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

Objective: 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: An observational study of the male fetus, comparing pregnancies where 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, hCG, LH and cotinine, expression of 30 reproductive/developmental genes, liver concentrations of 16 polycyclic aromatic hydrocarbons (PAHs) 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 PAHs which 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 conclude that reduced DHH is part of a mechanism linking maternal gestational smoking with impaired reproductive development in male offspring.