Cryptorchidism and endocrine disrupting chemicals

Prospective clinical studies have suggested that the rate of congenital cryptorchidism has increased since the 1950s. It has been hypothesized that this may be related to environmental factors. Testicular descent occurs in two phases controlled by Leydig cell-derived hormones insulin-like peptide 3 (INSL3) and testosterone. Disorders in fetal androgen production/action or suppression of Insl3 are mechanisms causing cryptorchidism in rodents. In humans, prenatal exposure to potent estrogen diethylstilbestrol (DES) has been associated with increased risk of cryptorchidism. In addition, epidemiological studies have suggested that exposure to pesticides may also be associated with cryptorchidism. Some case-control studies analyzing environmental chemical levels in maternal breast milk samples have reported associations between cryptorchidism and chemical levels. Furthermore, it has been suggested that exposure levels of some chemicals may be associated with infant reproductive hormone levels.     

Environmental chemicals and thyroid function

There is growing evidence that environmental chemicals can disrupt endocrine systems. Most evidence originates from studies on reproductive organs. However, there is also suspicion that thyroid homeostasis may be disrupted. Several groups of chemicals have potential for thyroid disruption. There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis. Similarly, flame retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce. Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals. Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic-pituitary-thyroid axis at different levels. Mechanisms of action may involve the sodium-iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms. The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes. Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable. It is therefore urgent to clarify whether the animal data showing effects of chemicals on thyroid function can be extended to humans.     

Amphibian metamorphosis as a model for studying endocrine disruption on vertebrate development: Effect of bisphenol A on thyroid hormone action

Thyroid hormone (TH) is essential for proper development in vertebrates. TH deficiency during gestation and early postnatal development produces severe neurological, skeletal, metabolism and growth abnormalities. It is therefore important to consider environmental chemicals that may interfere with TH signaling. Exposure to environmental contaminants that disrupt TH action may underlie the increasing incidence of human developmental disorders worldwide. One contaminant of concern is the xenoestrogen bisphenol A (BPA), a chemical widely used to manufacture polycarbonate plastics and epoxy resins. The difficulty in studying uterus-enclosed mammalian embryos has hampered the analysis on the direct effects of BPA during vertebrate development. As TH action at the cellular level is highly conserved across vertebrate species, amphibian metamorphosis serves as an important TH-dependent in vivo vertebrate model for studying potential contributions of BPA toward human developmental disorders. Using Xenopus laevis as a model, we and others have demonstrated the inhibitory effects of BPA exposure on metamorphosis. Genome-wide gene expression analysis revealed that surprisingly, BPA primarily targets the TH-signaling pathway essential for metamorphosis in Xenopus laevis. Given the importance of the genomic effects of TH during metamorphosis and the conservation in its regulation in higher vertebrates, these observations suggest that the effect of BPA in human embryogenesis is through the inhibition of the TH pathway and warrants further investigation. Our findings further argue for the critical need to use in vivo animal models coupled with systematic molecular analysis to determine the developmental effects of endocrine disrupting compounds.     

Promoting activity of di(2-ethylhexyl)phthalate in rat liver foci bioassay

Summary The plasticizer DEHP but not DEHS exerted a weak promoting effect in a 12-week rat liver foci bioassay, using weanling female Sprague-Dawley rats. The effect was similar after doses of 200 and 500 mg/kg body weight, given 3 times weekly by gavage for 11 consecutive weeks after initiation with a single oral dose of 8 mg DEN/kg body weight. Lower doses were ineffective. The incidence of foci with deficiency in ATPase was enhanced about twice compared to rats treated with DEN only. The incidence of foci with expression of GGTase was not affected by DEHP treatment. The results match the findings with lifetime exposure studies, when liver tumors were found in rats and mice. The actual risk for man from environmental DEHP contamination seems to be low; the intake from highly contaminated food is calculated to be about 400-fold lower than the lowest effective dose in this study.Abbreviations DEHP di(2-ethylhexyl)phthalate - DEHS di(2-ethylhexyl)sebacate - ATPase adenosine-5-triphosphatase (EC 3.6.1.3) - GGTase gamma-glutamyltranspeptidase (EC 2.3.2.2) - DEN diethylnitrosamine Supported by grants from Umweltbundesamt Berlin (UBA 10604017)     

Quantitative analysis of the early changes of hepatocyte nuclei after treating Syrian golden hamsters with Di(2-ethylhexyl)phthalate

Summary Although the biological action of phthalates has been widely discussed there is little information on early cellular changes indicative for toxic or carcinogenic effects. To study subtle alterations in the cell morphology, we have by means of image processing evaluated the nuclei of hamster hepatocytes after treatment with di(2-ethylhexyl)phthalate given in single i.p. doses of 30, 300, and 3000 mg/kg. The results indicate that by using specially developed methods for analysis of images of cell nuclei and chromatin structure, it is possible to recognize changes eluding detection with usual light microscopy.Dedicated to Professor Dietrich Schmähl on the occasion of his 60th birthday     

Environmental chemicals impacting the thyroid: targets and consequences.

Thyroid hormone (TH) is essential for normal brain development, but the specific actions of TH differ across developmental time and brain region. These actions of TH are mediated largely by a combination of thyroid hormone receptor (TR) isoforms that exhibit specific temporal and spatial patterns of expression during animal and human brain development. In addition, TR action is influenced by different cofactors, proteins that directly link the TR protein to functional changes in gene expression. Considering the importance of TH signaling in development, it is important to consider environmental chemicals that may interfere with this signaling. Recent research indicates that environmental chemicals can interfere with thyroid function and with TH signaling. The key issues are to understand the mechanism by which these chemicals act and the dose at which they act, and whether adaptive responses intrinsic to the thyroid system can ameliorate potential adverse consequences (i.e., compensate). In addition, several recent studies show that TRs may be unintended targets of chemicals manufactured for industrial purposes to which humans and wildlife are routinely exposed. Polychlorinated biphenyls, polybrominated diphenyl ethers, bisphenol-A, and specific halogenated derivatives and metabolites of these compounds have been shown to bind to TRs and perhaps have selective effects on TR functions. A number of common chemicals, including polybrominated biphenyls and phthalates, may also exert such effects. When we consider the importance of TH in brain development, it will be important to pursue the possibilities that these chemicals-or interactions among chemical classes-are affecting children's health by influencing TH signaling in the developing brain.     

Chronic daily ethanol and withdrawal: 5. Diurnal effects on plasma thyroid hormone levels

We previously demonstrated that chronic daily ethanol consumption and daily withdrawal by male rats in a modified ethanol liquid diet paradigm produced (a) chronically increased adrenal glucocorticoid activity; (b) decreased plasma testosterone; (c) decreased forebrain proopiomelanocortin gene expression; and (d) corresponding alterations in plasma leptin levels—all of which are consistent with reported changes during alcohol abuse and alcoholism. Each of these systems interact with hypothalamo-pituitary-thyroid (HPT) regulation, and links between chronic alcohol abuse and thyroid dysfunction have been suggested by both human and rat studies. Accordingly, we have begun to investigate potential HPT mediation of, or response to, alterations in these systems by investigating plasma thyroid hormone levels in the same chronic daily ethanol/withdrawal paradigm. Chronic daily episodes of ethanol consumption and withdrawal by male Sprague-Dawley rats decreased plasma levels of free (non-protein-bound) triiodothyronine (T3) (p<0.01) and free thyroxine (T4) (p<0.05) in the morning but not in the afternoon, relative to both ad libitum-fed and pair-fed controls (n=9/treatment). Plasma total T4 levels were likewise suppressed (p<0.01) in the morning, whereas total T3 levels were increased (p<0.05) in the afternoon. These changes eliminated normal diurnal patterns (higher in the morning) of plasma free T3, free T4, and total T3 concentrations. Three weeks after cessation of ethanol consumption, morning plasma levels of free and total T3 and T4, as well as plasma thyroid-stimulating hormone (TSH), were all not significantly changed by the prior ethanol consumption or pair-feeding. These results reveal that plasma thyroid hormone concentrations are suppressed in a time of day dependent manner by chronic daily ethanol consumption and daily withdrawal in this model of chronic ethanol abuse. During subsequent long-term “abstinence,” these thyroid hormones returned to control levels. These results are consistent with evidence that thyroid function is commonly diminished in alcoholism, with variable reports of recovery during abstinence. Further investigations with this rat model of daily ethanol consumption and daily withdrawal will help resolve interactions and roles of the HPT axis in alcohol abuse.     

Autoimmune thyroid disease associated with environmental thyroidal irradiation.

Reports of increased rates of thyroid disease in populations exposed to radiation as a result of the Chernobyl accident have increased awareness and concern about the risk of autoimmune-related thyroid disease possibly associated with environmental radiation exposure. While the association between thyroidal irradiation and an increased risk of thyroid neoplasia is well established, much less attention has been devoted to the potential effects of environmental irradiation on the function of the thyroid. However, since the Chernobyl accident new studies have been published that appear to link radiation exposure to an increased risk of autoimmune thyroiditis. In order to assess the plausibility of this association, we reviewed published studies that evaluate the possible association between environmental thyroidal radiation and the presence of antithyroid antibodies as well as autoimmune thyroid disease (hypothyroidism and hyperthyroidism). These data have not been summarized elsewhere. Although some epidemiologic evidence of an association exists, long-term, well-designed studies are needed to accurately evaluate the complex association between low-dose environmental radiation exposure and clinically significant non-neoplastic thyroid disease. The results of these studies will be important in determining the appropriate clinical follow-up of persons exposed to environmental thyroidal irradiation.     

Can persistent organic pollutants and plastic‐associated chemicals cause cardiovascular disease?

During the last decade, associations between persistent organic pollutants (POPs), such as polychlorinated biphenyls, dioxins and pesticides, and cardiovascular (CV) risk factors and overt CV disease (CVD) have been reported in humans. Recently, associations between plastic-associated chemicals (PACs), such as bisphenol A and phthalates, and CVD have also begun to emerge. Several approaches to evaluating such associations have been used: accidents with a high level of exposure, occupational exposure studies, geographical studies of subjects living near a contaminated area and traditional case-control or cohort studies with measurements of circulating levels of different environmental contaminants in the general population. Exposure to POPs has consistently been associated with diabetes using all the approaches described above, including prospective studies. The evidence regarding associations between exposure to POPs and other CV risk factors, such as hypertension, obesity and lipids, is less strong and is mainly based on cross-sectional data. Associations between overt CVD and POPs have been reported using all the above approaches, but prospective data from population-based studies are still lacking to provide firm evidence of an important and independent role of POP exposure in the pathogenesis of CVD. Nevertheless, taken together, current evidence suggests that further longitudinal and experimental studies should be conducted to investigate the effect of exposure to both POPs and PACs, such as bisphenol A and phthalates.     

Role of ATG16L, NOD2 and IL23R in Crohn's disease pathogenesis

Inflammatory bowel disease is a group of diseases that includes Crohn's disease (CD) and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne's disease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500,000 people in North America and Europe. It ranges from 27 to 48 cases per 100,000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple population studies performed worldwide.     

Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands

BACKGROUND & AIMS: Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal acid reflux. TLESR is mediated via vagal pathways, which may be modulated by metabotropic glutamate receptors (mGluRs). Group I mGluRs (mGluR1 and 5) have excitatory effects on neurons, whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) are inhibitory. This study determined the effect of mGluRs on triggering of TLESR and reflux in an established conscious ferret model. METHODS: Esophageal manometric/pH studies were performed in ferrets with chronic esophagostomies. TLESR were induced by a gastric load of 25 mL glucose (pH 3.5) and 30 mL air. RESULTS: In control treated animals, gastric load induced 3.52 +/- 0.46 TLESRs per 47-minute study, 89.7% of which were associated with reflux episodes (n = 16). The mGluR5 antagonist MPEP inhibited TLESR dose dependently, with maximal 71% +/- 7% inhibition at 35 micromol/kg (n = 9; P < .0001). MPEP also significantly reduced reflux episodes (P < .001) and increased basal lower esophageal sphincter pressure (P < .05). MPEP inhibited swallowing dose dependently, suggesting a common action on trigger mechanisms for swallowing and TLESR. The more selective analogue, MTEP, had more potent effects (90% +/- 6% inhibition TLESR at 40 micromol/kg; n = 8; P < .0001). In contrast, the group I agonist DHPG tended to increase TLESR. The group II agonist (2R, 4R)-APDC was ineffective, whereas the group III agonist L-(AP4 slightly reduced TLESR (33% at 11 micromol/kg; P < .05). The selective mGluR8 agonist (S)-3, 4-DCPG inhibited TLESR by 54% at 15 micromol/kg (P < .01). CONCLUSIONS: mGluR5 antagonists potently inhibit TLESR and reflux in ferrets, implicating mGluR5 in the mechanism of TLESR. mGluR5 antagonists are therefore promising as therapy for patients with GERD.     

Exposure of 1800 MHz Radiofrequency with SAR 1,6 W/kg Caused a Significant Reduction in CD4+ T Cells and Release of Cytokines In-Vitro

Background: Although there have been many studies investigating the effects of electromagnetic fields on humans cells and tissues, the effects of radiofrequency electromagnetic fields exposure on the cells of the immune system are still controversial. Objective: To investigate the effects of 1800 MHz RF-EMF exposure on peripheral blood mononuclear cells by measuring T helper cells count and the cytokine profile under different conditions of durations and distances. Methods: The peripheral blood mononuclear cells (PBMCs) from healthy human subjects were exposed to 1800 MHz RF-EMF, with durations of 15, 30, 45, and 60 minutes and distances of 5 and 25 cm. The effects of RFEMF exposure on the number of CD4+ T cells, and the expression of IL-2,IL-10, and IL-17a after 48 hours of culture were evaluated using flow cytometry. Results: Our findings indicated that closer distance and longer exposure inducedlower number of CD4+ T cells. Similarly the percentagesof IL-2, IL-10 and IL-17a expressing CD4+ T cells weredecreased significantly. The number of IL-2 expressing CD4+T cells wasincreased significantly as the duration of exposure was increased, but the number was decreased after 60 minutes exposure when compared with control group with no exposure. Conclusions: Exposure to RF-EMF for 60 minutes at 5 cm distance causes a significant reduction in the number of CD4+ T cells, IL-2, IL-10 and IL-17a expressing T cells.     

Possible reproductive toxicity of styrene in peripubertal male mice

Environmental estrogens (endocrine disruptive chemicals) have been shown to affect reproduction in wild life and it has been reported that maternal exposure to those chemicals has adverse effects on the male reproductive tract. However, little is known about the potential effects of prepubertal or pubertal exposure to environmental estrogens on the male reproductive tract. Here we examine plasma hormone levels of mice following 4-week oral administration of styrene. Plasma free testosterone levels were dramatically decreased following 4 weeks of styrene treatment compared with control group. No differences in plasma corticosterone and luteinizing hormone levels were seen between styrene and control groups. Thus, exposure to styrene around pubertal period may directly disrupt the male reproductive tract. These facts suggest that more detailed studies regarding assessment of the risk to the developing human testes from exposure to styrene and other environmental estrogens in prepubertal and pubertal period are warranted.     

Allergènes de contact forts

Two important parameters control skin sensitization to a xenobiotic molecule: its sensitizing potential, an intrinsic property of each chemical, and exposure. It is often difficult to quantify a patient's exposure to a given allergen, which makes it difficult to define strong allergens. Indeed, the prevalence of an allergen, as determined by patch testing, reflects not its strength but a combination of sensitizing potential and exposure. The definition of strong sensitizers is therefore mainly derived from animal experiments where it is possible to assess a sensitization threshold or the dose per square centimeter that is able to induce significant sensitization. It has been shown in a limited number of case studies, that there is a good correlation between sensitization thresholds assessed in mice by the Local Lymph Node Assay (LLNA) and those obtained in humans with the Human Repeated Insult Patch Test (HRIPT). Based on this classification, one can recognize that strong sensitizers are quite common and that the general population is exposed regularly to them. Although the strong sensitizers include a broad diversity of chemicals, they have in common the ability to rapidly modify nucleophilic residues of proteins.     

Endocrine disrupters and female reproductive health

There is growing evidence of the impact of estrogenic contaminants in the environment. Studies have shown that male fish in detergent-contaminated water express female characteristics, turtles are sex-reversed by polychlorinated biphenyls (PCBs), male frogs exposed to a common herbicide form multiple ovaries, pseudohermaphroditic offspring are produced by polar bears, and seals in contaminated water have an excess of uterine fibroids. Endocrine-disrupting chemicals (those found in the external environment that can mimic or inhibit endogenous hormones) mostly exhibit estrogenic effects, but a few are anti-estrogenic or anti-androgenic. Many of these compounds are industrial contaminants, such as pesticides and plasticizers, and others are natural phytoestrogens found in plants such as soy and in herbal supplements. Recent work shows that human development can also be feminized by exposure to estrogenic chemicals. Estrogen is the key hormone in the initiation (puberty) and the end (menopause) of reproductive life in women and thus of considerable importance in women's health. The same chemicals that affect wildlife may affect breast growth and lactation, and could have a role in uterine diseases such as fibroids and endometriosis. New studies provide a mechanism of action for estrogenic chemicals and other endocrine disrupters at the molecular level (called epigenetics) that may help explain the long-term effects of endocrine disruption.     

Energy balance and pollution by organochlorines and polychlorinated biphenyls

Organochlorines are fat‐soluble chemical compounds resistant to degradation, so they are stored in the adipose tissue of practically every organism on the planet, including humans. Accumulation of these compounds in the body seems to be related to fat mass, obese individuals having a higher plasma organochlorine concentration than lean subjects. During body weight loss, lipid mobilization and a decrease in fat mass result in increased concentrations of organochlorines in plasma and adipose tissue. Organochlorines may have adverse health effects. For example, they have been associated with altered immune and thyroid functions and with some types of cancer. As these compounds may reach their target organs whilst in the circulation, their increase in plasma during weight loss might be associated with some physiological changes occurring during weight loss. Relationships have indeed been reported among weight loss‐induced increase in plasma organochlorine concentration and decreased triiodothyronine (T₃) concentration, resting metabolic rate, and skeletal muscle markers for fat oxidation. Although further studies are needed to assess the causality of these relationships, they raise concern about some potential undesirable effects of weight loss. Indeed, the effects of organochlorines on energy balance could complicate body weight loss and even favour weight regain. These notions lend support for weight‐loss strategies favouring a moderate weight loss, which would reduce risks for cardiovascular diseases, diabetes and hypertension, without resulting in a substantial release of organochlorines.     

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero

Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shown to be associated with decreased adult testosterone (T) levels and increased Leydig cell numbers. As yet, little is known about DEHP effects in utero on fetal Leydig cells (FLC). The present study investigated effects of DEHP on FLC function. Pregnant Long-Evans female rats received vehicle (corn oil) or DEHP at 10, 100, or 750 mg/kg by oral gavage from gestational day (GD)2-20. At GD21, T production, FLC numbers and distribution, and testicular gene expression were examined. The percentage of FLC clusters containing 6-30 cells increased in all treatment groups, with 29 +/- 2% in control vs. 37 +/- 3, 35 +/- 3, and 56 +/- 4% in rats receiving 10, 100, and 750 mg/kg DEHP, respectively. In contrast, FLC numbers were 33% and 39% lower than control after exposures to 100 and 750 mg/kg DEHP, respectively. At these doses, mRNA levels of leukemia inhibitory factor (LIF) increased. LIF was found to induce cell aggregation in FLCs in vitro, consistent with the hypothesis that DEHP induced FLC aggregation. Testicular T levels were doubled by the 10 mg/kg dose and halved at 750 mg/kg. The mRNA levels of IGF-1 and c-Kit ligand (KITL) were induced by 10 mg/kg DEHP. These results, taken together, indicate that fetal exposures to DEHP have effects on FLC number, distribution, and most importantly, steroidogenic capacity and suggest that abnormal expressions of IGF1, KITL, and LIF genes may contribute to the reproductive toxicity of phthalates.