Are estrogens carcinogenic during development of the testes?

Many chemicals in the environment mimic the female sex hormone, estrogen. Exposure to environmental estrogens during early fetal development was proposed by Sharpe & Skakkebaek as a potential risk factor for subsequent testicular disease, including neoplasia and poor semen quality. To understand the mechanisms of action of estrogenic chemicals during differentiation of the male genital tract, we have studied developmental exposure to the synthetic estrogen, diethylstilboestrol (DES). While DES is a much more potent estrogen than most environmental chemicals examined, several of these compounds share some of the same properties as DES, such as a relative lack of binding to serum estrogen carrying proteins. Prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism and testicular neoplasia in mice. A rare form of testicular cancer, rete testis carcinoma, was observed in five percent of male mice treated in utero with DES. We also demonstrated altered regulation of an estrogen responsive gene, lactotransferrin (LTF) in the seminal vesicles of treated mice, but not the controls. Likewise, LTF was irreversibly altered in the uteri of developmentally treated females; at the molecular level altered methylation of the gene appears to be involved, thus, providing a potential marker for hormonal effects during development. The induction of permanent or "imprinted" responses during the development of a relatively estrogen-free reproductive tract cell suggests that undifferentiated targets for estrogen action may be sites for subsequent growth and differentiation defects associated with neoplasia.     

An updated review of environmental estrogen and androgen mimics and antagonists

For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Man-made compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate flasks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 microg of bisphenol-A were retrieved from saliva collected during the first hour after polymerization. Other xenoestrogens recently identified among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male fish were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identified antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors.     

Prenatal estrogens and the development of homosexual orientation.

In psychobiological research on sexual orientation, the prenatal hormone theory has a central position. This article examines the hypothesis that prenatal estrogens contribute to the development of human sexual orientation. Several groups of women with a history of prenatal exposure to diethylstilbestrol (DES), a nonsteroidal synthetic estrogen, were compared with several samples of control women in the context of a comprehensive study of the psychiatric and psychologic effects of prenatal DES. Various aspects of sexual orientation were assessed by systematic interview. Consistently across samples, more DES-exposed women than controls were rated as bisexual or homosexual (scores 2–6 on Kinsey-format scales ranging from 0 to 6). The data are compatible with the hypothesis that prenatal estrogens may play a role in the development of human sexual orientation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Environmental endocrine disruptors

This review outlines the historical background of environmental endocrine disruptor issues and the particular sensitivity of the developing animals to exposure to estrogenic agents in the induction of longterm changes in reproductive and nonreproductive organs, and research needs of adverse effects of endocrine disruptors in experimental animals, wildlife and humans. Many chemicals released into the environment disrupt the endocrine system in wildlife and humans, and many of which have estrogenic activity by binding to the estrogen receptor. The animal and cell culture models can be utilized as an indicator of possible consequences of exposure to environmental endocrine disruptors. In humans, although the causes are not clear, hypospadia increased twice from 1970' and sperm count decreased and testicular cancer incidence increased. Epidemiological studies are needed to clarify the cause of these abnormalities in humans. More attention should be paid to abnormalities in genital organs exposed to endocrine disruptors during fetal and early postnatal development in wildlife, experimental animals and humans.     

Environmental estrogens and reproductive health: a discussion of the human and environmental data

Estrogenic activity of certain xenobiotics is an established mechanism of toxicity that can impair reproductive function in adults of either sex, lead to irreversible abnormalities when administered during development, or cause cancer. The concern has been raised that exposure to ambient levels of estrogenic xenobiotics may be having widespread adverse effects on reproductive health of humans and wildlife. The purpose of this review is to evaluate (a) the nature of the evidence supporting this concern, and (b) the adequacy of toxicity screening to detect, and risk assessment procedures to establish safe levels for, agents acting by this mechanism. Observations such as adverse developmental effects after maternal exposure to therapeutic levels of the potent estrogen diethylstilbestrol or male fertility problems after exposure to high levels of the weak estrogen chlordecone clearly demonstrate that estrogenicity is active as a toxic mechanism in humans. High level exposures to estrogenic compounds have also been shown to affect specific wildlife populations. However, there is little direct evidence to indicate that exposures to ambient levels of estrogenic xenobiotics are affecting reproductive health. Reports of historical trends showing decreasing reproductive capacity (e.g., decreased sperm production over the last 50 years) are either inconsistent with other data or have significant methodologic inadequacies that hinder interpretation. More reliable historical trend data show an increase in breast cancer rate, but the most comprehensive epidemiology study to data failed to show an association between exposure to persistent, estrogenic organochlorine compounds and breast cancer. Clearly, more work needs to be done to characterize historical trends in humans and background incidence of abnormalities in wildlife populations, and to test hypotheses about ambient exposure to environmental contaminants and toxic effects, before conclusions can be reached about the extent or possible causes of adverse effects. It is unlikely that current lab animal testing protocols are failing to detect agents with estrogenic activity, as a wide array of estrogen-responsive endpoints are measured in standard testing batteries. Routine testing for aquatic and wildlife toxicity is more limited in this respect, and work should be done to assess the validity of applying mammalian toxicology data for submammalian hazard identification. Current risk assessment methods appear to be valid for estrogenic agents, although the database for evaluating this is limited. In conclusion, estrogenicity is an important mechanism of reproductive and developmental toxicity; however, there is little evidence at this point that low level exposures constitute a human or ecologic health risk. Given the potential consequences of an undetected risk, more research is needed to investigate associations between exposures and effects, both in people and animals, and a number of research questions are identified herein. The lack of evidence demonstrating widespread xenobiotic-induced estrogenic risk suggests that far-reaching policy decisions can await these research findings.     

Endometrial hyperplasia and apoptosis following neonatal diethylstilbestrol exposure and subsequent estrogen stimulation in both host and transplanted hamster uteri

Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes morphogenetic alterations and neoplasia in the human reproductive tract. In the hamster, neonatal DES exposure alters early uterine morphogenesis and induces endometrial adenocarcinomas in adults. We now demonstrate that the preneoplastic stages of this phenomenon in the hamster reflect an abnormal uterotropic response to estrogen that is characterized by hyperplastic lesions in the endometrial epithelium and includes an immune and/or inflammatory component. Interestingly, biochemical and in situ analysis revealed that the hyperplastic epithelium is also an active site of cell death by apoptosis. To further probe the mechanism of this phenomenon, uteri from 7-day-old control or DES-exposed donors were transplanted into the cheek pouches of control or neonatally DES-exposed adult hosts, and both host groups were treated to provide high circulating levels of estradiol. Among the four ectopic scenarios, histopathological lesions (epithelial hyperplasia, dysplasia, and apoptosis), segregated almost exclusively to the two that consisted of neonatally DES-exposed uteri. The virtual absence of lesions in control uteri transplanted to DES hosts eliminated host systemic factors as causative agents. Therefore, we conclude that DES or its metabolites alter the cellular physiology and/or composition of the developing uterus (initiating event) in such a way that it thereafter responds abnormally to estrogenic stimulation (promoting event). These observations serve to further define a unique experimental system for probing: (a) various aspects of the clinical "DES Syndrome"; (b) how estrogen regulates normal uterine growth and morphogenesis; and (c) how this process can degenerate to the unregulated neoplastic state.     

Phytoestrogens: potential endocrine disruptors in males

Exposure to diethylstilbestrol (DES) induces persistent structural and functional alterations in the developing reproductive tract of males. It is possible that xenoestrogens other than DES alter sexual differentiation in males and account for the increasing incidence of developmental disorders of the reproductive tract in men and wild animals. Phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert their estrogenic activity by interacting with estrogen receptors (ERs) in vitro. They may also act as antiestrogens by competing for the binding sites of estrogen receptors or the active site of the estrogen biosynthesizing and metabolizing enzymes, such as aromatase and estrogen-specific 17 beta-hydroxysteroid oxidoreductase (type 1). In theory, phytoestrogens and structurally related compounds could harm the reproductive health of males also by acting as antiestrogens. There are very little data on effects of phytoestrogens in males. Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. In doses comparable to the daily intake from soybased feed, isoflavonoids such as genistein were estrogen agonists in the prostate of adult laboratory rodents. When given neonatally, no persistent effects were observed. In contrast, the central nervous system (CNS)-gonadal axis and the male sexual behavior of the rat appear to be sensitive to phytoestrogens during development. The changes were similar but not identical to those seen after neonatal treatment with DES, but higher doses of phytoestrogens were needed.     

Validation and application of a rapid in vitro assay for assessing the estrogenic potency of halogenated phenolic chemicals

The E-Screen assay serves as an in vitro tool for the detection of estrogenic activity of chemicals and extracts of environmental samples. Based on the induction of proliferation in human estrogen receptor-positive MCF-7 breast cancer cells we could substantially simplify the assay. As one important step of validation we applied the modified assay for testing nine known xenoestrogens. We could confirm the results of other groups assuring the reproducibility of the E-Screen assay. The results provide evidence that the E-Screen assay is suitable for determination of estradiol equivalency factors (EEFs) for environmental estrogens to rank their estrogenic potency relative to the natural estrogen 17 beta-estradiol. Further, we used the optimized proliferation test to screen nine halogenated phenolic compounds for their possible estrogenic potency. Three widely applied chemicals expressed a weak receptor-mediated estrogenic activity: the flame retardant Tetrabromo-Bisphenol-A, the disinfectant 4-chloro-3-methylphenol, and the herbicide educt 4-chloro-2-methylphenol. Their estrogenic potencies were five to six orders of magnitude lower than that of 17 beta-estradiol.     

Effects of environmental synthetic chemicals on thyroid function

Synthetic chemicals are released into the environment by design (pesticides) or as a result of industrial activity. It is well known that natural environmental chemicals can cause goiter or thyroid imbalance. However, the effects of synthetic chemicals on thyroid function have received little attention, and there is much controversy over their potential clinical impact, because few studies have been conducted in humans. This article reviews the literature on possible thyroid disruption in wildlife, humans, and experimental animals and focuses on the most studied chemicals: the pesticides DDT, amitrole, and the thiocarbamate family, including ethylenethiourea, and the industrial chemicals polyhalogenated hydrocarbons, phenol derivatives, and phthalates. Wildlife observations in polluted areas clearly demonstrate a significant incidence of goiter and/or thyroid imbalance in several species. Experimental evidence in rodents, fish, and primates confirms the potentiality for thyroid disruption of several chemicals and illustrates the mechanisms involved. In adult humans, however, exposure to background levels of chemicals does not seem to have a significant negative effect on thyroid function, while exposure at higher levels, occupational or accidental, may produce mild thyroid changes. The impact of transgenerational, background exposure in utero on fetal neurodevelopment and later childhood cognitive function is now under scrutiny. There are several studies linking a lack of optimal neurological function in infants and children with high background levels of exposure to polychlorinated biphenyls (PCBs), dioxins, and/or co-contaminants, but it is unclear if the effects are caused by thyroid disruption in utero or direct neurotoxicity.     

PCBs as environmental estrogens: turtle sex determination as a biomarker of environmental contamination

Polychlorinated biphenyls (PCBs) are widespread, low-level environmental pollutants associated with adverse health effects such as immune suppression and teratogenicity. There is increasing evidence that some PCB compounds are capable of disrupting reproductive and endocrine function in fish, birds, and mammals, including humans, particularly during development. Research on the mechanism through which these compounds act to alter reproductive function indicates estrogenic activity, whereby the compounds may be altering sexual differentiation. Here we demonstrate the estrogenic effect of some PCBs by reversing gonadal sex in a reptile species that exhibits temperature-dependent sex determination.     

Prenatal exposure to diethylstilbestrol (DES) and the development of sexually dimorphic cognitive abilities and cerebral lateralization.

Investigated the possibility that the perinatal hormonal environment is related to the development of cognitive sex differences in humans by comparing 25 women who had been exposed prenatally to DES, a synthetic estrogen, to their unexposed sisters. All Ss completed word fluency and spatial relations tests, the Wonderlic Personnel Test, and a dichotic listening task. The DES-exposed Ss showed a more masculine pattern of lateralization (i.e., a stronger right-ear advantage) than did their sisters on a verbal dichotic task. However, no differences were observed between exposed and unexposed Ss in verbal or visuospatial ability. Although interpretation of these data must be cautious, they provide some support for a relationship between high prenatal estrogen levels and the development of masculine-typical function in humans. Implications for previous studies of biological contributions to cognitive sex differences and possible mechanisms for estrogenic effects on the development of lateralization are discussed. (114 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretreatment of skin with a Ginkgo biloba extract/sodium carboxymethyl-beta-1,3-glucan formulation appears to inhibit the elicitation of allergic contact dermatitis in man

Transplacental exposure to diethylstilbestrol (DES) causes morphological and functional changes including the disruption of follicular maturation in murine ovaries. Since the function of ovarian sympathetic nerves is thought to be related to the follicular maturation, we examined changes in the distribution pattern of the sympathetic nerves between prenatally DES-exposed rat ovaries and normal controls using immunohistochemistry of tyrosine hydroxylase (TH). In the DES-exposed ovaries, the TH-positive nerve innervation was poor and the innervation density was reduced to about half as compared to that in the controls. Simultaneously, follicular maturation was disrupted in the DES-exposed ovaries. These findings suggest that the prenatal DES exposure inhibited the development of ovarian sympathetic nervous system, which might be closely associated with the disruption of follicular maturation.     

Endometrial pattern in diethylstilboestrol-exposed women undergoing in-vitro fertilization may be the most significant predictor of pregnancy outcome

The objective of this study was to compare prospectively pregnancy outcome as it is related to ultrasonic endometrial echo pattern in women exposed to diethylstilboestrol (DES) in utero by their mother's consumption with women not exposed to DES, all of whom were undergoing in-vitro fertilization (IVF). Pregnancy outcome relative to endometrial thickness and pattern was evaluated in 540 cycles of IVF including DES (n = 50) and non-DES-exposed (n = 490) women. Endometrial patterns were designated as p1 = solid; p2 = ring; and p3 = intermediate. DES patients exhibited p1 more often than the majority of the non-DES-exposed group. There was no significant difference in endometrial thickness among the cycles where p1 was noted when comparing the DES (10.3 mm) with the non-DES-exposed (10.7 mm) groups. Notably, within the group exhibiting p1, no pregnancies occurred in the 18 cycles of DES-exposed women compared with a 39.2% clinical pregnancy and 36.5% delivery rate in the non-DES-exposed controls (P < 0.0001 and P = 0.008 respectively). Pregnancy rates were not significantly different in the cycles where the other endometrial patterns were found when comparing the two groups. The impact of uterine shape on pregnancy outcome was also investigated. A T-shaped uterine configuration was noted in 11 out of 18 (61.1%) cycles of DES-exposed women with pattern p1 compared with nine out of 23 (39.1%) with pattern p2. Of cycles where a T-shaped uterus was demonstrated, none out of 11 (0%) with pattern p1 compared with four out of nine (44.4%) with pattern p2 resulted in pregnancy (P = 0.026). These data suggest that endometrial pattern is one of the most significant variables for pregnancy outcome in DES-exposed women undergoing IVF.     

Vaginal embryogenesis, estrogens, and adenosis

The recent outbreak of vaginal adenocarcinoma and the associated genital tract anomalies in women with histories of prenatal exposure to diethylstilbestrol (DES) has generated interest in vaginal embryogenesis and the influence of hormones on the developing genital tract. In this report the embryology of the vagina and the role of sex hormones in normal and abnormal sex duct development are presented and discussed in relation to the DES-induced anomalies. Although the teratogenic activity of DES in humans has been confirmed, the available evidence suggests that the clear cell carcinomas are initiated by endogenous estrogens and not the prenatally administered DES.     

Vaginal and cervical squamous cell dysplasia in women exposed to diethylstilbestrol in utero

Two hundred and fifty patients were examined because of a history of in utero exposure to diethylstilbestrol (DES) or because of the presence of physical findings suggesting such exposure. One thousand biopsies were examined for the presence of neoplasia and then compared to the colposcopic findings. There were no cases of glandular or squamous cell carcinoma. Fifteen (6 per cent) of the patients had squamous cell dysplasia. The degree of dysplasia was mild in 11 and moderate in only 4 (1.6 per cent) of the women. The majority of the cases of dysplasia involved the cervix, whereas the vagina was involved in only four cases, with simultaneous cervical dysplasia in three of these. Patients with cervical mosaic and white epithelium had dysplasia on biopsy much more frequently as compared with patients with similar colposcopic appearances in the vagina. Our results suggest a low incidence of significant squamous precancerous change in the DES-exposed population and provide evidence that colposcopic data concerning dysplasia pertinent to the cervix cannot be applied without modification to the evaluation of dysplasia in vaginal adenosis.     

Intellectual impairment in children exposed to polychlorinated biphenyls in utero

BACKGROUND: In utero exposure to polychlorinated biphenyls, a ubiquitous environmental contaminant, has been linked to adverse effects on neurologic and intellectual function in infants and young children. We assessed whether these effects persist through school age and examined their importance in the acquisition of reading and arithmetic skills. METHODS: We tested 212 children, recruited as newborns to overrepresent infants born to women who had eaten Lake Michigan fish contaminated with polychlorinated biphenyls. A battery of IQ and achievement tests was administered when the children were 11 years of age. Concentrations of polychlorinated biphenyls in maternal serum and milk at delivery were slightly higher than in the general population. A composite measure of prenatal exposure was derived from concentrations in umbilical-cord serum and maternal serum and milk. RESULTS: Prenatal exposure to polychlorinated biphenyls was associated with lower full-scale and verbal IQ scores after control for potential confounding variables such as socioeconomic status (P = 0.02). The strongest effects related to memory and attention. The most highly exposed children were three times as likely to have low average IQ scores (P <0.001) and twice as likely to be at least two years behind in reading comprehension (P = 0.03). Although larger quantities of polychlorinated biphenyls are transferred by breast-feeding than in utero, there were deficits only in associated with transplacental exposure, suggesting that the developing fetal brain is particularly sensitive to these compounds. CONCLUSIONS: In utero exposure to polychlorinated biphenyls in concentrations slightly higher than those in the general population can have a long-term impact on intellectual function.     

Management of the adolescent girl exposed in utero to DES

Attention in this discussion of the management of the adolescent girl exposed "in utero" to diethylstilbestrol (DES) is directed to the following: history; scope of the problem; pathogenesis/embryology; management; future fertility; squamous cell carcinoma; and male factors. In the late 1940s and early 1950s, estrogen deficiency was thought to play a role in the high fetal death rate among pregnant diabetic women. DES was 1st used in diabetics and soon thereafter in patients who were threatening to miscarry, who had previous stillbirths, and previous spontaneous abortions. Estrogens were used by some physicians through the late 1960s. In 1970 Herbst and Scully reported 7 carcinomas of the vagina in young women. On careful review, it was found that the mothers of these young women with clear-cell cancer had been treated with DES at various stages of their pregnancies. Subsequent investigation led to the discovery of the condition of vaginal adenosis in many young women exposed "in utero" to DES. It is estimated that 80-90% of patients exposed to intrauterine DES will show gross and microscopic evidence of vaginal and cervical adenosis. It is now felt by most authorities that adenosis coexists with the clear-cell cancer rather than preceding the tumor. A clear-cell tumor registry has been established and, to date, over 400 cases have been registered. The age-range of DES-exposed clear-cell carcinoma is between 7 and 31 years of age. The care of a girl exposed to DES begins when the physician is informed that the patient's mother either received the medication or there was any possibility of such medication. If bleeding occurs before the menarche, the patient should be hospitalized and examined under anesthesia. In the women of menstrual age, management has been somewhat controversial. The use of the colposcope has allowed careful initial examination of the cervix and vagina as well as providing an excellent means of follow-up. The colposcope has been very helpful in delineating the changes caused by DES. There are numerous gross findings that represent adenosis. These include the cervical changes of the "cockscomb" or anterior cervical ridge or "hood," a cervix within a cervix, and a hermicervix. With the colposcope, the areas of adenosis are seen as grape-like projections which, on biopsy, represent columnar epithelium. Areas of metaplastic squamous tissue are easily identified. On occasion dysplasia can occur in areas of adenosis. Of equal importance is the digital examination of the vagina. At this time it is felt that adenosis requires no other treatment than observations. The treatment of clear-cell carcinoma of the vagina or cervix is best determined by a gynecologic oncologist. 80% of DES patients have had live births.     

Transplacental and transgenerational carcinogenesis

Effects of exposure to carcinogens at early stages of ontogenesis are considered. An increased cancer risk due to prenatal exposure may be related to: 1) exposure of the fetus during pregnancy to chemicals able to cross the placental barrier or to radiation; 2) exposure to a chemical or radiation of the parents or one parent prior to conception. In transplacental carcinogenesis, the effects observed after birth are a consequence of a direct interaction of the carcinogen with somatic cells of the fetus. DES and radiation were shown to increase cancer risk in humans following exposure during pregnancy, while in experimental animals a large variety of chemicals of quite different structure (including the widely used therapeutic agent cisplatin) were demonstrated to induce tumors in the progeny after administration during pregnancy. The experimental multigeneration effect of carcinogens is manifested in an increased incidence of tumors in several generations of untreated descendants of: a) females exposed to carcinogen during pregnancy; b) males exposed to carcinogen prior to mating with untreated females. The inherited change may be an initiating event revealed by the exposure during post-natal life to a promoting agent. In humans deleterious information inherited through the germ cells (occurring either following a spontaneous error in DNA replication and repair or as a consequence of a chemical or physical agent) can increase the risk of developing cancer in certain individuals by several orders of magnitude (retinoblastoma, familial polyposis of the colon and some others). The multigeneration transmission of carcinogenic risk is also demonstrated by cancer prone families that are probably more frequent than originally thought, with a risk that is one order of magnitude higher than in general population. Familial clusterings of cancer may also indicate germline mutations in one or more genes. Thus the inherited predisposition to cancer that is observed today may, at least in part, be explained by the exposure to environmental noxious agents in previous generation(s). Since humans are exposed throughout life to many environmental agents, either carcinogenic or capable to enhance the progression of cancer, an understanding of the contribution of prenatal exposure to carcinogens could improve the efficacy of prevention.