JOURNAL OF NEUROCHEMISTRY | 2013 | 127 | 721
12356
*Indian Institute of Science Education and Research, Pashan, Pune, India
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
Centre for Environmental Research and Sustainable Technology, Bremen, Germany
Abstract
Formaldehyde is an environmental pollutant that is also
generated in substantial amounts in the human body during
normal metabolism. This aldehyde is a well-established
neurotoxin that affects memory, learning, and behavior. In
addition, in several pathological conditions, including Alzhei-
mers disease, an increase in the expression of formaldehyde-
generating enzymes and elevated levels of formaldehyde in
brain have been reported. This article gives an overview on
the current knowledge on the generation and metabolism of
formaldehyde in brain cells as well as on formaldehyde-
induced alterations in metabolic processes. Brain cells have
the potential to generate and to dispose formaldehyde. In
culture, both astrocytes and neurons efciently oxidize form-
aldehyde to formate which can be exported or further oxidized.
Formaldehyde chemistry
Formaldehyde (HCHO) is the simplest aldehyde that is also
known as methanal. This compound was rst described in
1855 by Alexander Butlerov, while its chemical synthesis by
methanol dehydration was rst achieved in 1867 by August
Wilhelm von Hofmann (Salthammer et al. 2010). In the
following decades, the properties of formaldehyde were
extensively studied and this compound was one of the
earliest to obtain a CAS registry number (50-00-0). Form-
aldehyde is highly reactive. It can undergo hydration and
forms hemiacetals with alcohols or thiohemiacetals with
thiols. Formaldehyde also reacts with amines to form Schiff
bases and cross-links proteins by forming methylene bridges
between amino groups (Metz et al. 2004, 2006). This high
reactivity of formaldehyde is the reason for its extensive use
in industries (Tang et al. 2009).
Due to its protein cross-linking ability, formaldehyde is
frequently used for tissue preservation and xation (Nazar-
ian et al. 2009). Formalin solution that is used in pathology
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
doi: 10.1111/jnc.
Although moderate concentrations of formaldehyde are not
acutely toxic for brain cells, exposure to formaldehyde
severely affects their metabolism as demonstrated by the
formaldehyde-induced acceleration of glycolytic ux and by
the rapid multidrug resistance protein 1-mediated export of
glutathione from both astrocytes and neurons. These formal-
dehyde-induced alterations in the metabolism of brain cells
may contribute to the impaired cognitive performance
observed after formaldehyde exposure and to the neurode-
generation in diseases that are associated with increased
formaldehyde levels in brain.
Keywords: formaldehyde, glutathione, glycolysis, metabolism,
neurodegeneration, neurotoxicity.
J. Neurochem. (2013) 127, 721.
contains 35% formaldehyde, while for xation of tissues,
tissue sections, or cultured cells, a 4% formaldehyde
solution is frequently used (Kiernan 2000). Such a 4%
formaldehyde solution contains the aldehyde in a concen-
tration of above 1 M. Thus, the concentrations of formal-
dehyde that are used for technical processes are several
orders of magnitude higher than the concentrations of
Received May 30, 2013; revised manuscript received June 12, 2013;
accepted June 21, 2013.
Address correspondence and reprint requests to Dr. Ralf Dringen,
Centre for Biomolecular Interactions Bremen, University of Bremen,
PO. Box 330440, D-28334 Bremen, Germany.
E-mail: ralf.dringen@uni-bremen.de
Abbreviations used: AD, Alzheimers disease; ADH, alcohol dehy-
drogenase; ALDH, aldehyde dehydrogenase; GSH, glutathione; GSSG,
glutathione disulde; JHDM, JmjC domain-containing histone demeth-
ylases; LSD, lysine-specic demethylase; MCT, monocarboxylate
transporter; Mrp, multidrug resistance protein; MS, multiple sclerosis;
MTHFD, methylene tetrahydrofolate dehydrogenase; SSAO, semicar-
bazide-sensitive amine oxidases; THF, tetrahydrofolate; VAP, vascular
adhesion protein.
7
8 K. Tulpule and R. Dringen
formaldehyde (0.10.4 mM) that are found in body uids
and tissues under normal and pathological conditions (Heck
and Casanova 2004; Tong et al. 2013a).
Endogenous and exogenous sources of
formaldehyde
Formaldehyde exposure is caused by the generation of this
aldehyde within the body and can also be a consequence of
contact with elevated levels of environmental formaldehyde
(Fig. 1). Some of the endogenous enzymatic reactions that
generate formaldehyde as well as exogenous sources of
formaldehyde are described below.
Formaldehyde is the oxidation product of methanol. This
alcohol can be generated within the body by hydrolysis of
protein carboxymethyl esters either non-enzymatically or
catalyzed by methylesterases (Lee et al. 2008). In addition,
accidental or intentional intake of methanol will further
expose the body to this alcohol. In cells, methanol is oxidized
to formaldehyde by alcohol dehydrogenase (ADH) 1, by
catalase or by a non-enzymatic reaction of methanol with
hydroxyl radicals (Harris et al. 2003; MacAllister et al.
2011). In humans and primates, ADH1 appears to be
predominately responsible for methanol oxidation, while
Fig. 1 Endogenous and exogenous sources of formaldehyde (HCHO)
and pathways involved in cellular formaldehyde disposal. For details
see text. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydroge-
nase; cy, cytosolic; JHDM, JmjC domain-containing histone demeth-
ylases; LSD, lysine-specic demethylase; mt, mitochondrial; MTHFD,
methylene tetrahydrofolate dehydrogenase; SSAO, semicarbazide-
sensitive amine oxidases; VAP, vascular adhesion protein.
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
the majority of methanol oxidation in rats has been reported
to be mediated by catalase (Tephly 1991; Skrzydlewska
2003).
Another endogenous source of formaldehyde are semicar-
bazide-sensitive amine oxidases (SSAO) which represent a
group of copper-containing amine oxidases that are inhibited
by semicarbazide and most of them contain topa-quinone at
their catalytic centre (Jalkanen and Salmi 2001; Yu et al.
2003). Oxidative deamination of methylamine by SSAO
generates formaldehyde together with ammonia and hydro-
gen peroxide (Yu et al. 2003; OSullivan et al. 2004). In
mammals, SSAO are either membrane-associated or circulate
in a soluble form in the vascular system (Jalkanen and Salmi
2001). Among the SSAO, the vascular adhesion protein
(VAP) 1 is one of the most extensively studied members of
this group of enzymes (Smith and Vainio 2007; Jalkanen and
Salmi 2008).
Formaldehyde is also generated as by-product of reactions
catalyzed by lysine-specic demethylase (LSD) 1 and JmjC
domain-containing histone demethylases (JHDM) (Cloos
et al. 2008; Hou and Yu 2010). These enzymes remove
methyl groups from lysine residues in histones, thereby
altering the chromatin structure (Cheng and Zhang 2007;
Cloos et al. 2008; Hou and Yu 2010; Izzo and Schneider
2010). LSD1 is a avin-containing enzyme that selectively
demethylates the mono- or dimethylated lysine residue in
position 4 of histone H3 (Forneris et al. 2009; Hou and Yu
2010). On the other hand, JHDM can remove methyl groups
from mono-, di-, or trimethylated lysine residues and require
Fe2+ and a-ketoglutarate as cofactors (Cloos et al. 2008; Hou
and Yu 2010).
In addition to endogenous sources, the body can also
encounter environmental formaldehyde, since a number of
commonly used products contain either formaldehyde or
formaldehyde-releasing substances (Sasseville 2004;
de Groot et al. 2009). Some examples of such products are
construction materials, agricultural fertilizers, fumigants,
paints, cosmetics, antiperspirants, polish, cleaning agents,
and toiletries (Sasseville 2004; de Groot et al. 2009, 2010).
In addition, formaldehyde can be produced and released from
burning of wood, coal, tobacco, natural gas, and kerosene
(de Groot et al. 2009; Laitinen et al. 2010). Moreover, foods
like coffee, codsh, meat, poultry, and maple syrup naturally
contain formaldehyde (Dhareshwar and Stella 2008; de
Groot et al. 2009). Thus, this ubiquitously present compound
can enter the human body by inhalation, ingestion, or entry
through the skin.
One pertinent question is whether exogenous formalde-
hyde can pose a big threat to the central nervous system by
entering the blood and ultimately reaching the brain after
crossing the bloodbrain barrier. In healthy individuals, the
formaldehyde concentration in the blood is around 0.1 mM
(Heck and Casanova 2004) and that in the brain is
0.20.4 mM (Tong et al. 2013a). Inhalation of moderate

doses of formaldehyde does not severely increase the
formaldehyde level in blood (Heck et al. 1985; Franks
2005). This is expected as the formaldehyde-oxidizing
enzymes ADH3 and aldehyde dehydrogenase (ALDH) 2
(Fig. 1) are ubiquitously expressed in all tissues (Nishimura
and Naito 2006; Alnouti and Klaassen 2008) and will
quickly clear a low excess of environmentally derived
formaldehyde. However, exposure to high concentrations of
exogenous formaldehyde that exceeds the peripheral form-
aldehyde oxidation capacity will elevate the normal tolerable
concentration of formaldehyde in the blood and could lead
to neural damage. Indeed, exposure to exogenous formal-
dehyde has been reported to cause neurotoxicity in humans
and animals and the extent of damage depends on the dose
of formaldehyde and the duration of the exposure (Kilburn
et al. 1985a, b; Songur et al. 2008, 2010). Especially,
individuals who carry functional polymorphisms in the
genes encoding for formaldehyde-metabolizing enzymes,
ADH3 or ALDH2, which are discussed to be associated with
reduced formaldehyde-oxidizing capacity (Hedberg et al.
2001; Wang et al. 2002), may be more vulnerable to
neural damage by endogenously generated or environmental
formaldehyde.
Metabolism of formaldehyde
Despite of the multiple endogenous and exogenous sources
of formaldehyde, a low physiological level of formaldehyde
in body uids and tissue is maintained by the continuous
action of cellular formaldehyde-metabolizing enzymes
(Fig. 1). ADH1 is considered to play a negligible role in
formaldehyde reduction to methanol because of its very high
KM-value for formaldehyde (about 30 mM) (Skrzydlewska
2003). The formaldehyde oxidation product formate is
generated by two independent pathways that are mediated
by either the mitochondrial ALDH2 or the cytosolic ADH3
(Teng et al. 2001; Friedenson 2011; MacAllister et al.
2011). ADH3, also known as glutathione (GSH)-dependent
formaldehyde dehydrogenase, oxidizes formaldehyde to
formate in a two-step process (Harris et al. 2003; Staab
et al. 2009; Thompson et al. 2010; MacAllister et al. 2011).
In the rst step, GSH reacts with formaldehyde in an
enzyme-independent manner to form S-hydroxymethyl GSH
that is subsequently used as ADH3 substrate to generate S-
formyl GSH (Harris et al. 2003; Staab et al. 2009; Thomp-
son et al. 2010; MacAllister et al. 2011). The conjugate S-
formyl GSH is hydrolyzed by a thiolase to generate formate
and GSH (Teng et al. 2001; Harris et al. 2003; MacAllister
et al. 2011). Unlike ADH3, the reaction catalyzed by
ALDH2 is a single-step GSH-independent process (Teng
et al. 2001; MacAllister et al. 2011). Since ADH3 has a
very low KM-value for S-hydroxymethyl GSH (less than
10 lM) compared to that of ALDH2 for formaldehyde (0.2
0.5 mM) (Casanova-Schmitz et al. 1984; Heck et al. 1990),
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
Formaldehyde in brain 9
ADH3 is likely to be especially important for the oxidation
of low concentrations of formaldehyde.
The formate generated by formaldehyde oxidation can
undergo further oxidization to carbon dioxide in a metabolic
pathway involving tetrahydrofolate (THF), wherein formate
is rst converted to 10-formyl THF (Fig. 1) in an ATP-
dependent reaction (Skrzydlewska 2003; Krupenko 2009;
Krupenko et al. 2010). This reaction is catalyzed either by
the cytosolic methylene tetrahydrofolate dehydrogenase
(MTHFD) 1 or by its mitochondrial isoform MTHFD1L
(Tibbetts and Appling 2010). 10-formyl THF is subsequently
oxidized by the cytosolic 10-formyl THF dehydrogenase,
also known as ALDH1L1, or its mitochondrial isoform
ALDH1L2 to carbon dioxide. Both enzymes use NADP+ as a
co-factor and regenerate THF (Skrzydlewska 2003; Kru-
penko 2009; Krupenko et al. 2010). Although formate
oxidation takes place predominantly by the THF-dependent
pathway, catalase-mediated oxidation of formate has also
been reported (Cook et al. 2001; Skrzydlewska 2003).
Formaldehyde metabolism (Fig. 1) is best studied for the
liver (Skrzydlewska 2003; Tibbetts and Appling 2010), but it
is very likely that other organs including the brain will also
use the enzymatic pathways that are well known for
formaldehyde metabolism in liver. In brain, at least all the
enzymes required for complete formaldehyde oxidation are
expressed (Table 1).
Differences in the rate of formaldehyde metabolism have
been described between species for the formaldehyde
metabolism. For example, formate is metabolized at a slower
rate in the liver of monkeys and humans compared to rats,
partly because rats have a higher hepatic THF content
(Tephly 1991; Skrzydlewska 2003). Also, species-specic
differences in the kinetic parameters of the enzymes involved
in formaldehyde metabolism may contribute to the different
rates of formaldehyde oxidation observed and subsequently
may determine the consequences of an exposure to formal-
dehyde and/or it metabolites.
Generation and oxidation of formaldehyde
in brain cells
Several reports have demonstrated that the enzymes required
to produce or metabolize formaldehyde are expressed in the
brain on the mRNA or protein level (Table 1). Of these
enzymes, only the expression of ADH1 in the brain has been
controversially discussed, since this dehydrogenase was not
detected in brain by some investigators (Julia et al. 1987;
Galter et al. 2003). Despite the presence of ADH1 mRNA in
cultured neural cells, methanol generation was not found for
formaldehyde-exposed cultured brain cells (Tulpule and
Dringen 2012; Tulpule et al. 2013), suggesting that oxida-
tion to formate is the preferred pathway of formaldehyde
metabolism in brain cells. Cultured astrocytes and neurons
contain the mRNAs for SSAO and LSD1 as well as for the
10 K. Tulpule and R. Dringen
Table 1 Formaldehyde-producing and formaldehyde-metabolizing enzymes in the brain
Species
Enzymes Rat
Formaldehyde generation
ADH1 Martinez et al. (2001)
Catalase Zimatkin and Lindros (1996); Schad et al. (2003)
SSAO/VAP1 Obata and Yamanaka (2000)
LSD1 Zibetti et al. (2010)
JHDM Wolf et al. (2007)
Formaldehyde oxidation
ADH3 Julia et al. (1987); Iborra et al. (1992);
Galter et al. (2003)
ALDH2 Guo et al. (2013)
Formate oxidation
MTHFD1 Thigpen et al. (1990)
MTHFD1L
ALDH1L1 Neymeyer et al. (1997); Anthony and Heintz (2007)
ALDH1L2
enzymes involved in formaldehyde metabolism (Tulpule and
Dringen 2012; Tulpule et al. 2013). These studies indicate
that formaldehyde may be produced locally in the brain and
that among the different types of brain cells at least astrocytes
and neurons have the potential to generate and oxidize
formaldehyde.
Acute formaldehyde exposure in concentrations of up to
1 mM for up to 3 h does not cause severe toxicity in cultured
astrocytes or neurons (Song et al. 2010; Tulpule and Dringen
2011, 2012; Tulpule et al. 2013). A rapid metabolism of
cellular formaldehyde may contribute to the resistance of
cultured brain cells to formaldehyde toxicity, since formal-
dehyde has been reported to be more cytotoxic than its
metabolites, methanol and formate (Oyama et al. 2002; Lee
et al. 2008). Both, cultured astrocytes and neurons clear
exogenously applied formaldehyde with a similar rate of
around 0.2 lmol/(h 9 mg) (Tulpule and Dringen 2012;
Tulpule et al. 2013) which is about 20% of the formaldehyde
oxidation rate reported for liver cells (Dicker and Cederbaum
1984). The KM-value for formaldehyde clearance by cultured
astrocytes is around 0.19 mM, suggesting that both the
cytosolic ADH3 and mitochondrial ALDH2 could contribute
to formaldehyde oxidation (Tulpule and Dringen 2012).
Although cultured astrocytes and neurons have compara-
ble rates of formaldehyde clearance, the metabolic fate of the
disposed formaldehyde differs between these two types of
neural cells. Although astrocytes convert the majority
(> 90%) of formaldehyde to formate that is subsequently
exported from the cells (Tulpule and Dringen 2012), only
about 25% of the formaldehyde cleared by cultured neurons
is detected as extracellular formate (Tulpule et al. 2013). The
underlying reason for this difference might be a poor export
of formate from cultured neurons and/or a higher capacity of
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
Mouse Human
Meinerz et al. (2013) van Horssen et al. (2008)
Ferrer et al. (2002); Unzeta et al. (2007);
Valente et al. (2012)
Zhang et al. (2010) Zibetti et al. (2010)
Fukuda et al. (2011) Wolf et al. (2007)
Galter et al. (2003) Galter et al. (2003)
Alnouti and Klaassen (2008) Stewart et al. (1996)
MacFarlane et al. (2009) Fountoulakis et al. (2003)
Prasannan et al. (2003)
Cahoy et al. (2008) Oldham et al. (2008)
Krupenko et al. (2010)
these cells to further oxidize formate to carbon dioxide
(Fig. 1). Although the putative formate exporters, GABA-
gated channels (Mason et al. 1990) and monocarboxylate
transporter (MCT) 1 (Moschen et al. 2012) are expressed in
both astrocytes and neurons (Debernardi et al. 2003; Olsen
and Sieghart 2009; Lee et al. 2011; Velez-Fort et al. 2011),
the expression level of MCT1 in neurons has been reported
to be very low (Debernardi et al. 2003). However, if poor
export of formate would be the only reason behind the lower
extracellular accumulation of this metabolite in cultured
neurons, these cells should accumulate large amounts of
formaldehyde-derived formate, which is not the case (Tulp-
ule et al. 2013). Thus, the lower extracellular accumulation
of formaldehyde-derived formate in cultured neurons com-
pared to cultured astrocytes is likely to be predominantly
caused by oxidation of formaldehyde-derived cellular
formate to carbon dioxide. The enzymes involved in the
oxidation of 10-formyl THF require NADP+ as electron
acceptor (Krupenko 2009; Krupenko et al. 2010), and the
availability of NADP+ in cytosol and mitochondria depends
on the pathways involved in NADPH consumption and
NADPH regeneration. As such pathways differ between
astrocytes and neurons (Dringen et al. 2007), the NADP+
availability could also contribute to the differences observed
in formate release from astrocytes and neurons that were
exposed to formaldehyde (Tulpule and Dringen 2012;
Tulpule et al. 2013).
Alterations of the metabolism of brain
cells upon exposure to formaldehyde
A large number of adverse consequences have been reported
for an exposure of brain cells to formaldehyde in vivo and

Table 2 Consequences of a formaldehyde exposure of rodent brain cells in vivo and in vitro
In vivo
Decrease in the number of neuron
Decreased level of GSH
Lowered levels of superoxide dismutase and catalase
Increase in levels of nitric oxide, malondialdehyde
and protein carbonyls
Increase in apoptotic events
Decit in memory and learning
In vitro
Elevated glycolysis in neurons and astrocytes
Mrp1-stimulated GSH export from neurons and astrocytes
Decreased glutamate uptake in cultured astrocytes
Lower expression of neuronal NMDA receptor subunits
The articles by Lu et al. (2008), Usanmaz et al. (2002), and Tong et al. (2011) describe data that have been obtained on mice, whereas all other
studies were performed on rats or rat brain cells.
in vitro (Table 2). Recently, it was demonstrated that
formaldehyde in the concentration range between 0.1 mM
and 1 mM strongly affects basal metabolic properties of
cultured astrocytes and neurons, that is, formaldehyde
stimulates glycolytic ux and the export of the antioxidative
tripeptide GSH from brain cells.
Formaldehyde-stimulated glycolysis
Astrocytes are more glycolytic than neurons (Bola~ nos et al.
2010), a feature which has been attributed to expression of
the glycolysis-promoting enzyme PFKFB3 in astrocytes
(Herrero-Mendez et al. 2009), an inhibited pyruvate dehy-
drogenase complex (Halim et al. 2010) and a low rate of
NADH shuttling into mitochondria in astrocytes (Berkich
et al. 2007; Neves et al. 2012). Despite the differences in
basal rates of glucose consumption and lactate release in
cultured astrocytes and neurons, application of formaldehyde
signicantly increases these rates in both types of brain cells
(Tulpule and Dringen 2012; Tulpule et al. 2013). However,
the extent of stimulation of glycolytic ux in formaldehyde-
exposed cells compared to the basal condition differs
between the culture types investigated. For example, at a
formaldehyde concentration of 0.5 mM, the lactate release
and glucose consumption rates were doubled in cultured
neurons (Tulpule et al. 2013), while this concentration of
formaldehyde did not affect glycolysis in cultured astrocytes
(Tulpule and Dringen 2012). Astrocytes had to be exposed to
1 mM formaldehyde to elevate glycolysis by 50% (Tulpule
and Dringen 2012).
The accelerated glycolysis in formaldehyde-exposed neu-
ral cells is likely to be caused by the formaldehyde-derived
formate which is known to inhibit mitochondrial cytochrome
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
Formaldehyde in brain 11
References
Gurel et al. (2005); Aslan et al. (2006); Sarsilmaz et al. (2007)
Lu et al. (2008)
Gurel et al. (2005); Zararsiz et al. (2006, 2007, 2011); Lu et al. (2008);
Songur et al. (2008)
Gurel et al. (2005); Zararsiz et al. (2006, 2007, 2011); Lu et al. (2008);
Songur et al. (2008)
Zararsiz et al. (2006, 2007)
Pitten et al. (2000); Usanmaz et al. (2002); Malek et al. (2003);
Sorg et al. (2004); Lu et al. (2008); Turkoglu et al. (2008);
Tong et al. (2011, 2013a, b)
Tulpule and Dringen (2012); Tulpule et al. (2013)
Tulpule and Dringen (2011); Tulpule et al. (2013)
Song et al. (2010)
Tong et al. (2013a)
c oxidase (Nicholls 1975; Wallace et al. 1997). This view is
supported by the observation that incubation of astrocytes
with formaldehyde for 90 min is required for the accelerated
lactate release to persist even after removal of formaldehyde
(Tulpule and Dringen 2012). This long delay most likely
reects the slow mitochondrial accumulation of formalde-
hyde-derived formate to concentrations that are sufcient to
inactivate respiration, as most of the formate is efciently
exported from astrocytes. Moreover, the persistent lactate
release of astrocytes exposed to formaldehyde was not
further enhanced by application of azide, an inhibitor of
mitochondrial cytochrome c oxidase (Tulpule and Dringen
2012). Thus, formaldehyde-derived formate is likely to
stimulate glycolytic ux as a consequence of an inhibited
respiration, as also other inhibitors of respiratory chain
complexes stimulate glycolytic lactate production in cultured
astrocytes and neurons (Pauwels et al. 1985; Scheiber and
Dringen 2011).
Formaldehyde-accelerated glutathione export
GSH is an important antioxidant (Lushchak 2012; Schmidt
and Dringen 2012; Lu 2013) that is also involved in the
formaldehyde oxidation catalyzed by ADH3 (Fig. 1). Under
basal conditions, cultured astrocytes and neurons as well as
cells of the oligodendroglial cell line OLN-93 export GSH,
although with variable rates (Tulpule and Dringen 2011;
Tulpule et al. 2012, 2013). Formaldehyde treatment stimu-
lated GSH export from all three types of cultured neural cells
without severely altering the ratio of GSH to glutathione
disulde (GSSG) (Tulpule and Dringen 2011; Tulpule et al.
2012, 2013). This accelerated GSH export from formalde-
hyde-treated neural cells is mediated by multidrug resistance
12 K. Tulpule and R. Dringen
protein (Mrp) 1 (Tulpule and Dringen 2011; Tulpule et al.
2012, 2013). Mrp1 is a member of ATP-binding cassette
transporters and transports, besides GSH, a wide array of
substrates including GSSG and GSH conjugates (Keppler
2011; Yin and Zhang 2011). The potential of formaldehyde
to accelerate GSH export differs between different brain cell
culture types. For example, exposure to 0.5 mM formalde-
hyde increased the respective GSH export rates of cultured
astrocytes, neurons and OLN-93 cells by 10-, 5- and 20-fold,
respectively (Tulpule and Dringen 2011; Tulpule et al. 2012,
2013). However, half-maximal cellular GSH depletions were
observed at similar incubation parameters for all types of
neural cells after incubation for 1 h with 0.3 mM formalde-
hyde (Tulpule and Dringen 2011; Tulpule et al. 2012, 2013).
Formaldehyde exposure does not impair the capacity of
neural cells to synthesize GSH. At least formaldehyde-treated
neurons restored their cellular GSH levels after application of
amino acid precursors for GSH synthesis (Tulpule et al.
2013).
The molecular mechanism involved in the formaldehyde-
accelerated Mrp1-mediated GSH export from neural cells is
not resolved so far. Since the stimulation of GSH export is
observed within minutes after formaldehyde application
(Tulpule and Dringen 2011; Tulpule et al. 2012, 2013),
de novo synthesis of Mrp1 is unlikely to explain the
stimulated GSH efux. Furthermore, the nding that removal
of formaldehyde instantly decelerates the stimulated GSH
export (Tulpule and Dringen 2011; Tulpule et al. 2012,
2013) indicates that the mechanism responsible for formal-
dehyde-accelerated GSH export is quickly reversible.
Assuming that cellular GSH is the transported Mrp1
substrate (Fig. 2a), formaldehyde could stimulate GSH
export by a reversible, covalent activation of this transporter.
Alternatively, a formaldehyde-induced recruitment of intra-
cellular Mrp1 molecules into the cell membrane could
explain the accelerated GSH export. Such a reversible
translocation of Mrp1 from the Golgi to the cell surface
(a) (b)
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
has been reported for cultured astrocytes treated with
bilirubin (Gennuso et al. 2004).
Mrp1 efciently exports GSH conjugates (Keppler 2011;
Yin and Zhang 2011). As the formaldehyde metabolism in
neural cells involves the generation of the GSH conjugates
S-hydroxymethyl GSH and S-formyl GSH (Fig. 1), these
conjugates could also serve as substrates of Mrp1 (Fig. 2b).
Since both conjugates are known to be labile (Ahmed and
Ahmed 1978; Uotila 1981), they are likely to disintegrate
into GSH and formaldehyde or formate immediately after
being exported.
Direct experimental evidence that discriminates between
the potential two mechanisms (Fig. 2) that may be involved
in the formaldehyde-induced accelerated GSH export via
Mrp1 is missing so far. However, determination of the
kinetic parameters for the GSH export from astrocytes
revealed that the KM-values of the basal as well as the
formaldehyde-accelerated GSH export from astrocytes are
identical (about 100 nmol/mg or 25 mM), but that the
Vmax-value for the stimulated GSH export is eightfold higher
than that for the basal GSH export (Tulpule et al. 2012).
These data suggest that at least for formaldehyde-treated
astrocytes GSH rather than a GSH conjugate is exported via
Mrp1, since the KM-values of Mrp1 for its substrate GSH are
normally higher than 5 mM, while that for GSH conjugates
are below 1 mM (Burg et al. 2002; Cole and Deeley 2006;
Deeley and Cole 2006).
Application of formaldehyde does not deprive the cells
completely of their GSH and about 5% residual GSH still
remains within neural cells (Tulpule and Dringen 2011;
Tulpule et al. 2012, 2013). In cultured astrocytes, this low
cellular GSH content represents a residual GSH concentra-
tion of about 0.4 mM (Dringen and Hamprecht 1998) which
will be sufcient to drive ADH3-catalyzed GSH-dependent
formaldehyde oxidation, since the KM-value of ADH3 for
S-hydroxymethyl GSH is less than 10 lM (Casanova-
Schmitz et al. 1984; Heck et al. 1990) and this reaction
Fig. 2 Potential mechanisms involved in
formaldehyde-stimulated glutathione (GSH)
export from brain cells. (a) Formaldehyde
directly stimulates Mrp1-mediated GSH export.
(b) The GSH conjugates S-hydroxymethyl
GSH and/or S-formyl GSH which are
intermediates of cellular formaldehyde
metabolism are exported by Mrp1. The
labile conjugates immediately disintegrate
after export to generate GSH.
 Formaldehyde in brain 13

involves recycling of GSH (Fig. 1). Thus, the stimulated Increased expression of formaldehyde-generating enzymes
GSH export is unlikely to compromise GSH-dependent (Table 3) as well as elevated formaldehyde levels have also
formaldehyde oxidation. been reported in brains of patients suffering from neurode-
generative diseases like Alzheimers disease (AD) or multi-
ple sclerosis (MS) (Khokhlov et al. 1989 cited in Miao and
Evidence for the role of formaldehyde in pathology
He 2012; Tong et al. 2011, 2013a). Some hypotheses have
In healthy individuals, the formaldehyde concentration in the been postulated that link the increase in formaldehyde level
blood has been reported to be around 0.1 mM (Heck and to neuropathology. For example, some human subjects who
Casanova 2004) while that in the brain is about 0.2 mM suffered from methanol poisoning developed symptoms of
(hippocampus) and 0.4 mM (cortex) (Tong et al. 2013a). MS which has been discussed to be an effect of methanol
These levels of formaldehyde represent the normal phy- oxidation to formaldehyde and the subsequent modication
siological balance between formaldehyde-generating and of proteins resulting in an immune reaction (Schwyzer and
formaldehyde-disposing processes. However, an increased Henzi 1983; Henzi 1984). Along that line it was discussed
activity of formaldehyde-generating enzymes or an acute that formaldehyde methylates proteins like tau (in AD) or
exposure to high amounts of exogenous formaldehyde myelin basic protein (in MS) which in turn elicits an immune
without a concurrent elevation in the capacity to clear response by the body that is characteristic for these diseases
formaldehyde will raise formaldehyde level in the body and (Monte 2010; Lu et al. 2013). Also, inhibition of SSAO in a
will lead to formaldehyde stress (He et al. 2010). Indeed, an murine model of MS has been shown to reduce the incidence
increased expression/activity of the formaldehyde-generating and severity of this disease (Wang et al. 2006) which could,
enzymes VAP1/SSAO, LSD1 and JHDM has been reported at least partly, be the consequence of a lowered formaldehyde
for various diseases (Table 3). While a broad spectrum of generation. Moreover, formaldehyde exposure has been
pathological conditions are associated with elevated levels of implicated to be a risk factor for the development of
VAP1/SSAO, an increase in the expression of the histone amyotrophic lateral sclerosis (Weisskopf et al. 2009), a
demethylases has especially been observed in different types disease that is characterized by degeneration of motor
of cancer (Table 3). The elevated expression of formalde- neurons (Kiernan et al. 2011).
hyde-generating enzymes is accompanied by increased
formaldehyde levels in diabetic rats (Tong et al. 2013a), in
Formaldehyde-induced alterations in neural
cancer tissue (Tong et al. 2010) and in some human cancer
metabolism as potential contributors to
cell lines (Kato et al. 2001; Tong et al. 2010).
neurodegeneration
Figure 3 summarizes the current knowledge on formalde-
Table 3 Elevation in expression or activity of formaldehyde-generat-
hyde metabolism and on formaldehyde-induced alterations in
ing enzymes in human diseases
the glucose and GSH metabolism of neural cells. The
potential of cultured brain cells to efciently metabolize
Enzyme Disease References
formaldehyde suggests that also the cells in brain deal quite
SSAO/VAP1 Alzheimers disease Ferrer et al. (2002); del Mar well with the moderate amounts of formaldehyde that are
Hernandez et al. (2005); generated under physiological conditions. Similar to liver
Unzeta et al. (2007) cells, brain cells are likely to use both cytosolic and
Multiple sclerosis Airas et al. (2006) mitochondrial pathways for formaldehyde oxidation to
Heart disease Boomsma et al. (2000, 2005)
formate and further to carbon dioxide (Figs 1 and 3).
Diabetes mellitus Meszaros et al. (1999);
Cultured brain cells efciently produce and export glyco-
and diabetic Gronvall-Nordquist
lytically generated lactate and also release GSH into the
complications et al. (2001); Karadi et al.
(2002); Boomsma et al.
medium, although the basal rates of glycolysis and GSH
(2005); Obata (2006) export differ between different types of neural cells (Tulpule
Chronic liver disease Kurkijarvi et al. (2000) and Dringen 2011, 2012; Tulpule et al. 2012, 2013). These
LSD1/JHDM Sarcoma Schildhaus et al. (2011); pathways are not affected by low concentrations of formal-
Bennani-Baiti et al. (2012) dehyde, but as soon as formaldehyde levels are increased in
Peripheral nerve Schildhaus et al. (2011) pathological conditions, an accelerated generation of formate
sheath tumor is likely to stimulate glycolytic ux by inhibition of the
Neuroblastoma Schulte et al. (2009) mitochondrial respiration (Fig. 3). In addition, an excess of
Bladder cancer Hayami et al. (2010, 2011)
formaldehyde deprives brain cells of GSH by stimulating
Breast cancer Lim et al. (2010)
Mrp1-mediated GSH export (Fig. 3). Although, caution should
Prostate cancer Kahl et al. (2006); Xiang
be exercised while extrapolating in vitro data to the situation
et al. (2007)
in the brain, a speculation on potential consequences of

2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21

14 K. Tulpule and R. Dringen
Fig. 3 Metabolic consequences of a formaldehyde exposure in
cultured brain cells. Exogenous formaldehyde is entering brain cells
most likely by diffusion through the cell membrane and is oxidized
within the cell to formate either in a glutathione (GSH)-dependent
reaction that is mediated by cytosolic alcohol dehydrogenase (ADH) 3
or by the mitochondrial aldehyde dehydrogenase (ALDH) 2. Part of the
elevated formaldehyde levels in brain on the cellular metab-
olism is tempting, especially since the formaldehyde concen-
trations that have been shown to alter metabolic properties of
cultured brain cells (0.11 mM) are in the concentration
range reported for the normal brain (0.20.4 mM). Thus, mild
elevations in brain formaldehyde concentrations could already
strongly affect energy and GSH metabolism of this organ.
The potential pathological implications of metabolic
changes exerted by excess of formaldehyde in the brain are
shown in Fig. 4. Astrocytes and neurons in brain are likely to
efciently metabolize an excess of formaldehyde, as also
reported for brain homogenates (Iborra et al. 1992). Subse-
quently, the formate generated from formaldehyde is either
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
generated formate is exported, while a fraction is further oxidized to
carbon dioxide. Remaining cellular formate is likely to inhibit mito-
chondrial cytochrome c oxidase which leads to accelerated glycolytic
ux. Formaldehyde also induces a rapid Mrp1-mediated GSH export
from brain cells. Small black squares indicate transporters that are
required for membrane transport of the indicated metabolites.
Fig. 4 Potential consequences of an
excess of formaldehyde in brain. Presence
of excess of formaldehyde or formaldehyde-
derived metabolites will acutely modulate
metabolic pathways of brain cells (light gray
squares) which are likely to cause delayed,
indirect consequences (dark gray squares)
that nally lead to the adverse effects
reported for formaldehyde exposure.
released from brain cells or inactivates mitochondrial cyto-
chrome c oxidase. An inhibition of the mitochondrial
respiratory chain will stimulate glycolytic ux in the brain
cells to, at least transiently, meet their energy demand.
However, prolonged exposure to formaldehyde is likely to
result in energy crisis that in turn will disrupt the functions of
brain cells. This may also be the underlying mechanism of
the neurotoxicity of formate in hippocampal brain slices
(Kapur et al. 2007). Besides this impairment of energy
metabolism, formaldehyde-induced accumulation of both
formate and lactate in the brain would cause cerebral acidosis
(Skrzydlewska 2003; Rose 2010) which would subsequently
induce astrocytic swelling, impairment of neuronal signal

transmission and neurological decits (Staub et al. 1993; Li
et al. 2011; Zhao et al. 2011).
Exposure to high levels of formaldehyde will cause GSH
depletion in brain cells together with GSH accumulation in
the extracellular space. As GSH is involved in important
cellular functions in the brain like protection against reactive
oxygen species and detoxication of xenobiotics (Lushchak
2012; Schmidt and Dringen 2012; Lu 2013), GSH depletion
may contribute to the severe oxidative stress reported for
brain after prolonged exposure to formaldehyde (Zararsiz
et al. 2006, 2007, 2011; Songur et al. 2008). A loss in
cellular GSH would under normal conditions be compen-
sated by increased GSH synthesis. However, lactacidosis
caused by the formaldehyde-induced production of lactate
(Skrzydlewska 2003; Rose 2010) impairs GSH synthesis
(Lewerenz et al. 2010) and cellular GSH levels are likely to
remain low. Thus, chronic exposure to formaldehyde may
render brain cells incapable of fully restoring their cellular
GSH levels.
The formaldehyde-induced accumulation of extracellular
GSH in brain can also be detrimental, since GSH has been
suggested to act as a neurotransmitter and neuromodulator at
glutamate receptors (Janaky et al. 2007) which play impor-
tant roles in memory and learning (Davis et al. 2013;
Mukherjee and Manahan-Vaughan 2013). Also, accelerated
extracellular GSH hydrolysis by the astrocytic ectoenzyme
c-GT (Dringen et al. 1997) caused by the increased extra-
cellular GSH concentration would generate the neurotrans-
mitter glutamate (Fernandez-Fernandez et al. 2012; Schmidt
and Dringen 2012). Thus, excessive accumulation of extra-
cellular GSH as well as GSH-derived glutamate may cause
excitotoxicity which has at least been demonstrated in vitro
(Regan and Guo 1999a, b).
To address the molecular mechanisms that are involved in
the development of adverse neural effects of an elevated
concentration of formaldehyde, it has to be discriminated
between direct and indirect consequences of formaldehyde
exposure. Acute exposure of neural cells to formaldehyde
and/or the rapid generation of formaldehyde-derived metab-
olites will directly affect basal metabolic parameters (Fig. 4,
light gray squares), which may subsequently lead to indirect,
delayed consequences (Fig. 4, dark gray squares). Little is
known so far on the mechanisms that link acute direct
consequences of a formaldehyde exposure, such as acceler-
ated glycolysis or GSH export, to the known adverse effects
of formaldehyde on neural cells (Table 2). Activation of
signaling cascades as well as alterations in protein expression
are likely to be involved in the development of the delayed
indirect effects of an exposure to excess of formaldehyde.
For example, formaldehyde-exposed neuronal PC12 cells
show endoplasmic reticulum stress, decreased levels of the
antioxidant proteins thioredoxin and paraoxonase 1 (Tang
et al. 2011; Luo et al. 2012) and a decreased expression of
the anti-apoptotic protein Bcl-2, while the expression of pro-
2013 International Society for Neurochemistry, J. Neurochem. (2013) 127, 7--21
Formaldehyde in brain 15
apoptotic Bax protein increases (Tang et al. 2012). Also, the
expression of the rate-limiting enzyme in dopamine synthesis,
tyrosine hydroxylase, is lowered in PC12 cells after exposure
to formaldehyde (Lee et al. 2008). Further studies are now
required to investigate the signaling pathways that link the
acute formaldehyde-induced metabolic alterations to the
known brain pathology of an excess of formaldehyde
(Table 2)
Conditions such as aging and diseases like MS and AD
which are associated with increased levels of formaldehyde
in brain (Khokhlov et al. 1989 cited in Miao and He 2012;
Tong et al. 2011, 2013a, b) show impaired mitochondrial
function (Sullivan and Brown 2005; Mahad et al. 2008;
Boumezbeur et al. 2010; Leuner et al. 2012) together with
an increase in brain lactate content (Parnetti et al. 2000; Ross
et al. 2010; Paling et al. 2011). Moreover, ageing, MS and
AD have been connected with oxidative stress in the brain
(Haider et al. 2011; van Horssen et al. 2011; Belkacemi
and Ramassamy 2012; Sohal and Orr 2012; Steele and
Robinson 2012). These reports strengthen the view that
formaldehyde may, at least to some extent, have a role in the
initiation and/or progression of pathological symptoms of
neurodegenerative conditions (Yu 2001; Monte 2010). An
adequate supply of lactate to neurons has been shown to
foster memory formation (Suzuki et al. 2011), while GSH
depletion in the brain has been demonstrated to result in
behavioral changes (Steullet et al. 2010). Thus, the formal-
dehyde-induced alterations in glucose and GSH metabolism
may contribute to the decits in behavior, cognition and
learning observed in formaldehyde-exposed animals (Pitten
et al. 2000; Malek et al. 2003; Lu et al. 2008; Tong et al.
2011, 2013a, b)
Conclusions and future perspectives
In conclusion, elevation of brain formaldehyde levels is
likely to alter brain cell metabolism which may affect the
function of this vital organ. Although some studies have
correlated that neurodegenerative conditions are associated
with increased levels of formaldehyde in the brain and others
have connected such diseases with impaired energy metab-
olism and oxidative stress, a direct causal link between
formaldehyde, impaired metabolism and oxidative stress
remains to be demonstrated. Interestingly, resveratrol which
is known to be neuroprotective for AD (Richard et al. 2011;
Li et al. 2012) is a formaldehyde scavenger (Tyihak and
Kiraly-Veghely 2008), suggesting that the benecial effects
of resveratrol could also include removal of excess formal-
dehyde. Further studies that will combine the quantication
of formaldehyde levels in post-mortem brains with metab-
olite proles and analysis of oxidative stress markers are now
required to provide further experimental evidence for a direct
contribution of formaldehyde in the pathology of neurode-
generative disorders.
16 K. Tulpule and R. Dringen
Conflict of interest
The authors have no conict of interest to declare.
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