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. 2022 Sep 30;13(1):54.
doi: 10.1186/s13293-022-00463-x.

Gestational hypoxia in late pregnancy differentially programs subcortical brain maturation in male and female rat offspring

E Nicole Wilson  1 , Steve Mabry  1 , Jessica L Bradshaw  1 , Jennifer J Gardner  2   1 , Nataliya Rybalchenko  1 , Rachel Engelland  1 , Oluwadarasimi Fadeyibi  1 , Oluwatobiloba Osikoya  2 , Spencer C Cushen  2   3 , Styliani Goulopoulou  2   4 , Rebecca L Cunningham  5
Affiliations

Gestational hypoxia in late pregnancy differentially programs subcortical brain maturation in male and female rat offspring

E Nicole Wilson et al. Biol Sex Differ. .

Abstract

Background: Hypoxia is associated with pregnancy complications, such as preeclampsia, placental abruption, and gestational sleep apnea. Hypoxic insults during gestation can impact the brain maturation of cortical and subcortical pathways, such as the nigrostriatal pathway. However, the long-term effects of in utero hypoxic stress exposure on brain maturation in offspring are unclear, especially exposure during late gestation. The purpose of this study was to determine the impact of gestational hypoxia in late pregnancy on developmental programming of subcortical brain maturation by focusing on the nigrostriatal pathway.

Methods: Timed pregnant Long-Evans rats were exposed to chronic intermittent hypoxia or room air normoxia from gestational day (GD) 15-19 (term 22-23 days). Male and female offspring were assessed during two critical periods: puberty from postnatal day (PND) 40-45 or young adulthood (PND 60-65). Brain maturation was quantified by examining (1) the structural development of the nigrostriatal pathway via analysis of locomotor behaviors and the substantia nigra dopaminergic neuronal cell bodies and (2) the refinement of the nigrostriatal pathway by quantifying ultrasonic vocalizations (USVs).

Results: The major findings of this study are gestational hypoxia has age- and sex-dependent effects on subcortical brain maturation in offspring by adversely impacting the refinement of the nigrostriatal pathway in the absence of any effects on the structural development of the pathway. During puberty, female offspring were impacted more than male offspring, as evidenced by decreased USV call frequency, chirp USV call duration, and simple call frequency. In contrast, male offspring were impacted more than female offspring during young adulthood, as evidenced by increased latency to first USV, decreased simple USV call intensity, and increased harmonic USV call bandwidth. No effects of gestational hypoxia on the structural development of the nigrostriatal pathway were observed.

Conclusions: These novel findings demonstrate hypoxic insults during pregnancy mediate developmental programming of the cortical and subcortical pathways, in which male offspring exhibit long-term adverse effects compared to female offspring. Impairment of cortical and subcortical pathways maturation, such as the nigrostriatal pathway, may increase risk for neuropsychiatric disorders (e.g., mood disorders, cognitive dysfunction, brain connectivity dysfunction).

Keywords: Chronic intermittent hypoxia; Oxidative stress; Prenatal programming; Sex differences; Substantia nigra; Ultrasonic vocalizations.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Description of study design. For study one and two, Long–Evans pregnant female rats were exposed to chronic intermittent hypoxia (CIH) or room air (normoxia) on gestational days (GD) 15–19 (n = 6-8/group). For study one, dams were allowed to give birth (term = GD 22–23) and litters were reduced to eight pups/litter and, when possible, to equal number of males and females. Offspring were weaned at postnatal day (PND) 28 and separated into two groups: Puberty (n = 2/sex/dam; behavior testing = PND 40–45; euthanasia = PND 48) and Young Adult (n = 2/sex/dam; behavior testing = PND 60–65; euthanasia = PND 66). For study two, dams and fetuses were euthanized on GD 20
Fig. 2
Fig. 2
Representative spectrograms of ultrasonic vocalizations (USVs). USVs collected during a 5-min cage mate separation were analyzed. USVs were manually selected within spectrograms and categorized by call type. A Chirp calls were defined as low intensity USVs with a duration less than 0.02 s (20 ms). B Simple calls were defined as USVs longer than 0.02 s (20 ms) with “straight-line” intensity. C Harmonic calls were defined as a single USV with distinct tones of varying duration and intensity that create a “harmony”. Color-coded decibel level shown in key. kHz = kilohertz; s = seconds; dB = decibel
Fig. 3
Fig. 3
Total call frequency and latency to first call. Total call frequency (A, B) and latency to first call (C, D) produced by pubertal (A, C) and young adult (B, D) male and female offspring exposed to normoxia or chronic intermittent hypoxia (CIH) in utero. Analyzed by Two-way ANOVA with Tukey’s multiple comparisons test, n = 9–17/group. Frequency = number of calls per 5-min interval; s = seconds. * = main effect of CIH; & = Tukey’s comparison. *, & = p < 0.05
Fig. 4
Fig. 4
Characterization of pubertal and young adult offspring chirp calls. Frequency (A, B), duration (C, D), intensity (E, F), and bandwidth (G, H) of chirp calls emitted by pubertal (A, C, E, G) and young adult (B, D, F, H) male and female offspring exposed to normoxia or chronic intermittent hypoxia (CIH) in utero. Analyzed by Two-way ANOVA with Tukey’s multiple comparisons test, n = 8–14/group. Frequency = number of calls per 5-min interval, ms = milliseconds, dB = decibels, kHz = kilohertz. * = main effect of CIH; # = main effect of sex; & = Tukey’s comparison; *, #, & = p < 0.05
Fig. 5
Fig. 5
Characterization of pubertal and young adult offspring simple calls. Frequency (A, B), duration (C, D), intensity (E, F), and bandwidth (G, H) of simple calls emitted by pubertal (A, C, E, G) and young adult (B, D, F, H) male and female offspring exposed to normoxia or chronic intermittent hypoxia (CIH) in utero. Analyzed by Two-way ANOVA with Tukey’s multiple comparisons test, n = 4–10/group. Frequency = number of calls per 5-min interval, ms = milliseconds, dB = decibels, kHz = kilohertz. * = main effect of CIH; # = main effect of sex; & = Tukey’s comparison; *, #, & = p < 0.05
Fig. 6
Fig. 6
Bandwidth of harmonic calls emitted by pubertal and young adult offspring. Bandwidth of harmonic calls produced by (A) pubertal and (B) young adult male and female offspring exposed to normoxia or chronic intermittent hypoxia (CIH) in utero. Analyzed by Two-way ANOVA with Tukey’s multiple comparisons test, n = 5–12/group. kHz = kilohertz. * = main effect of CIH; # = main effect of sex, & = Tukey’s comparison; *, #, & = p < 0.05
Fig. 7
Fig. 7
Distance traveled and total rearing behavior by pubertal and young adult offspring during modified open field behavior test. Total distance traveled (A, B) and total rears (C, D) by pubertal and young adult male and female offspring exposed to normoxia (A, C) or chronic intermittent hypoxia (CIH, B, D) in utero. Analyzed by Two-way ANOVA with Tukey’s multiple comparisons test, n = 9–16/group. kHz = kilohertz. * = main effect of CIH, & = Tukey’s comparison; *, & = p < 0.05
Fig. 8
Fig. 8
Circulating advanced oxidation protein products (AOPP) in rat offspring plasma. Concentration of plasma oxidative stress marker, AOPP, in (A) pubertal and (B) young adult male and female offspring exposed to normoxia or chronic intermittent hypoxia (CIH) in utero. Analyzed by two-way ANOVA with Tukey’s multiple comparisons test, n = 10–20/group
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