sequence per se, they may cause permanent modifications of the genome by changing the methylation of DNA or through some other similar processes. Gluckman and Hansen [1] have discussed the concept of ‘developmental plasticity’ which is based on the notion that irreversible epigenetic changes due to a specific environment may lead to the development of different phenotypes from a single genotype. This is also one of the reasons why genotypically similar siblings or monozygotic twin pregnancies can be rather different phenotypically, depending on the expression of their respective genome. Thus, eventually, it is not the genome which exclusively governs our present and future but how the genome is expressed, and this can be influenced by the intra-and extrauterine environment and may therefore also be to a considerable extent under our control. Fetal programming may create predisposition factors for adult disease and is also crucial for behavioral and cognitive normalcy or deviation thereof. The importance of fetal programming cannot be overstated. Currently, much scientific effort is being invested to gather more hard evidence on this fascinating topic. Consider Project VIVA (http://www.dacp.org/viva/index.html), an NIH-and CDC-sponsored pioneering longitudinal cohort study which is following over 2,500 children starting in their intrauterine life. Since September 2008, over 50 studies have been published by the group, in addition to numerous book chapters and editorials. An even more monumental longitudinal study was initiated in 2003, namely ‘The National Children’s Study’ (http://www.nationalchildrensstudy.gov/Pages/default.aspx). This study aims to enroll 100,000 American women before and during pregnancy and to examine the effects of the environment and genetics on the growth, development, and health of offspring from before birth until the age of 21. Interagency and congressional funding of the study during the past decade has exceeded USD 600 million.
Hormonal and Genetic Aspects of Fetal Sex Determination
One of the most crucial time windows which the human embryo faces occurs during a few hours sometime between 41 and 44 days after conception (in obstetrical terms during the 6th week of pregnancy). During these few fateful hours in that narrow time window, nature determines whether the developing fetus will be phenotypically male or female. Of course, chromosomal sex determination has already taken place during fertilization but, phenotypically, all odds are still open. If nothing happens during this time window, the embryo will by default develop into a phenotypic female. However, if a Y chromosome is present and a very specific single gene which is located on the short arm of that Y chromosome is activated, then the primitive gonad develops into a testicle and soon begins to secrete large amounts of testosterone and the embryo begins its development to become a phenotypic male. This sex-determining gene is named after its location on the Y chromosome, hence sex-determining region on the Y chromosome, in short SRY. The ensuing enormous testosterone production of the fetal testes will have a crucial impact on the subsequent development of intrauterine and extrauterine gender differences.
The chromosomal makeup and the hormonal environment and the appropriate functional receptors for various hormones thus determine the phenotypic sex.
Exogenous Effects on the Intrauterine Environment
It is now common understanding that prenatal life is no safe haven for the fetus and that the environment in which the pregnant mother lives has a direct impact on the development of the fetus. In effect, there is no other time throughout the life span of an individual where it is so intimately exposed to the environment. Whatever affects the pregnant mother may well affect her growing embryo and fetus, in many cases in a greatly amplified manner. The impact of exogenous toxins on the developing fetus is dependent on qualitative and quantitative factors and also on when they occur during the development of the fetus. First trimester exposure will generally have teratogenic effects while second and third trimester exposure will more often be expressed in growth restriction and organ failure.
Environmental toxins are abundant. Whyatt et al. [2] examined the home use of pesticides (mostly against cockroaches) in a cohort of 314 pregnant women from an urban minority group. More than 85% reported the use of pesticides in their home and all had detectable blood levels of at least three pesticides, which are known neurotoxins for the developing fetus and may cause permanent brain damage that may even be transmitted to subsequent generations. Alcohol is a good example of how the intrauterine environment may be affected by exogenous toxins resulting in an enormous negative impact on the fetus and embryo. Up to 1% of US live births are affected by fetal alcohol spectrum disorders (FASD), which is defined by any impairment related to fetal exposure to alcohol, and 0.05-0.5% of live births are affected by the devastating results of fetal alcohol syndrome [3]. It is estimated that alcohol consumption during pregnancy is responsible for more cases of mental retardation in the USA than all other known causes combined, including chromosomal aberrations [3]. Unfortunately, there is virtually no threshold for alcohol toxicity, and postconceptional alcohol consumption by the pregnant woman, i.e. before she even knows about her pregnancy, may be as hazardous to the fetus or even more so than throughout pregnancy. Tobacco is another example: maternal smoking affects the developing fetus directly and causes reduced placental perfusion, lower birth weight, and a whole spectrum of adverse outcomes in the fetus and newborn and in later life. Xiao et al. [4] showed in a rat model that intrauterine exposure to nicotine increases the blood pressure response to angiotensin II in adult offspring. This phenomenon is gender specific as it could be demonstrated in male rats but not in female rats. Prenatal exposure to tobacco also increases the prevalence of cognitive and auditory processing deficits in the adult offspring, probably based on thinning of the cerebral cortex, and is more commonly observed in female adolescents than in males. Some other adverse effects also seem to be sex specific. Jacobsen et al. [5] evaluated 181 male and female smokers and nonsmokers with or without prenatal exposure to maternal smoking. Individuals exposed prenatally to nicotine showed a reduction of cortical cholinergic markers on which attentional function is highly dependent. Reductions in auditory and visual attention were greatest among females who were exposed prenatally to nicotine and who were smokers themselves. Intrauterine exposure to nicotine in males was associated with marked deficits in auditory attention.
Effects of Intrauterine Testosterone
The male gonad commences testosterone secretion as early as the 7th week of pregnancy. Testosterone levels peak around 14-18 weeks of gestation and testosterone levels in the developing male fetus may become close to adult levels. Testosterone exerts manifold effects on the developing organism, like sex-specific development of genitalia and growth rate. The effect of fetal sex steroids on mammalian brain development is most striking. Dependent on the availability of testosterone receptors, testosterone affects cell apoptosis and is involved in the establishment of neural connectivity. The results of this development are far reaching and are of crucial importance for ‘male’ behavior after birth and throughout life, including childhood play behavior, and may also be involved in the establishment of sexual orientation and sexual identity. High exogenous or endogenous testosterone levels in female embryos (or neonates) will lead to behavior patterns typical of males. On the other hand, neonatal castration in male rats or rhesus monkeys will lead to typical female behavior. In humans, much insight related to the effect of increased intrauterine levels of androgens has been gained from observations in females with congenital adrenal hyperplasia (CAH), a genetic disorder with autosomal recessive heritance. Affected individuals lack the enzyme 21 - hydroxylase (21 - OH) and produce therefore high levels of testosterone by the end of the first trimester of pregnancy. Phenotypically, these girls are born with various degrees of genital virilization or ambiguous genitalia. In spite of successful postnatal
