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Maternal Smoking during Pregnancy Specifically Reduces Human Fetal Desert Hedgehog Gene Expression during Testis Development

Departments of Obstetrics and Gynaecology (P.A.F., S.C., S.B.) and Biomedical Sciences (J.M.C.), Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Biomathematics and Statistics Scotland (M.J.B.), Animal Ecology (S.M.R.), Macaulay Institute, Aberdeen AB15 8QH, United Kingdom; School of Veterinary Medicine and Sciences (R.G.L.), University of Nottingham, Loughborough LE12 5RD, United Kingdom; and Department of Veterinary Preclinical Studies (P.J.B., P.J.O.), Division of Veterinary Physiology and Pharmacology, University of Glasgow Veterinary School, Glasgow G61 1QH, United Kingdom

Address all correspondence and requests for reprints to: Dr. Paul Fowler, Ph.D., Institute of Medical Sciences, OBGYN, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. E-mail: p.a.fowler{at}abdn.ac.uk.

Context: Maternal cigarette smoking during gestation increases cryptorchidism and hypospadias and reduces testis size and fertility in sons by unknown mechanisms.

Objective: The objective of the study was to determine whether maternal smoking is linked with changes in male human fetal endocrinology, testis gene expression, and liver concentrations of cigarette smoke chemicals.

Design: This was an observational study of the male fetus, comparing pregnancies during which the mothers either did or did not smoke.

Setting: The study was conducted at the universities of Aberdeen, Glasgow, and Nottingham and Macaulay Institute (Aberdeen).

Patients/Participants: Testes, blood, and livers were collected from 69 morphologically normal human male fetuses of women undergoing elective termination of normal second-trimester pregnancies.

Main Outcome Measures: Testosterone, human chorionic gonadotropin, LH, and cotinine; expression of 30 reproductive/developmental genes; liver concentrations of 16 polycyclic aromatic hydrocarbons; and Leydig, Sertoli. and germ cell numbers were determined.

Results: There were no significant differences in fetal size, testis weight, cell numbers, seminiferous tubule diameter, or circulating LH and testosterone. Fetuses from smoking mothers had smoking range cotinine levels and liver concentrations of polycyclic aromatic hydrocarbons that were significant predictors of maternal smoking (P < 0.001). Only the Sertoli cell-specific gene, desert hedgehog (DHH), was significantly altered by maternal smoking (reduced 1.8-fold, P = 0.013).

Conclusions: The consequences of reduced DHH signaling in men and mice are consistent with epidemiology for effects of gestational maternal smoking on sons. Given the absence of other observed effects of maternal smoking, we concluded that reduced DHH is part of a mechanism linking maternal gestational smoking with impaired reproductive development in male offspring.

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