The Inadvertent and Continuous Exposure of Fetuses to Environmentally Active Chemicals

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.                 

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.full

Don

The Ratio Between Index and Ring Finger

The ratio between index and ring finger is believed to be linked to exposure to the male hormone testosterone in the womb. On average, men tend to have longer ring fingers and women longer index fingers. The higher the testosterone, the greater the length of the ring finger and the more "masculine" the resulting child – whether male or female.

Why Men's Ring Fingers Are Longer Than Their Index Fingers: Male-Female Ring Finger Proportions Tied to Sex Hormones in Embryo

ScienceDaily (Sep. 6, 2011) — Biologists at the University of Florida have found a reason why men's ring fingers are generally longer than their index fingers -- and why the reverse usually holds true for women.

The finding could help medical professionals understand the origin of behavior and disease, which may be useful for customizing treatments or assessing risks in context with specific medical conditions.

Writing in the Proceedings of the National Academy of Sciences, developmental biologists Martin Cohn, Ph.D., and Zhengui Zheng, Ph.D., of the Howard Hughes Medical Institute and the department of molecular genetics and microbiology at the UF College of Medicine, show that male and female digit proportions are determined by the balance of sex hormones during early embryonic development. Differences in how these hormones activate receptors in males and females affect the growth of specific digits.

The discovery provides a genetic explanation for a raft of studies that link finger proportions with traits ranging from sperm counts, aggression, musical ability, sexual orientation and sports prowess, to health problems such as autism, depression, heart attack and breast cancer.

It has long been suspected that the digit ratio is influenced by sex hormones, but until now direct experimental evidence was lacking.

"The discovery that growth of the developing digits is controlled directly by androgen and estrogen receptor activity confirms that finger proportions are a lifelong signature of our early hormonal milieu," Cohn said. "In addition to understanding the basis of one of the more bizarre differences between the sexes, it's exciting to think that our fingers can tell us something about the signals that we were exposed to during a short period of our time in the womb. There is growing evidence that a number of adult diseases have fetal origins. With the new data, we've shown that that the digit ratio reflects one's prenatal androgen and estrogen activity, and that could have some explanatory power."

Cohn and Zheng, also members of the UF Genetics Institute, found that the developing digits of male and female mouse embryos are packed with receptors for sex hormones. By following the prenatal development of the limb buds of mice, which have a digit length ratio similar to humans, the scientists controlled the gene signaling effects of androgen -- also known as testosterone -- and estrogen.

Essentially, more androgen equated to a proportionally longer fourth digit. More estrogen resulted in a feminized appearance. The study uncovered how these hormonal signals govern the rate at which skeletal precursor cells divide, and showed that different finger bones have different levels of sensitivity to androgen and estrogen.

Since Roman times, people have associated the hand's fourth digit with the wearing of rings. In many cultures, a proportionally longer ring finger in men has been taken as a sign of fertility.
"I've been struggling to understand this trait since 1998," said John T. Manning, Ph.D., a professor at Swansea University in the United Kingdom, who was not involved in the current research. "When I read this study, I thought, thank goodness, we've attracted the attention of a developmental biologist with all the sophisticated techniques of molecular genetics and biology."

In dozens of papers and two books, including the seminal "Digit Ratio" in 2002, Manning has studied the meaning of the relative lengths of second and fourth digits in humans, known to scientists as the 2D:4D ratio.

"When Zheng and Cohn blocked testosterone receptors, they got a female digit ratio," Manning said. "When they added testosterone they got super male ratios, and when they added estrogen, super female ratios. And they've provided us with a list of 19 genes that are sensitive to prenatal testosterone and prenatal estrogen.

"I find this completely convincing and very useful," Manning said. "We can now be more focused in our examination of the links between digit ratio and sex-dependent behaviors, diseases of the immune system, cardiovascular disorders and a number of cancers."

Cohn, whose uses the tools of genetics, genomics and molecular biology to study limb development, said his lab began studying the digit ratios after Zheng became determined to find an explanation.
"He suggested that the 2D:4D ratio would be an interesting question, and I have to admit to being skeptical," Cohn said. "When he came back with the initial results, I was blown away. We looked at each others hands, then got busy planning the next experiment."

Finger Length Predicts Mental Toughness in Sport

ScienceDaily (Dec. 3, 2010) — Mental toughness and an aptitude for sport may be biologically determined.

This is one of the findings of an ongoing research project involving post-doctoral and doctoral research by Dr Jim Golby and Jennifer Meggs from Teesside University who will present their work on November 10 at the Division of Sport and Exercise Psychology's Annual Conference being held at the Holiday Inn London -- Camden Lock.

Previous research has shown that the 2D:4D ratio (index finger/ring finger) has the potential to explain sporting success. An index finger that is much shorter than the ring finger is caused by exposure to testosterone in the womb. This research investigated the relationship between 2D:4D and mental toughness, optimism, aggression and performance.

Sixty-seven participants had their fingers measured and completed personality and aggression questionnaires.

The results showed that participants with 2D:4D ratio were more likely to demonstrate mental toughness and have higher levels of sporting achievements.

Dr Golby explained: "It appears that high prenatal levels of testosterone may result in increased mental toughness, optimism and hence aptitude towards sport. This provides tentative support for the conclusion that mental toughness may be partially biologically predetermined."

Osteoarthritis Risk Linked To Finger Length Ratio

..............Professor Michael Doherty, lead researcher, said: “The 2D:4D length ratio appears to be a new risk factor for the development of OA. Specifically, women with the 'male' pattern of 2D:4D length ratio — that is, ring finger relatively longer than the index finger — are more likely to develop knee OA.”

As the first study to examine the relationship between 2D:4D length ratio and OA, it also raises questions.

Finger Length Points to Prostate Cancer Risk

The study led by The University of Warwick and The Institute of Cancer Research (ICR) found men whose index finger is longer than their ring finger were one third less likely to develop the disease than men with the opposite finger length pattern.

"Our results show that relative finger length could be used as a simple test for prostate cancer risk, particularly in men aged under 60," says joint senior author Professor Ros Eeles from the ICR and The Royal Marsden NHS Foundation Trust. "This exciting finding means that finger pattern could potentially be used to select at-risk men for ongoing screening, perhaps in combination with other factors such as family history or genetic testing.".......................

Don

High Levels of Potentially Toxic Flame Retardants in California Pregnant Women

Flame retardant chemicals, known as polybrominated diphenyl ethers (PBDEs), have been widely used in furniture foam, plastics, carpets, consumer electronics, wire insulation, and other products since the 1970s.

ScienceDaily (Aug. 11, 2011) — A new study finds that pregnant women in Northern California have the highest PBDE flame retardant exposures reported to date among pregnant women worldwide. It also describes some of the first evidence from humans that certain flame retardants may interfere with thyroid hormone signaling during pregnancy, which is critical to fetal brain development.

 

The study, described as one of the most extensive to date on flame retardant exposures in pregnant women, appears in the ACS journal Environmental Science & Technology.

Ami Zota and colleagues note that the flame retardant chemicals, known as polybrominated diphenyl ethers (PBDEs), have been widely used in furniture foam, plastics, carpets, consumer electronics, wire insulation, and other products since the 1970s. Although California banned manufacture and import of certain PBDEs in 2004, human exposure continues from old products, house dust, food, and other sources. Studies suggest that PBDE exposure during pregnancy may disrupt thyroid function, with adverse effects on normal development of the fetus's brain that persist throughout life, and also have adverse effects on the mother.

In their study of 25 second-trimester pregnant women in California, the researchers found the highest-ever levels of certain PBDEs among pregnant women worldwide. The high exposure most likely was the unintended consequence of California's furniture flammability standards, which manufacturers have met since 1975 by adding PBDE's to foam in upholstered furniture, Zota and colleagues said. While preliminary, the study also found a link between PBDE levels and levels of thyroid-stimulating hormone, a substance produced in the brain, that helps regulate activity of the thyroid gland.