HyperoxiaPaper

Int. J. Devl Neuroscience 48 (2016) 31–37
Contents lists available at ScienceDirect
International Journal of Developmental Neuroscience
journal homepage: www.elsevier.com/locate/ijdevneu
Neonatal hyperoxia induces alterations in neurotrophin gene
expression
T. Sengoku, K.M. Murray, M.E. Wilson∗
University of Kentucky, Department of Physiology, 800 Rose Street, MS 508, Lexington, KY 40536, USA
a r t i c l e i n f o
Article history:
Received 3 September 2015
Received in revised form
13 November 2015
Accepted 14 November 2015
Available online 22 November 2015
Keywords:
BDNF
GDNF
DNA methylation
Hyperoxia
DNMT1
DNMT3a
a b s t r a c t
Each year in the United States, nearly 500,000 infants a year are born prematurely. Babies born before
35 weeks gestation are often placed on ventilators and/or given supplemental oxygen. This increase in
oxygen, while critical for survival, can cause long-term damage to lungs, retinas and brains. In particular,
hyperoxia causes apoptosis in neurons and alters glial activity. Brain-derived neurotrophic factor (BDNF)
and glial cell line-derived neurotrophic factor (GDNF) are members of the neurotrophin family of pro-
teins that function to promote the growth, differentiation and development of the nervous system. We
hypothesized that hyperoxia can alter the regulation of these genes and by doing so adversely affect the
development of the brain. We predicted that mice exposed to hyperoxic conditions would have differ-
ences in BDNF and GDNF mRNA expression and relative level of methylated promoter regions coinciding
with differences in the relative levels of DNMT1 and DNMT3a mRNA expression. To test this hypothesis,
newborn C57Bl/6 mice and their littermates were placed in hyperoxic or normoxic conditions from post-
natal day 7 to 12. There were significant decreases in BDNF mRNA expression in the prefrontal cortex
following hyperoxia, but a significant increase in the isocortex. GDNF mRNA expression was significantly
increased in both the isocortex and prefrontal cortex following hyperoxia. DNMT1 mRNA expression was
significantly decreased in the isocortex but significantly increased in the prefrontal following hyperoxia.
Together these data suggest that short-term exposure to hyperoxic conditions can affect the regulation
and expression of BDNF and GDNF potentially leading to alterations in neural development.
Published by Elsevier Ltd. on behalf of ISDN.
1. Introduction
Babies born prematurely are often placed on ventilators and
given supplemental oxygen for varying lengths of time. This
increase in oxygen, while critical for survival, can cause long-term
damage to the lungs, retinas and brains of these babies (Askie
et al., 2011). As preterm babies develop, they are at a significantly
increased risk for anxiety and inattention-associated disorders
(Aarnoudse-Moens et al., 2009; Johnson et al., 2010a,b; Johnson
and Marlow, 2011; Schmitz et al., 2012). In a rodent model of hyper-
oxia there was a significantly increased amount of cell death in the
CA1 and dentate gyrus of the hippocampus, prefrontal cortex, pari-
etal cortex, subiculum, and retrosplenial cortex of hyperoxic rats
(Yis et al., 2008; Endesfelder et al., 2014). Specifically, hyperoxia
causes apoptosis in neurons and alters glial activity. There is, how-
ever, little known about the molecular mechanisms underlying the
potential long term effects on the brain following hyperoxia.
∗ Corresponding author.
E-mail address: melinda.wilson@uky.edu (M.E. Wilson).
Brain derived nerve growth factor (BDNF) and glial derived
nerve growth factor (GDNF) are both neurotrophins widely dis-
tributed in the central nervous system. Neurotrophins are a family
of proteins that promote and induce the growth, differentia-
tion and development of the nervous system. During early brain
development, BDNF and GDNF expression contribute to neuronal
migration, survival, and maintenance (Cohen-Cory et al., 2010;
Horch et al., 2004; Pearson-Fuhrhop and Cramer, 2010). These
factors are also associated with learning and memory as well as
positive outcomes following brain injury (Hennigan et al., 2007;
Hicks et al., 1998). Conditions that disrupt the timing and regula-
tion of the expression of these critical factors can lead to long-term
detrimental effects thus the effects of hyperoxia on the expression
of these factors could be critical.
Regulation of gene expression involves a variety of mecha-
nisms. One of these mechanisms is epigenetic modification of DNA
resulting in lasting changes in gene transcription. DNA methyl-
transferases enzymatically transfer a methyl group to cytosine
residues followed by a guanine (CpG). Following methylation of
cytosines in the promoter region of a gene, methyl-CpG-binding
proteins (methyl binding proteins 1–4 and MeCp2) can inhibit
http://dx.doi.org/10.1016/j.ijdevneu.2015.11.003
0736-5748/Published by Elsevier Ltd. on behalf of ISDN.

32 T. Sengoku et al. / Int. J. Devl Neuroscience 48 (2016) 31–37
0
2
4
6
8
10
12
0
0.5
1
1.5
2
2.5
3
Normoxic
Hyperoxic
*
*
*
*
Isocortex Prefrontal
Cortex
Cortex
mRNAexpression
(relativetoNormoxicIsocortex)
mRNAexpression
BDNF
GDNF
Fig. 1. Semi-quatitiative real-time RT-PCR for BDNF mRNA levels (Top panel) and GDNF (Bottom panel). BDNF mRNA expression was significantly increased following
hyperoxia the isocortex (p < 0.03) and significantly decreased in the prefrontal cortex (p < 0.004). The level of GDNF mRNA expression was significantly increased following
hyperoxia (p < 0.05) in the isocortex. GDNF mRNA expression was signifcantly increased following hyperoxia in the prefrontal cortex (p < 0.04). All comparisons were made
relative to normoxic controls. * = significant difference less than p = 0.05. n, 4–8.
transcription by interfering with the normal transcriptional
machinery (Nan et al., 1998). BDNF and GDNF mRNA expression
have previously been shown to be regulated by DNA methylation
in models of development and learning (Martinowich et al., 2003;
Sui et al., 2012). Changes in DNA methylation, total DNMT levels,
and DNMT mRNA levels have been reported in conjunction with
BDNF-mediated synaptogenesis and LTP. In addition, the epige-
netic regulation of GDNF has been shown to play a critical role
in the behavioral response to chronic stress (Uchida et al., 2011).
Together, these studies suggest that changes in the epigenetic reg-
ulation of BDNF and GDNF are critical for brain function. In the
present study we investigated whether exposure to hyperoxic con-
ditions can result in alterations in neurotrophin gene expression in
the developing brain.
2. Materials and methods
2.1. Mice
Pregnant C57Bl/6 dams were purchased from Harlan Labora-
tories. Pups were housed with their mother and maintained in
constant temperature conditions on a 12 h light/dark cycle and
were provided food and water ad libitum. On postnatal day 7
(PND7, with day of birth defined as PND0) the home cage contain-
ing the mother and pups (6 pups/mother/treatment) was placed in
a plexiglass chamber connected to a BioSpherix OxyCycler (model
A84XOV). The pups were exposed to 73% oxygen from PND7-12
after which they were placed back in normal air. PND7-12 was
chosen because this time frame represents mid-third trimester of
fetal development in humans. At PND 21 the brains were removed
for processing. Both male and female pups were used. No sex dif-
ferences in gene expression were observed, so the groups were
combined for analysis. The animal care and use committee of the
University of Kentucky approved all experimental procedures.
2.2. Tissue collection and quantitative real time PCR (RT-PCR)
To examine gene expression following hyperoxia, we isolated
and collected isocortex (CTX) and prefrontal cortex (PFC) from
approximately Bregma +1.98 to Bregma +0.74. Tissue was collected
from C57Bl/6 male and female mice killed at postnatal day (PND)
21. Fifty to one hundred milligrams of tissue from CTX and PFC
was isolated and homogenized in 1 ml of TRIZOL Reagent (Invitro-
gen, Carlsbad, CA). The resulting RNA pellet was briefly air dried
and suspended in 50 ␮l RNase-free water. The suspended RNA was
incubated at 56 ◦C for 10 min and stored at −80 ◦C until reverse
transcription. DEPC H20 was added to bring 1 ␮g of total RNA for
each sample up to a final volume of 10 ␮l. One microliter of Random
Primers (Invitrogen) and 1 ␮l of 10 mM dNTP’s were added to each
reaction. The samples were incubated at 65 ◦C for 5 min and then
chilled on ice. Four microliters of 5× first strand buffer, 2 ␮l 0.1 M
DTT, 1 ␮l RNasin, and 1 ␮l Superscript RT (Invitrogen) were added
to each sample. Samples were then incubated at room temperature
for 10 min, 42 ◦C for 50 min, and 70 ◦C for 15 min. For qPCR, each

T. Sengoku et al. / Int. J. Devl Neuroscience 48 (2016) 31–37 33
Normoxic
Hyperoxic
Isocortex
Isocortex
Prefrontal
Cortex
Prefrontal
Cortex
0
0.5
1
1.5
2
2.5
3
3.5
DNMT3a
0
0.5
1
1.5
2 *
*
DNMT1
mRNAexpression
mRNAexpression
Fig. 2. Semi-quatitiative real-time RT-PCR for DNA methyltransferase enzyme expression. DNMT1 mRNA expression was significantly decreased in female isocortex following
hyperoxia (p < 0.001). DNMT1 mRNA expression was significantly increased in male pfc following hyperoxia (p < 0.05). There were no significant changes in DNMT3a mRNA
expression in male or female isocortex or PFC following hyperoxia.
reaction contained 21.25 ␮l of DEPC H20, 25 ␮l of 2× SYBRGreen
Brilliant Master Mix (Stratagene, La Jolla, CA), 1 ␮l of upstream
primer at a concentration of 250 nm, 1 ␮l of downstream primer
at a concentration of 50 nm, 0.75 ␮l of Reference Dye (Strata-gene,
diluted 1:500) and 1 ␮l of appropriate cDNA. Primer concentra-
tions were previously optimized for each gene and result in a single
DNA PCR product with no primer dimer formation (Prewitt and
Wilson, 2007; Park et al., 2005; Dubal et al., 2001). Each 96 well
plate contained a non-template control and each sample was run
in triplicate. Cycling parameters were as follows: 1 cycle at 95 ◦C
for 10 min, 40 cycles of 95 ◦C for 30 s, annealing temperature for
1 min, 72 ◦C for 30 s, and 1 cycle of 95 ◦C for 1 min and 55 ◦C for 30 s.
Real time fluorescent measurements were taken at every cycle and
change in threshold cycle ( Ct) was calculated. The Ct for each
sample was compared back to the normoxic condition of the same
sex. All data was normalized to the housekeeping gene Histone 3.1.
Primers for DNA methyltransferases DNMT1 and DNMT3A as well
as the primers for the housekeeping control, Histone 3.1 have also
been previously described (Nishino et al., 2004).
2.3. Methylation-specific PCR
For methylation-specific PCR (MSP), genomic DNA was
extracted from male and female CTX and PFC at PND 21–25 using
previously described methods (Westberry et al., 2008). Briefly,
20–50 mg of tissue was homogenized in 250 ␮l of lysis solu-
tion (10 mM Tris–HCl (pH 8.0), 150 mM EDTA, 1% SDS, 100 g/ml
proteinase K) and incubated for 20 min at 55 ◦C. One hundred
microliters of RNase solution, consisting of 10 mM Tris–HCl (pH
8.0), 1 mM EDTA (TE) and 30 units of RNase was added, and
the mixture was incubated at 37 ◦C for 1 h. Two rounds of
phenol–chloroform extraction were performed and 150 ␮l of 1.0 M
sodium acetate (pH 7.0) and 2 volumes of 100% ethanol were
added to separated supernatant and ethanol precipitation was per-
formed. Sodium bisulfite modification was conducted on 500 ng of
genomic DNA using the EZ Methylation Gold kit (Zymo Research).
For MSP, the sodium bisulfite modified DNA was amplified in a 25 ␮l
reaction. Each PCR reaction contained 1× PCR Buffer (Invitrogen),
1.2 mM MgCl2 (Invitrogen), 0.1 mM dNTP’s, 2 pM forward primer, 2
pM reverse primer, and 2.5 units Platinum Taq Polymerase (Invitro-
gen). The cycling conditions were: 95 ◦C for 2 min, 35 cycles of 95 ◦C
30 s, appropriate annealing temperature for 30 s, 72 ◦C for 30 s, sub-
sequently followed by 72 ◦C for 10 min. The primers used for each
promoter were designed using Methprimer (http://www.genome.
wi.mit.edu/genomesoftware/other/primer3.html) and have been
previously described (Hashim and Guillet, 2002; O’Donovan and
Fernandes, 2000; Schmitz et al., 2011). Optical density of bands on
the ethidium bromide gel were analyzed using NIH ImageJ.
2.4. Immunohistochemistry
For immunohistochemistry (IHC), 20 ␮m sections were fixed on
slides with 4% paraformaldehyde for 30 min. After blocking endoge-
nous peroxidase activity with 0.30% peroxide and non-specific

0
0.5
1
1.5
2
2.5
3
0
0.5
1
1.5
2
Normoxic
Hyperoxic
Cortex
Cortex
MethylatedDNAlevels
MethylatedDNAlevels
BDNF
GDNF
Fig. 3. Methylation specific PCR to examine known methylation regions of the BDNF and GDNF promoters. There were no significant changes in methylation in the promoters
in the isocortex or PFC following hyperoxia.
binding with 10% Normal Donkey Serum, sections were incubated
with a mouse anti-NeuN (Millipore, Billerica, MA, MAB377, 1:500),
rabbit anti-Iba1 (Santa Cruz, Santa Cruz, CA, 98,468, 1:500), rabbit
anti-Olig2 (Millipore, Billerica, MA, AB9610, 1:500), or rabbit anti-
GFAP (AbCam, Cambridge, MA, ab16997, 1:250) antibody overnight
at 4 ◦C, followed by incubation in secondary donkey anti-mouse or
anti-rabbit Alexa Fluor 488 (Molecular Probes, Eugene, OR, 1:500)
for 1 h at room temperature. The sections were then cover-slipped
with VectaShield (Vector labs, Burlingame, CA) and visualized
on a fluorescent microscope. For control experiments, either the
primary antibody or the secondary antibody was excluded from
the blocking buffer during incubation. We did not observe any
immunoreactive (-IR) cells in these control conditions. Three ran-
dom fields at 100x were sampled for each of three animals.
Immunofluoresence values were compared using NIH ImageJ.
2.5. Statistical analysis
Results are expressed as means ± SEM. The data were analyzed
by one-way ANOVA to determine if the effect of hyperoxia on indi-
vidual gene expression in specific brain regions. Differences were
considered statistically significant at p < 0.05.
3. Results
3.1. Neurotrophic factors: BDNF and GDNF mRNA expression
The isocortex (CTX) includes motor and sensory cortex and
is involved in generating motor commands, sensory perception,
and spatial reasoning. The prefrontal cortex (PFC) is thought to
be involved with attention, behavioral inhibition and working
memory. Many of the neurodevelopmental disorders that develop
following hyperoxia include components that involve both isocor-
tex and prefrontal cortex, therefore we will focus our studies on
examining the expression of BDNF, GDNF and DNA methyl trans-
ferases in these two brain regions. Additionally, we examined gene
expression at PND21 because this age represents the end of the
period of dramatic changes in gene expression that occur in the
developing rodent cortex that is thought to establish adult patterns
of expression (Prewitt and Wilson, 2007; Hara et al., 2015). Our
initial hypothesis was that receptors for the neurotrophic steroid
hormone, estrogen, would be altered by hyperoxia. However, they
were not, so the focus of the current study was on other potential
neurotrophic factors.
To determine the effect of hyperoxia on BDNF and GDNF
gene expression, mRNA from normoxic and hyperoxic postnatal
day 21 mice isocortex and PFC were isolated and mRNA levels
determined by quantitative real-time PCR (RT-PCR). BDNF mRNA
expression significantly increased following hyperoxia in the iso-
cortex (p < 0.03) (Fig. 1). BDNF mRNA expression was significantly
lower in the PFC following hyperoxia (p < 0.004). GDNF mRNA
expression was significantly elevated following hyperoxia in the
CTX (p < 0.05) and in the PFC (p < 0.004).
3.2. DNA methyltransferase mRNA expression
DNA methyltransferase are key enzymes in the process of DNA
methylation and subsequent gene silencing. DNMT1 is the main-
tenance enzyme while DNMT3a initiates mehtylation of DNA. To
determine the effect of hyperoxia on DNMT1 and DNMT3a gene

Fig. 4. (A) Numbers of cells following hyperoxia. Cell counts were made in the prefrontal cortex and expressed as a percentage of normoxic controls. There was no significant
change in the number of oligodendrocytes present. There was however a significant increase in the number of astrocytes and a significant decrease in the number of microglia
and neurons (p < 0.05). * = significant difference less than p = 0.05. n, 4. (B). Representative micrographs of himmunohistochemistry. All images were taken from prefrontal
cortex at a magnification of 100×, except Iba1 which was is shown at 400×.
expression, mRNA from normoxic and hyperoxic postnatal day 21
mice isocortex and PFC were isolated and mRNA levels determined
by quantitative real-time PCR (RT-PCR). DNMT1 mRNA expres-
sion significantly decreased in the isocortex following hyperoxia
(p < 0.03) (Fig. 2). DNMT1 mRNA was significantly increased in PFC
following hyperoxia (p < 0.04). There were no significant changes
in DNMT3a in either the isocortex or PFC following hyperoxia
(n = 6–8).
3.3. Methylated BDNF Exon IV and GDNF promoter regions
To examine the methylation status of individual pro-
moters we utilize methylation specific PCR (Fig. 3). There

were no significant changes in methylated BDNF exon IV
in either isocortex or PFC. Additionally, there were no
significant changes in methylated GDNF promoter regions in either
the isocortex or PFC following hyperoxia (n = 4–6). DNA methyla-
tion of these promoter regions was also assesed by pyrosequencing
and revealed no differences (data not shown).
3.4. Immunohistochemistry
To determine if particular cell types were more vulnerable
to the affects of hyperoxia, we took 20 ␮m sections fixed with
4% paraformaldehyde. Sections were incubated with antibodies,
cover-slipped and visualized by fluorescent microscopy. Following
hyperoxia there was a significant increase in GFAP immunopositive
cells (p < 0.01) accompanied by a significant loss of NeuN (neu-
ronal marker) (p < 0.005) and Iba1 (microglia marker) (p < 0.04)
immunopositive cells in the cortex compared to normoxic con-
trols (Fig. 4A) (n = 4). There was no significant change in Olig2
(oligodendrocyte marker) immunoreactive cells following hyper-
oxia. Representative micrographs are shown in Fig. 4B.
4. Discussion
Preterm infants are often given increased oxygen in order
to prevent death. The long term effects of this hyperoxia may
include cardiovascular disease, repiratory illness, severe retinal
damage, cerebral palsy, and attention deficit hyperactivity dis-
order (Deuber and Terhaar, 2011). The cumulative cost of care
for the surviving preterm neonates is considerable (Petrou et al.,
2010). Elucidating mechanisms that provide some neuroprotection
against these unwanted oxygen-induced side effects could improve
the outcomes for these surviving preterm neonates. The molecu-
lar mechanisms that lead to the pathophysiological changes in the
brain following hyperoxia are not fully understood. In the present
study we determined that neonatal hyperoxia altered neurotrophic
factor gene expression in a brain region-specific fashion. Addi-
tionally, we observed changes in DNA methyltransferase mRNA
expression.
BDNF mRNA expression was significantly increased in the iso-
cortex and decreased in the PFC following hyperoxia. The medial
PFC is associated with cognition and emotion and in particular
BDNF plays an important role in neural plasticity in this brain
region. The decreased BDNF mRNA expression in mouse PFC in our
study may be a contributing factor in the abberant development
of neuronal architecture following hyperoxia. In addition, DNMT1
mRNA expression was significantly increased in PFC indicating
that the decrease in BDNF mRNA expression in PFC is potentially
mediated through epigenetic regulation, specifically DNA methy-
lation. In our studies, however, we did not observe significant
alterations in the methylation state of the BDNF promoter. We ana-
lyzed promoter methylation using methods that had previously
been described (Martinowich et al., 2003; Guo et al., 2010) that
demonstrated alterations in promoter methylation associated with
decreased mRNA levels. It is possible that a more systematic anal-
ysis of the entire promoter and intra-exonic regions of the gene
could reveal such alterations.
We also observed a corresponding decrease in DNMT1 mRNA
expression in the isocortex and significantly increased expression
of DNMT1 mRNA in the PFC following hyperoxia. These data suggest
that perhaps epigenetic regulation of BDNF expression is likely to be
an important target in the isocortex and PFC following hyperoxia.
Although the methylation-specific PCR results showed no signifi-
cant changes in methylated BDNF exon IV promoter, a systematic
examination of the degree of methylation in the promoter regions
of BDNF may very well further confirm the influence of DNA methy-
lation in the regulation of BDNF expression. Additionally, DNMT1
has many targets and a thorough investigation of other genes is
warranted.
GDNF expression was significantly increased in the PFC fol-
lowing hyperoxia. Although increased expression of neurotrophic
factors are generally thought to be largely neuroprotective,
increased GDNF expression has been associated with neuronal
damage in several studies. GDNF has been associated with
increased neuronal cell death following oxygen–glucose depriva-
tion in rodent hippocampal slice cultures (Bonde et al., 2003) and
GDNF protein expression is increased in neonatal rat brain follow-
ing ischemic injury (Ikeda et al., 2002). Increased GDNF expression
may also be associated with astrogliosis following brain injury.
Indeed, there was a significant increase in the number of GFAP
immunopositive cells following hyperoxia that could account for
the increased GDNF mRNA expression that we observed.
We also observed differences in BDNF mRNA expression follow-
ing hyperoxia between different brain regions. In the isocortex,
BDNF mRNA expression increased rather than decline. BDNF has
previously been shown to play a role in hypoxic conditioning and
tolerance in the isocortex (Samoilov et al., 2014). It is entirely pos-
sible and likely that the factors that regulate BDNF in specific brain
regions are different and in the isocortex are particularly responsive
to changes in oxygen levels.
Following hyperoxia there are many cellular changes in the
brain that occur including marked neuronal and glial changes as
well as increased microglia and macrophage presence (Gerstner
et al., 2008). Hyperoxia has also been shown to significantly
increase death in immature oligodendrocytes of the developing
white matter in a rodent model (Yis et al., 2008). Given these
previous findings it seemed likely that changes in cellular compo-
sition of the isocortex and prefrontal cortex would occur following
hyperoxia. Following hyperoxia there were significantly more glia
and significantly fewer microglia and neurons present. It has been
shown that astrocyte-derived GDNF suppresses microglia activa-
tion which could explain the significant decrease in microglia cells
following hyperoxia that we observed (Rocha et al., 2012).
Our studies are the first to show that BDNF mRNA expression in
mouse isocortex is significantly increased while it is significantly
reduced in PFC following hyperoxia. These changes correspond to a
significant decrease in DNMT1 mRNA expression in the cortex and
a significant increase in DNMT1 mRNA expression in the PFC fol-
lowing hyperoxia. These changes in gene expression in the PFC may
be a contributing factor in the increased incidence of neurological
disturbances following hyperoxia. These data begin to elucidate the
possible mechanisms by identifying potential genes involved in the
pathophysiology of the isocortex and prefrontal cortex following
hyperoxia. The functional role of these potential targets are under
investigation.
Acknowledgements
We would like to thank Dr. Jayakrishna Ambati for the use of the
BioSpherix OxyCycler. Supported by NSF IOS0919944 (MEW).
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