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Cited by 122Birth, Development, and HealthStress Responses and CortisolMaternal Mental Health During Pregnancy and Postpartum

The DOI matches its Crossref record; 72 of the 73 references it cites were found in a registry or an index.

Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission

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Moisiadis, Vasilis G., Constantinof, Andrea, Kostaki, Alisa, Szyf, Moshe, Matthews, Stephen G.·2017·Scientific Reports
DOI 10.1038/s41598-017-11635-wPMC PMC5603559
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Abstract

Fetal exposure to high levels of glucocorticoids programs long-term changes in the physiologic stress response and behaviours. However, it is not known whether effects manifest in subsequent generations of offspring following maternal (MT) or paternal (PT) transmission. We treated pregnant guinea pigs with three courses of saline or synthetic glucocorticoid (sGC) at a clinically relevant dose. Altered cortisol response to stress and behaviours transmitted to juvenile female and male F 2 and F 3 offspring from both parental lines. Behavioural effects of sGC in F 1-F 3 PT females associated with altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus (PVN). Exposure to sGC programmed large transgenerational changes in PVN gene expression, including type II diabetes, thermoregulation, and collagen formation gene networks. We demonstrate transgenerational programming to F 3 following antenatal sGC. Transmission is sex- and generation-dependent, occurring through both parental lines. Paternal transmission to F 3 females strongly implicates epigenetic mechanisms of transmission.

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Figures

Figure 1 Breeding scheme for (A) Veh and (B) sGC groups. Maternal (Mat) and paternal (Pat) lines originate from F1 female and male breeders (respectively). N represents the total number of independent litters for each treatment, breeding line and generation.
Figure 1 Breeding scheme for (A) Veh and (B) sGC groups. Maternal (Mat) and paternal (Pat) lines originate from F1 female and male breeders (respectively). N represents the total number of independent litters for each treatment, breeding line and generation.CC BY · PubMed Central
Figure 2 HPA response to open field stress on (A) PND 19 and (B) PND 24 for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open symbols, sGC (synthetic glucocorticoid) closed symbols. Insert: salivary cortisol AUCN (net area under the curve). Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P < 0.075.
Figure 2 HPA response to open field stress on (A) PND 19 and (B) PND 24 for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open symbols, sGC (synthetic glucocorticoid) closed symbols. Insert: salivary cortisol AUCN (net area under the curve). Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P < 0.075.CC BY · PubMed Central
Figure 3 Total locomotor activity in the open field on (A) PND 19 and (B) PND 24 for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open bars, sGC (synthetic glucocorticoid) closed bars. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P < 0.075.
Figure 3 Total locomotor activity in the open field on (A) PND 19 and (B) PND 24 for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open bars, sGC (synthetic glucocorticoid) closed bars. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P < 0.075.CC BY · PubMed Central
Figure 4 (A) Acoustic startle response (ASR; PND 23) and (B) percent inhibition of the startle response at increasing prepulse intensities (PPI; PND 23) for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open bars, sGC (synthetic glucocorticoid) closed bars. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P < 0.075.
Figure 4 (A) Acoustic startle response (ASR; PND 23) and (B) percent inhibition of the startle response at increasing prepulse intensities (PPI; PND 23) for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open bars, sGC (synthetic glucocorticoid) closed bars. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P < 0.075.CC BY · PubMed Central
Figure 5 (A) Locomotor activity and (B) average body temperature over 24-hour period in the animal’s home cage for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open symbols/bars, sGC (synthetic glucocorticoid) closed symbols/bars. (A) X-axis: solid bar indicates lights off, open bar indicates lights on. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P = 0.068. A significant 1-hour phase difference between Veh and Beta groups is represented as follows: P < 0.05.
Figure 5 (A) Locomotor activity and (B) average body temperature over 24-hour period in the animal’s home cage for F1-F3 female and male MT (Maternal Transmission) and PT (Paternal Transmission) offspring. Veh (Vehicle) open symbols/bars, sGC (synthetic glucocorticoid) closed symbols/bars. (A) X-axis: solid bar indicates lights off, open bar indicates lights on. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05; #P = 0.068. A significant 1-hour phase difference between Veh and Beta groups is represented as follows: P < 0.05.CC BY · PubMed Central
Figure 6 (A) Gene expression in the mPFC relative to the housekeeping gene Gapdh for F1-F3 female PT (Paternal Transmission) offspring. Veh (Vehicle) open bars, sGC (synthetic glucocorticoid) closed bars. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05. (B) Representative sections of the mPFC before and after tissue punch. Dashed line indicates site of punch.
Figure 6 (A) Gene expression in the mPFC relative to the housekeeping gene Gapdh for F1-F3 female PT (Paternal Transmission) offspring. Veh (Vehicle) open bars, sGC (synthetic glucocorticoid) closed bars. Data are expressed as mean ± SEM. A significant difference between Veh and sGC groups is represented as follows: *P < 0.05. (B) Representative sections of the mPFC before and after tissue punch. Dashed line indicates site of punch.CC BY · PubMed Central
Figure 7 (A) Venn diagram illustrating the number of genes that are significantly differentially expressed in the PVN from F1-F3 female PT (Paternal Transmission) and the number of genes that overlap between generations. Numbers in brackets indicate the total number of differentially expressed genes and the number of genes with increased or decreased expression in the sGC group. (B) Heat maps of significantly enriched gene sets in the PVN for F1-F3 PT female offspring (NES > 1.6, FDR < 0.25). Each row represents one gene, each column represents one animal. Green represents lowly expressed genes and red represents highly expressed genes. (C) Representative images of the PVN before and after tissue punch. Dashed line indicates site of punch.
Figure 7 (A) Venn diagram illustrating the number of genes that are significantly differentially expressed in the PVN from F1-F3 female PT (Paternal Transmission) and the number of genes that overlap between generations. Numbers in brackets indicate the total number of differentially expressed genes and the number of genes with increased or decreased expression in the sGC group. (B) Heat maps of significantly enriched gene sets in the PVN for F1-F3 PT female offspring (NES > 1.6, FDR < 0.25). Each row represents one gene, each column represents one animal. Green represents lowly expressed genes and red represents highly expressed genes. (C) Representative images of the PVN before and after tissue punch. Dashed line indicates site of punch.CC BY · PubMed Central

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Metadata

Authors
Moisiadis, V. G., Constantinof, A., Kostaki, A., Szyf, M., & Matthews, S. G.
Affiliations
University of Toronto (CA)
Corresponding author
Matthews, Stephen G.
ORCID
Matthews, Stephen G.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-09-18
Volume
7
Issue
1
Pages
11814-11814
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-11635-w
PMC
PMC5603559
OpenAlex
W2754298054
Cited by
122
References
73
Citations by year
2026: 2 · 2025: 10 · 2024: 11 · 2023: 12 · 2022: 6 · 2021: 10 · 2020: 43 · 2019: 14 · 2018: 11 · 2017: 3
FWCI
21.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Fondation Brain Canada
  • Kids Brain Health Network
  • Canadian Institutes of Health Research (126166, 126166_1)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
prenatal glucocorticoid exposure, transgenerational epigenetic inheritance, mother-to-child transmission, paternal transmission, stress response, cortisol, hypothalamic paraventricular nucleus, prefrontal cortex gene expression, type 2 diabetes, thermoregulation, collagen synthesis, guinea pig model
MeSH terms
Animals, Diabetes Mellitus, Type 2, Female, Glucocorticoids, Guinea Pigs, Male, Paraventricular Hypothalamic Nucleus, Pregnancy, Prenatal Exposure Delayed Effects, Epigenesis, Genetic

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