In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling

Fowler, P. A., Childs, A. J., Courant, F., MacKenzie, A., Rhind, S. M., Antignac, J.-P., Le Bizec, B., Filis, P., Evans, F., Flannigan, S., Maheshwari, A., Bhattacharya, Siladitya ORCID: https://orcid.org/0000-0002-4588-356X, Monteiro, A., Anderson, R. A. and O'Shaughnessy, P. J. 2014. In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling. Human Reproduction 29 (7) , pp. 1471-1489. 10.1093/humrep/deu117

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Abstract

STUDY QUESTION How does maternal cigarette smoking disturb development of the human fetal ovary? SUMMARY ANSWER Maternal smoking increases fetal estrogen titres and dysregulates several developmental processes in the fetal ovary. WHAT IS KNOWN ALREADY Exposure to maternal cigarette smoking during gestation reduces human fetal ovarian cell numbers, germ cell proliferation and subsequent adult fecundity. STUDY DESIGN, SIZE, DURATION The effects of maternal cigarette smoking on the second trimester human fetal ovary, fetal endocrine signalling and fetal chemical burden were studied. A total of 105 fetuses were studied, 56 from mothers who smoked during pregnancy and 49 from those who did not. PARTICIPANTS/MATERIALS, SETTING METHODS Ovary, liver and plasma samples were collected from electively terminated, normally progressing, second trimester human fetuses. Circulating fetal hormones, levels of 73 fetal ovarian transcripts, protein localization, density of oocytes/primordial follicles and levels of 16 polycyclic aromatic hydrocarbons (PAHs) in the fetal liver were determined. WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to chemicals in cigarette smoke is known to lead to reduced fecundity in women. Our study suggests, for the first time, that this occurs via mechanisms involving activation of AHR, disruption of inhibin/activin and estrogen signalling, increased exposure to estrogen and dysregulation of multiple molecular pathways in the exposed human fetal ovary. Our data also suggest that alterations in the ESR2 positive and dominant negative isoforms may be associated with reduced sensitivity of some fetuses to increased estrogens and maternal smoking. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by grants from the Chief Scientist Office (Scottish Executive, CZG/1/109, and CZG/4/742), NHS Grampian Endowments (08/02), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 212885, a Society for Reproduction & Fertility summer studentship, Medical Research Scotland (research grant 354 FRG) and the Medical Research Council (WBS: U.1276.00.002.00001 and G1100357). The authors declare they have no competing interests, be it financial, personal or professional.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	0268-1161
Date of Acceptance:	2 April 2014
Last Modified:	24 Oct 2022 08:20
URI:	https://orca.cardiff.ac.uk/id/eprint/117453

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