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. 2016 Mar:5:11-18.
doi: 10.1016/j.nepig.2016.02.001.

Impact of prenatal polycyclic aromatic hydrocarbon exposure on behavior, cortical gene expression and DNA methylation of the Bdnf gene

Rachel L Miller  1 , Zhonghai Yan  2 , Christina Maher  2 , Hanjie Zhang  2 , Kathryn Gudsnuk  3 , Jacob McDonald  4 , Frances A Champagne  3
Affiliations

Impact of prenatal polycyclic aromatic hydrocarbon exposure on behavior, cortical gene expression and DNA methylation of the Bdnf gene

Rachel L Miller et al. Neuroepigenetics. 2016 Mar.

Abstract

Prenatal exposure to polycyclic aromatic hydrocarbons (PAH) has been associated with sustained effects on the brain and behavior in offspring. However, the mechanisms have yet to be determined. We hypothesized that prenatal exposure to ambient PAH in mice would be associated with impaired neurocognition, increased anxiety, altered cortical expression of Bdnf and Grin2b, and greater DNA methylation of Bdnf. Our results indicated that during open-field testing, prenatal PAH exposed offspring spent more time immobile and less time exploring. Females produced more fecal boli. Offspring prenatally exposed to PAH displayed modest reductions in overall exploration of objects. Further, prenatal PAH exposure was associated with lower cortical expression of Grin2b and Bdnf in males, and greater Bdnf IV promoter methylation. Epigenetic differences within the Bdnf IV promoter correlated with Bdnf gene expression, but not with the observed behavioral outcomes, suggesting that additional targets may account for these PAH-associated effects.

Keywords: DNA methylation; N-methyl D-aspartate 2B; brain derived neurotrophic factor; novel object test; open-field testing; polycyclic aromatic hydrocarbons.

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Figures

Figure 1
Figure 1
Study design indicating timing of treatment and assessments of offspring. Abbreviations: OF=open-field; LD=light-dark box; GD=gestational day; PND=postnatal day
Figure 2
Figure 2
Schematic of Bdnf and Grin2b gene structure. (A) Proximal regions of the Bdnf promoter and exon III. The CpG islands (S1–S8) included in DNA methylation analyses and proximal transcription factor binding sites are shown. The pyrosequencing primers were listed as F and R (forward primer started from −251 base pairs, and reverse +43 base pairs from the transcription start site of exon IV). (B) Grin2b gene. The real-time PCR primers were designed to cover an exon-exon junction to eliminate gDNA amplification. Arrows demonstrate region amplified. Abbreviations: TSS=transcription start site; CREB=cAMP response element-binding protein; TrkB= tyrosine receptor kinase B.
Figure 3
Figure 3
Prenatal PAH exposure effects on open-field behavior. (A) Total distance travelled (m) during testing was not significantly impacted by prenatal PAH exposure. (B) Prenatal PAH exposure was associated with greater time (s) spent immobile and (C) reduced time (s) spent exploring the inner area of the field. (D) A sex by treatment effect was found on the number of fecal boli produced during testing, with PAH exposed females emitting more boli compared to controls (Tukey’s, p<.01). Sample sizes for behavioral analyses consisted of n=18 male/n=18 female control offspring and n=14 male/n=16 female PAH exposed offspring. * p<0.05, ** p<0.01
Figure 4
Figure 4
Prenatal PAH exposure and novel object investigation. (A) Prenatal PAH exposure predicted modest (but not significant; p<0.06) reductions in time spent exploring both novel and familiar objects. (B) Ratio preference for the novel object was modestly (though non-significantly; p<0.12) lower in PAH exposed males. Dashed line indicates cut-off ratio for demonstrating preference (>0.5 indicates greater that 50% time exploring the novel object as a function of total time exploring novel and familiar objects), with values above the time indicating novel object preference and values below the fine indicating familiar object preference. (C) Percentage of PAH-exposed and control male and female offspring exhibiting a novel object preference, indicating reductions in novel object preference in PAH-exposed males. Sample sizes consisted of n=18 male/n=18 female control offspring and n=14 male/n=16 female PAH exposed offspring. ** p<0.01
Figure 5
Figure 5
Cortical gene expression in prenatal PAH vs. control mice. Prenatal PAH exposed males (but not females) had reduced cortical mRNA levels of (A) Grin2b, (B) Bdnf III, and (C) Bdnf IV. n=10/sex/treatment. ***p<0.001. 10 males and 10 females per experimental exposure were studied.
Figure 6
Figure 6
Prenatal PAH exposure effects on Bdnf IV promoter DNA methylation in the cortex. Percentage DNA methylation was significantly higher in prenatal PAH exposed compared to control (A) males (at S5–S7), and (B) females (at S7). n=10/sex/treatment *p<0.05.
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