Molecular Mechanisms Underlying Altered Neurobehavioural Development of Female Offspring of Mothers with Polycystic Ovary Syndrome: FOS-mediated Regulation of Neurotrophins in Placenta

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2020 Sep 19

PMID 32949999

Citations 8

Authors

Fangfang Wang

Ningning Xie

Jue Zhou

Minchen Dai

Qing Zhang

Paul J Hardiman

Fan Qu

Affiliations

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Abstract

Background: This study explored the mechanisms underlying altered neurobehavioural development of female offspring born to mothers with polycystic ovary syndrome (PCOS).

Methods: In total, 20 women with PCOS and 32 healthy women who underwent caesarean deliveries with a single female foetus were recruited. Infants were assessed with Dubowitz scoring. Swan71 cell line with stable FOS overexpression was used to verify the regulatory effects of FOS on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) expression. Learning and memory in female first-generation (F1) and second-generation (F2) offspring in a rat model of PCOS was tested using the Morris water maze at puberty and adulthood. Transcriptome analysis of pubertal hippocampi and hypothalami of female F1 offspring was conducted.

Findings: Total score and behaviour subscales of Dubowitz scoring were significantly lower in female infants of women with PCOS. FOS and NGF protein levels were downregulated in placental villi of the PCOS group. FOS played a key role in BDNF inhibition and enhancing NGF in Swan71 cells. PCOS female F1 rats exhibited lower target crossing times during puberty when compared to controls. Transcriptome analysis revealed significant changes in hippocampal and hypothalamic neuronal pathways in female F1 rats at puberty.

Interpretation: FOS regulation of neurotrophins in the placenta negatively affects neurobehavioural development of female offspring of PCOS mothers.

Funding: This study was funded by the National Key R&D Program of China (2018YFC1004900 to F.Q. and F.W.) and the National Natural Science Foundation of China (81874480 to F.Q.; 81873837 to F.W.).

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References

Toti P, Ciarmela P, Florio P, Volpi N, Occhini R, Petraglia F . Human placenta and fetal membranes express nerve growth factor mRNA and protein. J Endocrinol Invest. 2006; 29(4):337-41. DOI: 10.1007/BF03344105. View

Garces M, Sanchez E, Torres-Sierra A, Ruiz-Parra A, Angel-Muller E, Alzate J . Brain-derived neurotrophic factor is expressed in rat and human placenta and its serum levels are similarly regulated throughout pregnancy in both species. Clin Endocrinol (Oxf). 2013; 81(1):141-51. DOI: 10.1111/cen.12391. View

Berry A, Bindocci E, Alleva E . NGF, brain and behavioral plasticity. Neural Plast. 2012; 2012:784040. PMC: 3306960. DOI: 10.1155/2012/784040. View

Chouthai N, Sampers J, Desai N, Smith G . Changes in neurotrophin levels in umbilical cord blood from infants with different gestational ages and clinical conditions. Pediatr Res. 2003; 53(6):965-9. DOI: 10.1203/01.PDR.0000061588.39652.26. View

Uchida S, Inanaga Y, Kobayashi M, Hurukawa S, Araie M, Sakuragawa N . Neurotrophic function of conditioned medium from human amniotic epithelial cells. J Neurosci Res. 2000; 62(4):585-90. DOI: 10.1002/1097-4547(20001115)62:4<585::AID-JNR13>3.0.CO;2-U. View

Autry A, Monteggia L . Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012; 64(2):238-58. PMC: 3310485. DOI: 10.1124/pr.111.005108. View

Mayeur S, Silhol M, Moitrot E, Barbaux S, Breton C, Gabory A . Placental BDNF/TrkB signaling system is modulated by fetal growth disturbances in rat and human. Placenta. 2010; 31(9):785-91. DOI: 10.1016/j.placenta.2010.06.008. View

Shen S, Park J, Lu Z, Lin L, Henry M, Wu Y . rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci U S A. 2014; 111(51):E5593-601. PMC: 4280593. DOI: 10.1073/pnas.1419161111. View

Marx C, Vance B, Jarskog L, Chescheir N, Gilmore J . Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 levels in human amniotic fluid. Am J Obstet Gynecol. 1999; 181(5 Pt 1):1225-30. DOI: 10.1016/s0002-9378(99)70113-4. View

10.

Norman R, Dewailly D, Legro R, Hickey T . Polycystic ovary syndrome. Lancet. 2007; 370(9588):685-97. DOI: 10.1016/S0140-6736(07)61345-2. View

11.

Zhang J, Zhang L, Jiao H, Zhang Q, Zhang D, Lou D . c-Fos facilitates the acquisition and extinction of cocaine-induced persistent changes. J Neurosci. 2006; 26(51):13287-96. PMC: 6675013. DOI: 10.1523/JNEUROSCI.3795-06.2006. View

12.

Lommatzsch M, Hornych K, Zingler C, Schuff-Werner P, Hoppner J, Virchow J . Maternal serum concentrations of BDNF and depression in the perinatal period. Psychoneuroendocrinology. 2005; 31(3):388-94. DOI: 10.1016/j.psyneuen.2005.09.003. View

13.

Kosidou K, Dalman C, Widman L, Arver S, Lee B, Magnusson C . Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol Psychiatry. 2015; 21(10):1441-8. PMC: 5030459. DOI: 10.1038/mp.2015.183. View

14.

Katsigianni M, Karageorgiou V, Lambrinoudaki I, Siristatidis C . Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry. 2019; 24(12):1787-1797. DOI: 10.1038/s41380-019-0398-0. View

15.

Dubowitz L, Mercuri E, Dubowitz V . An optimality score for the neurologic examination of the term newborn. J Pediatr. 1998; 133(3):406-16. DOI: 10.1016/s0022-3476(98)70279-3. View

16.

Kertes D, Bhatt S, Kamin H, Hughes D, Rodney N, Mulligan C . methylation in mothers and newborns is associated with maternal exposure to war trauma. Clin Epigenetics. 2017; 9:68. PMC: 5493129. DOI: 10.1186/s13148-017-0367-x. View

17.

Mayeur S, Lukaszewski M, Breton C, Storme L, Vieau D, Lesage J . Do neurotrophins regulate the feto-placental development?. Med Hypotheses. 2011; 76(5):726-8. DOI: 10.1016/j.mehy.2011.02.008. View

18.

Mackenzie R, Sandrim V, Carty D, McClure J, Freeman D, Dominiczak A . Endothelial FOS expression and pre-eclampsia. BJOG. 2012; 119(13):1564-71. DOI: 10.1111/1471-0528.12016. View

19.

Qu F, Wang F, Lu X, Dong M, Sheng J, Lv P . Altered aquaporin expression in women with polycystic ovary syndrome: hyperandrogenism in follicular fluid inhibits aquaporin-9 in granulosa cells through the phosphatidylinositol 3-kinase pathway. Hum Reprod. 2010; 25(6):1441-50. DOI: 10.1093/humrep/deq078. View

20.

Palomba S, Russo T, Falbo A, Di Cello A, Tolino A, Tucci L . Macroscopic and microscopic findings of the placenta in women with polycystic ovary syndrome. Hum Reprod. 2013; 28(10):2838-47. DOI: 10.1093/humrep/det250. View