(see also physiology of endocrine system, endocrinomodulatory drugs and disease of the endocrine system)

Most act as agonists or antagonists on estrogen receptor, androgen receptor, PPARg, and progesterone receptor. It has been well documented that estrogens and their metabolites (i.e. pharmaceuticals) cause sex ratio shifts in fish, as do estrogen mimics from many sources, such as personal care products, some pesticides, and some surfactants. These chemicals, and/or their metabolites, can originate from municipal wastewater treatment and many non-point sources and runoff from the land and groundwater.

Exposure of human fetuses to man-made estrogenic chemicals can occur through several sources. For example, fetal exposure to ethinylestradiol occurs because each year 3% of the 60 million women in the USA and Europe taking oral contraceptives become unintentionally pregnant. Exposure to the estrogenic chemical bisphenol A occurs through food and beverages because of significant leaching from polycarbonate plastic products and the hard plastic lining of tin cans exposed to high temperatures. Pregnant CD-1 mice were fed ethinylestradiol (0.1 µg/kg per day) and bisphenol A (10 µg/kg per day), which are doses below the range of exposure by pregnant women (the US government suggests people consume a maximum of 5 times this amount of bisphenol A). In male mouse fetuses, both ethinylestradiol and bisphenol A produced an increase in the number and size of dorsolateral prostate ducts and an overall increase in prostate duct volumeHistochemical staining of sections with antibodies to proliferating cell nuclear antigen and mouse keratin 5 indicated that these increases were due to a marked increase in proliferation of basal epithelial cells located in the primary ducts : male mice born to the latter group had 41% more ducts in their prostate glands than the control mice. Both ethinyl estradiol and DES produced a 25% increase in such ducts. The researchers suggest that increased exposure to synthetic oestrogen in the womb programs the cells of the prostate gland to become hyperactive. The resulting enlargement of the gland can cause serious discomfort later in life. Prostate enlargement affects 50% of all UK men over the age of 50. The urethra was malformed in the colliculus region and was significantly constricted where it enters the bladder, which could contribute to urine flow disorders. These effects were identical to those caused by a similar dose (0.1 µg/kg per day) of the estrogenic drug diethylstilbestrol (DES), a known human developmental teratogen and carcinogen. In contrast, a 2,000-fold higher DES dose completely inhibited dorsolateral prostate duct formation, revealing opposite effects of high and low doses of estrogen. Acceleration in the rate of proliferation of prostate epithelium during fetal life by small amounts of estrogenic chemicals could permanently disrupt cellular control systems and predispose the prostate to disease in adulthood. Because bisphenol A is not used for its sex-hormone effects, they expected the oestrogenic impacts to be 100 times less potent than the other 2, but it caused a much bigger effect. A growing body of evidence against bisphenol A has led California lawmakers to consider banning the chemical from plastics used in baby productsref. Since the 1990s, the work of vom Saal and others has revealed links between these drugs and sperm production, sex reversal in amphibians, early onset of puberty and a variety of behavioural changes. Not all of the evidence is confined to lab studies. For example, many women prescribed an anti-miscarriage diethylstilbestrol in the 1950s gave birth to babies who later developed genital abnormalities. Invented in Britain in 1938, DES was hailed as a 'wonder drug' capable of preventing miscarriage by boosting oestrogen levels. It was also given to relieve morning sickness and high blood pressure. DES (dubbed "the silent thalidomide") was used worldwide by 6 million women (200,000 women in the UK) : however, in 1953, a clinical study found DES did nothing to reduce the risk of miscarriage. But it was used until 1971, when it was found the daughters of women who took the drug were at an increased risk of rare cancers of the vagina and the cervix. Further research also linked DES to an increased the risk of breast cancer in mothers. DES daughters had a 40% increased risk of the cancer. The risk increased with age, with those over 40 some 90% more likely to get the disease (Palmer, Cancer Epidemiology Biomarkers & Prevention, 2006).

California may soon become the first US state to adopt legislation banning the manufacture and sale of children's products containing certain chemicals designed to soften plastics. The initiative follows mounting scientific evidence in recent years about the potential harm of phthalates and so-called endocrine disruptors such as Bisphenol A (BPA). If bill AB 319, introduced by Assembly-member Wilma Chan (D-Oakland), passes, California would be the first state to follow the lead set by a European Union directive six years ago that put an emergency ban on baby toys made from plastics containing phthalates. At the time, European ministers said their decision was based on the precautionary principle and they would review it in the light of new scientific data. Data indicate that dangers do in fact exist, and bans set to limit childhood exposure might not go far enough. Yet many argue over the merit of the model. There is enough evidence of potential harm to ban these chemicals. Nevertheless, the chemical industry insists that phthalates and BPA are harmless. The California bill as a scare campaign. The potential human exposure to BPA... is extremely low and poses no known risk to human health, citing safety assessments from European and US regulatory agencies. But these evaluations are outdated : most of the important articles have been published since the risk assessment exercises. European and US assessments are based on scientific literature published in the 1980s and 1990s. There are now over a hundred recent studies showing adverse affects of BPA in different animal models. But controversy surrounds the choice of animal models as well as the relevant dose ranges for testing. Ross says that tests performed on rodents cannot be extrapolated to indicate potential human health effects. Adverse effects of chemicals on rats cannot even predict similar effects on mice, much less on people. Rodent models are reasonable both for practical and theoretical reasons. But he notes the difficulty in extrapolating between species when it comes to endocrine issues. Other experts echo these concerns. The mouse is not a good model for the human in terms of fetal effects of estrogens. Murine estrogen levels are only modestly elevated in pregnancy compared with humans. So, BPA exposure may add more to the estrogen burden in the mouse. However, vom Saal rejects this argument, explaining that it is the amount of activated estrogens that are important and that small changes in endogenous estrogen levels have been linked to human birth defects. Appropriate dosing poses another problem. The dose issue is critical in any study of environmental estrogen effects, because it is possible, with high enough doses, to see responses to just about anything. Regulatory agencies attempt to apply a substantial safety factor when extrapolating from animal models to the human situation. For example, the US Environmental Protection Agency (EPA) calculated the acceptable daily intake level (known as the Reference Dose, or RfD) for BPA by dividing the rodent "lowest effect" level of 50,000 mg/kg/day by 1000 to obtain an RfD of 50 mg/kg/day. The European Commission adopted a more conservative acceptable daily intake level of 10 mg/kg/day. Nevertheless, many recent studies have highlighted potential harmful effects of very low doses of phthalates and estrogenic compounds. These studies raise questions as to the actual human exposure levels. Exposures to BPA are estimated in developed countries to be well below the safety limits. So, for the average person in the street there is not an immediate cause for concern. The situation changes, however, in the case of pregnant women, as BPA may be concentrated in the human placenta and amniotic fluid. MacLusky notes that fetal development represents the most sensitive period of life in terms of exposure to chemicals like phthalates and BPA. Fluctuations in the levels of the natural endogenous hormone estradiol induced changes in prostate development in utero. The recent awareness that many environmental chemicals act as hormone mimics led us to study the consequences further, using mouse prostate development as an animal model. They fed low levels of BPA (10 mg/kg/day) to pregnant mice for 4 daysref. They then removed fetuses by cesarean section and removed the prostates from male embryos. Using sophisticated 3-D image reconstruction, they made precise measurements of the developing prostate. As a positive control, Timms' group used diethylstilbestrol (DES), an estrogenic compound similar in structure to BPA and associated with reproductive organ defects and cancer in humans. Timms and vom Saal found that low-level exposure to the compounds caused an increase (up to 40%) in the size and the number of the prostate ducts, and increases in proliferation of the basal epithelial cells of the primary ducts. They also observed a narrowing of the bladder neck and urethra. The researchers suggest that the observed deformities could predispose animals to prostate cancer and bladder disease in later life, and the virtually identical effects of BPA and DES make a strong case for the relevance of the rodent model and the potential human hazards. Researchers in the field agree that the Timms study has carefully examined the issue of low doses. The doses used in the Timms study are well within the range of what is currently stated by both European and US government agencies to be 'safe' for human consumption. The study is particularly rigorous with respect to the sampling and the high anatomical resolution. Nevertheless, researchers are divided over the study's relevance to human health. I have doubts as to what it means. Nobody, as far as I am aware, including the authors, has shown that the effects that they report (i.e. an increase in prostatic budding, etc.) actually lead to any adverse change in the prostate in adulthood. Whether their endpoint is relevant to future prostate cancer, as they claim, is difficult to judge,. This is just one of many recently published works cautioning about the developmental effects of plastic components. Environmentally relevant doses of BPA affect mammary gland development in miceref. An association between male genital defects and phthalate exposure in pregnant women has been reportedref. Also, in collaboration with researchers at Yale University, MacLusky found evidence for BPA effects on brain development in rodentsref.  The interest in male reproduction was sparked by interest in male fertility the falling-sperm-counts story and the widespread rise in testicular cancer throughout the developed world. But none of these findings can explain the descriptive epidemiological findings that started the concern. The rise in testicular cancer, for example, began about a hundred years ago, before the introduction of BPA or phthalates. The take-home message from these recent studies is that the fetal basis of disease is becoming much more critical than we previously thought. His group recently found that the effects of high-dose antiandrogenic compounds could be passed on epigenetically for up to four generations in ratsref. Skinner has begun to study the effects of environmentally relevant doses and is investigating other phenotypes, such as cancer and prostate disease. Potential biohazards of environmental toxins now need to be reevaluated in terms of transgenerational effects. Moreover, he reiterates the susceptibility during fetal development. These conclusions will have consequences for future legislative initiatives, which are currently based on exposure to infants. Fetal, prenatal, and adult exposure should all be rethought. The EPA is currently considering this issue. The Californian bill may not go far enough since the exposure of women during pregnancy may be an even greater cause for concern than the exposure of children. In the case of children and babies, it is essential to err on the side of caution."

A major exposure route for persistent organochlorine pollutants (POPs) in Sweden is through consumption of fatty fish from the Baltic Sea. To investigate whether exposure to 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) affects semen quantity and quality and reproductive hormones, 195 Swedish fishermen, aged 2465 years, were investigated. The men provided semen samples which were analysed in a mobile laboratory unit. Blood samples and information relating to lifestyle, medical and reproductive history were obtained. The subjects had a median CB-153 serum level of 193 ng/g lipid (range 391460) and a median p,p'-DDE serum level of 240 ng/g lipid (range 3342251). When CB-153 was categorized into quintiles, the subjects in the quintile with the highest concentration (>328 ng/g lipid), tended to have decreased sperm motility compared with the subjects in the lowest quintile (<113 ng/g lipid). The age-adjusted mean difference was 9.9% (95% confidence interval 1.0 to 21% P=0.08). There was no significant associations between p,p'-DDE and semen characteristics or reproductive hormones. The association between CB-153 and sperm motility, although not formally significant, is of interest considering the possible endocrine-disrupting effects of polychlorinated biphenyls (PCBs)ref. There was a significant linear association between CB-153 and total amount of PSA (slope [beta]=-2.5, 95% confidence interval [CI] -4.0, -0.9; P=0.02). With age, abstinence time and smoking included in the model the association became non-significant (beta=-1.4, 95% CI-3.0, 0.1; P=0.07). There were no significant associations between CB-153 and zinc, fructose and NAG. As for the exposure variable p,p'-DDE and the outcome variables, no significant associations were foundref. POP exposure may have a slight negative impact on human sperm chromatin integrityref. But log transformed CB-153 as well as log transformed p,p'-DDE variables were both significantly positively associated with Y chromosome fractions (P-values=0.05 and <0.001, respectively). Neither age, smoking nor hormone levels showed any association with Y-chromosome fractionsref. These data add to the growing body of evidence that exposure to POPs may alter the offspring sex ratio.

Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Pregnant rats that were exposed to the endocrine disruptors vinclozolin (an antiandrogenic fungicide commonly used in vineyards), and methoxychlor (an estrogenic pesticide that replaced DDT), produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however, and when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems. The effect persisted through all generations tested, with > 90% of the male offspring in each generation affected. While the impact on the first generation was not a surprise, the transgenerational impact was unexpectedref1, ref2

Intersex in the clam Scrobicularia plana: a sign of endocrine disruption in estuaries? ref

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