al. Methylation
2008;24(1):45–9. https://doi.org/10.5487/TR.2008.24.1.045.
quantitative trait loci analysis in Korean exposome study. Mol Cell Toxicol.
100. Zeller J, Neuss S, Mueller JU, Kuhner S, Holzmann K, Hogel J, et al. Assessment
2020;16(2):175–83. https://doi.org/10.1007/s13273-019-00068-3.
of genotoxic effects and changes in gene expression in humans exposed to
78. Zou D, Ma L, Yu J, Zhang Z. Biological databases for human research. formaldehyde by inhalation under controlled conditions. Mutagenesis. 2011;
Genomics Proteomics Bioinformatics. 2015;13(1):55–63. https://doi.org/10.1 26(4):555–61. https://doi.org/10.1093/mutage/ger016.
016/j.gpb.2015.01.006.
79. Li Y, Chen L. Big biological data: challenges and opportunities. Genomics Proteomics
Bioinformatics. 2014;12(5):187–9. https://doi.org/10.1016/j.gpb.2014.10.001. Publisher’s Note
80. Choi YH, Han CY, Kim KS, Kim SG. Future directions of Pharmacovigilance Springer Nature remains neutral with regard to jurisdictional claims in
studies using electronic medical recording and human genetic databases. published maps and institutional affiliations.
Toxicol Res. 2019;35(4):319–30. https://doi.org/10.5487/TR.2019.35.4.319.