In utero exposure to environmental chemicals: lessons from maternal cigarette smoking and its effects on gonad development and puberty

Although tobacco use has declined in recent years, a significant minority of pregnant women still smoke and cessation during gestation is rare. Substantial passive exposure to tobacco smoke is an unavoidable hazard to many more. This is of great concern, since tobacco smoke contains a large number of toxins known to be hazardous to foetal development. These include carbon monoxide, nicotine and its breakdown products, polycyclic aromatic hydrocarbons, thiocyanate and many more. Some are known or suspected endocrine-disrupting chemicals (EDCs). In addition to providing further evidence to dissuade pregnant women and those around them from smoking, studying the effects of tobacco smoke on human development gives insight into effects of other EDCs and EDC mixtures which affect the same developmental processes and end points.
In utero development of the reproductive tract is a poorly understood process that is entirely dependent on the proper functioning of the maternal and foetal endocrine systems. It is vulnerable to disruption in both genders. Thus far, only the physiological effects of the disruption of oestrogen and androgen-mediated signalling and the hypothalamic-pituitary-gonadal (HPG) axis have been investigated in detail. Our knowledge of the process in both animals and humans is far from complete. Exposure of animal models to EDCs affecting sex steroid-mediated processes can cause a wide range of adverse reproductive outcomes. These include impaired gametogenesis and later subfertility, early reproductive senescence, neuroendocrine dysregulation affecting fertility and sexual behaviour, genital deformities and increased susceptibility to certain cancers. Effects on humans are thus far uncertain, but many epidemiological studies have associated EDC exposure with decreasing fertility, reductions in the age of pubertal onset and increases in susceptibility to certain cancers and deformities of the reproductive tract. Studies of the physiological and cellular effects of individual EDCs and EDC mixtures in vitro and in vivo have added plausibility to these associations.
Prenatal human tobacco smoke exposure has multiple known adverse effects on reproductive development and may affect the age of puberty in females at least.
Overall, maternal and foetal oestrogen and androgen synthesis are suppressed centrally by suppression of the HPG axis by the activation of the hypothalamic-pituitary-adrenal (HPA) axis and peripherally by the direct inhibition of their synthesis. The hypothalamic-pituitary-thyroid (HPT) axis and the peripheral transformation and utilization of thyroid hormones are also suppressed by activation of the HPA axis. Neuroendocrine programming of the HPA, HPT and HPG is perturbed.
Decreased fertility and fecundity have been noted in both genders, and exposed females are more likely to experience early menopause. Some epidemiological studies have reported a connection with malformations of the male reproductive tract (testicular dysgenesis syndrome), the plausibility of which is supported by evidence that the production of desert hedgehog, a morphogen essential for male sexual development, is halved by maternal smoking. These outcomes are similar to those observed in epidemiological and animal studies of other EDCs and EDC mixtures, but a great deal of further research is required to determine their exact physiological effects and properly quantify the risks they pose. The effects of tobacco
smoke and other EDC mixtures and EDCs on systems other than those directly mediated by the oestrogen receptors and androgen receptor have barely begun to be elucidated.