There is a third type of exposure that needs to be addressed: the inadvertent and continuous exposure of fetuses to environmentally active chemicals, such as dioxins and BPA.
The U.S. EPA has established the safe daily intake of BPA to be 50 μg/kg body weight/d based on the assumption that the main source of exposure is oral through food ingestion. However, recent publications suggest that food is not the only relevant source of exposure and that the half-life of BPA in humans is longer than expected (6). Numerous publications addressing fetal exposures to BPA have used parenteral administration. This practice was based on one hand on the fact that the fetus is exposed to BPA through the internal milieu of the mother, and on the other hand that parenteral administration via an osmotic minipump allows for a precise and constant level of exposure. Using this route of administration, exposure of a pregnant mouse dam to 25 and 250 ng BPA/kg body weight/d (namely, 2000 and 200 times lower than the safe dose) for 14 d beginning on d 8 gestation has been shown to impact certain aspects of development in their female offspring. When examined on gestational d 18, fetuses of mothers exposed to the higher dose of BPA exhibited altered growth parameters of the mammary gland anlagen. Changes in the appearance of the mammary epithelium were observed, such as decreased cell size and delayed lumen formation, as well as increased ductal area. In the stroma, BPA exposure promoted advanced maturation of the fat pad and altered localization of fibrous collagen (128). Because maturation of the fat pad is the driving event for ductal growth and branching, it is likely that the increased ductal area in BPA-exposed animals is due to the accelerated formation of their fat pads. By postnatal d 10, in the offspring born to mothers exposed to either dose of BPA, the percentage of proliferating epithelial cells was significantly decreased relative to those not exposed. At 30 d of age, the area and number of terminal end buds relative to the gland ductal area increased, whereas cell death in these structures decreased in BPA-exposed offspring compared with controls. It is likely that the reduced cell death in the terminal end buds of BPA-exposed females may be the cause of the observed ductal growth delay because cell death is essential for both the hollowing and the outward growth of the subtending duct. Collectively, these effects observed at puberty may be attributed to an increased sensitivity to estradiol that has been observed in the BPA-exposed animals (145). Because of the new epidemiological data cited above and the effects found in the low-dose animal studies using parenteral exposure, the EPA recommendations need to be reevaluated.
In animals exposed perinatally to BPA, there was also a significant increase of ductal epithelial cells that were positive for progesterone receptor at puberty. These positive cells were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in offspring born to mothers exposed to 25 ng BPA/kg body weight/d (145). These results are compatible with the notion that increased sensitivity to estrogens drives the induction of progesterone receptors in epithelial cells, leading to an increase in lateral branching. By 6 months of age, perinatally exposed virgin mice exhibit mammary glands that resemble those of a pregnant mouse, as reflected by a significant increase in the percentage of ducts, terminal ends, terminal ducts, and alveolar buds (146). Additionally, intraductal hyperplasias, which are considered preneoplastic lesions, were observed starting at 3 months of age (147).
To explore the links between prenatal BPA exposure and mammary gland neoplasia, a rat model was chosen because it closely resembles the human disease regarding estrogen dependency and histopathology. BPA was administered to pregnant dams at doses of 2.5, 25, 250, and 1000 μg/kg body weight/d. Fetal exposure to BPA, from gestational d 9 to postnatal d 1, resulted in the development of carcinomas in situ in the mammary glands of 33% of the rats exposed to 250 μg/kg body weight/d, whereas none of the unexposed animals developed neoplasias (148). These cancers were only observed after the animals had reached young adult age. Fetal exposure to BPA significantly increased the number of precancerous lesions (intraductal proliferation) by three to four times, an effect also observed in puberty and during adult life. The lesions observed in the BPA-exposed animals were highly proliferative and contained abundant ER-positive cells, suggesting that the proliferative activity in these lesions may be estrogen mediated. Comparable preneoplastic lesions were found in a study using a different rat strain (149). Additionally, this study found stromal alterations such as desmoplasia and mast cell invasion; these features are often observed during neoplastic development. Moreover, when challenged with a subcarcinogenic dose of nitrosomethylurea, only the BPA-exposed animals developed palpable tumors (carcinomas). The period of vulnerability of the mammary gland to BPA does not cease at the neonatal stage. BPA exposure during lactation followed to exposure to the carcinogen DMBA resulted in mammary tumor multiplicity and reduced tumor latency compared with control animals (exposed solely to DMBA) (150). These results indicate that perinatal exposure to environmentally relevant doses of BPA results in persistent alterations in mammary gland morphogenesis, development of precancerous lesions, and carcinoma in situ. Moreover, the altered growth parameters noted in the developing mammary gland on embryonic d 18 suggest that the fetal gland is a direct target of BPA, and that these alterations cause the mammary gland phenotypes observed in perinatally exposed mice at puberty and adulthood.
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Dioxins
Depending on the context (time of exposure, organ, presence or absence of estrogens) dioxins have either estrogenic or antiestrogenic effects. Despite cross-talk between the aryl hydrocarbon and ERs (139), the mechanisms underlying these opposite effects have yet to be elucidated. Rats exposed prenatally (gestational d 15) to TCDD and challenged with the chemical carcinogen DMBA at 50 d of age showed increased tumor incidence, increased number of tumors per animal, and shorter latency period than rats exposed prenatally to vehicle and to DMBA at 50 d of age. These TCDD-exposed animals had increased numbers of terminal end buds at puberty (140). Because these structures are believed to be the site where mammary cancer arises, these results were interpreted as evidence that TCDD increased the propensity to cancer by altering mammary gland morphogenesis. Interestingly, Fenton (31) showed that prenatal exposure to TCDD results in impaired development of terminal end buds that remain in the gland for prolonged periods, whereas in the normal animals terminal end buds are transient structures that regress when ductal development is completed.
BPA, a ubiquitous xenoestrogen
The ubiquitous use of BPA provides great potential for exposure of both the developing fetus, indirectly through maternal exposure, and the neonate, directly through ingestion of tinned food, infant formula, or maternal milk (11). Indeed, BPA has been measured in maternal and fetal plasma and placental tissue at birth in humans (141). A recently published study conducted by the Centers for Disease Control, the first using a reference human population, showed that 92.6% of over 2500 Americans had BPA in their urine (142). Measured urine concentrations were significantly higher in children and adolescents compared with adults. BPA has also been measured in the milk of lactating mothers. These data indicate that the developing human fetus and neonate are readily exposed to this chemical.
In rodents, BPA has been shown to readily cross the placenta (143, 144) and bind α-fetoprotein (the estrogen-binding protein that prevents maternal estrogen from entering the circulation of the fetus) with negligible affinity relative to estradiol; this results in enhanced bioavailability during neonatal development. BPA is present in the mouse fetus and amniotic fluid during maternal exposure in higher concentrations than that of maternal blood. The U.S. EPA has established the safe daily intake of BPA to be 50 μg/kg body weight/d based on the assumption that the main source of exposure is oral through food ingestion. However, recent publications suggest that food is not the only relevant source of exposure and that the half-life of BPA in humans is longer than expected (6). Numerous publications addressing fetal exposures to BPA have used parenteral administration. This practice was based on one hand on the fact that the fetus is exposed to BPA through the internal milieu of the mother, and on the other hand that parenteral administration via an osmotic minipump allows for a precise and constant level of exposure. Using this route of administration, exposure of a pregnant mouse dam to 25 and 250 ng BPA/kg body weight/d (namely, 2000 and 200 times lower than the safe dose) for 14 d beginning on d 8 gestation has been shown to impact certain aspects of development in their female offspring. When examined on gestational d 18, fetuses of mothers exposed to the higher dose of BPA exhibited altered growth parameters of the mammary gland anlagen. Changes in the appearance of the mammary epithelium were observed, such as decreased cell size and delayed lumen formation, as well as increased ductal area. In the stroma, BPA exposure promoted advanced maturation of the fat pad and altered localization of fibrous collagen (128). Because maturation of the fat pad is the driving event for ductal growth and branching, it is likely that the increased ductal area in BPA-exposed animals is due to the accelerated formation of their fat pads. By postnatal d 10, in the offspring born to mothers exposed to either dose of BPA, the percentage of proliferating epithelial cells was significantly decreased relative to those not exposed. At 30 d of age, the area and number of terminal end buds relative to the gland ductal area increased, whereas cell death in these structures decreased in BPA-exposed offspring compared with controls. It is likely that the reduced cell death in the terminal end buds of BPA-exposed females may be the cause of the observed ductal growth delay because cell death is essential for both the hollowing and the outward growth of the subtending duct. Collectively, these effects observed at puberty may be attributed to an increased sensitivity to estradiol that has been observed in the BPA-exposed animals (145). Because of the new epidemiological data cited above and the effects found in the low-dose animal studies using parenteral exposure, the EPA recommendations need to be reevaluated.
In animals exposed perinatally to BPA, there was also a significant increase of ductal epithelial cells that were positive for progesterone receptor at puberty. These positive cells were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in offspring born to mothers exposed to 25 ng BPA/kg body weight/d (145). These results are compatible with the notion that increased sensitivity to estrogens drives the induction of progesterone receptors in epithelial cells, leading to an increase in lateral branching. By 6 months of age, perinatally exposed virgin mice exhibit mammary glands that resemble those of a pregnant mouse, as reflected by a significant increase in the percentage of ducts, terminal ends, terminal ducts, and alveolar buds (146). Additionally, intraductal hyperplasias, which are considered preneoplastic lesions, were observed starting at 3 months of age (147).
To explore the links between prenatal BPA exposure and mammary gland neoplasia, a rat model was chosen because it closely resembles the human disease regarding estrogen dependency and histopathology. BPA was administered to pregnant dams at doses of 2.5, 25, 250, and 1000 μg/kg body weight/d. Fetal exposure to BPA, from gestational d 9 to postnatal d 1, resulted in the development of carcinomas in situ in the mammary glands of 33% of the rats exposed to 250 μg/kg body weight/d, whereas none of the unexposed animals developed neoplasias (148). These cancers were only observed after the animals had reached young adult age. Fetal exposure to BPA significantly increased the number of precancerous lesions (intraductal proliferation) by three to four times, an effect also observed in puberty and during adult life. The lesions observed in the BPA-exposed animals were highly proliferative and contained abundant ER-positive cells, suggesting that the proliferative activity in these lesions may be estrogen mediated. Comparable preneoplastic lesions were found in a study using a different rat strain (149). Additionally, this study found stromal alterations such as desmoplasia and mast cell invasion; these features are often observed during neoplastic development. Moreover, when challenged with a subcarcinogenic dose of nitrosomethylurea, only the BPA-exposed animals developed palpable tumors (carcinomas). The period of vulnerability of the mammary gland to BPA does not cease at the neonatal stage. BPA exposure during lactation followed to exposure to the carcinogen DMBA resulted in mammary tumor multiplicity and reduced tumor latency compared with control animals (exposed solely to DMBA) (150). These results indicate that perinatal exposure to environmentally relevant doses of BPA results in persistent alterations in mammary gland morphogenesis, development of precancerous lesions, and carcinoma in situ. Moreover, the altered growth parameters noted in the developing mammary gland on embryonic d 18 suggest that the fetal gland is a direct target of BPA, and that these alterations cause the mammary gland phenotypes observed in perinatally exposed mice at puberty and adulthood.
In summary, exposure to estrogens throughout a woman’s life, including the period of intrauterine development, is a risk factor for the development of breast cancer. The increased incidence of breast cancer noted during the last 50 yr may have been caused, in part, by exposure of women to estrogen-mimicking chemicals that have been released into the environment from industrial and commercial sources. Epidemiological studies suggest that exposure to xenoestrogens such as DES during fetal development, to DDT around puberty, and to a mixture of xenoestrogens around menopause increases this risk. Animal studies show that exposure in utero to the xenoestrogen BPA increases this risk. Moreover, these animal studies suggest that estrogens act as morphogens and that excessive perinatal exposure results in structural and functional alterations that are further exacerbated by exposure to ovarian steroids at puberty and beyond. These altered structures include preneoplastic lesions, such as intraductal hyperplasias, and carcinomas in situ. Additionally, these mammary glands are more vulnerable than their normal counterparts to carcinogenic stimuli. Exposures to other endocrine disruptors that are not estrogenic, such as dioxins, were reported to increase breast cancer incidence in humans and to alter mammary gland development in animal models. Collectively, these data support the notion that endocrine disruptors alter mammary gland morphogenesis and that the resulting dysgenic gland becomes more prone to neoplastic development.
Source: http://edrv.endojournals.org/content/30/4/293.fullDon
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