Multisystemic alterations in humans induced by bisphenol A and phthalates: Experimental, epidemiological and clinical studies reveal the need to change health policies.

A vast amount of evidence indicates that bisphenol A (BPA) and phthalates are widely distributed in the environment since these compounds are mass-produced for the manufacture of plastics and plasticizers. These compounds belong to a large group of substances termed endocrine-disrupting chemicals (EDC). It is well known that humans and living organisms are unavoidably and unintentionally exposed to BPA and phthalates from food packaging materials and many other everyday products. BPA and phthalates exert their effect by interfering with hormone synthesis, bioavailability, and action, thereby altering cellular proliferation and differentiation, tissue development, and the regulation of several physiological processes. In fact, these EDC can alter fetal programming at an epigenetic level, which can be transgenerational transmitted and may be involved in the development of various chronic pathologies later in the adulthood, including metabolic, reproductive and degenerative diseases, and certain types of cancer. In this review, we describe the most recent proposed mechanisms of action of these EDC and offer a compelling selection of experimental, epidemiological and clinical studies, which show evidence of how exposure to these pollutants affects our health during development, and their association with a wide range of reproductive, metabolic and neurological diseases, as well as hormone-related cancers. We stress the importance of concern in the general population and the urgent need for the medical health care system to closely monitor EDC levels in the population due to unavoidable and involuntary exposure to these pollutants and their impact on human health.

Hormone-Related Cancer and Autoimmune Diseases: A Complex Interplay to be Discovered.

Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.

Altered expression of cytokines and sex steroid receptors in the reproductive tract of cysticercotic male mice.

Infection with Taenia crassiceps cysticerci in male mice produces an increase in serum oestradiol levels, whereas serum testosterone is abolished. Concomitantly, complete atrophy of the reproductive tract of infected male mice is observed. The present study was undertaken to determine the expression pattern of cytokines involved in steroidogenesis and sex steroid receptors in the reproductive tissues of normal and infected male mice, and relating this expression pattern to whole parasite counts, serum sex steroid levels and pathology of the reproductive tract in infected male mice. The expression of IL-4, IFN-gamma and TNF-alpha in testes and seminal vesicles was markedly increased in infected mice; however, IL-10 and IL-1beta expression was importantly decreased in the same organs. IL-2 expression in reproductive tissues was not affected by infection. The infection markedly induced the expression of androgen receptor, in both reproductive organs tested, while subtypes of oestrogen receptors were decreased in both tissues.

Differential expression of AP-1 transcription factor genes c-fos and c-jun in the helminth parasites Taenia crassiceps and Taenia solium.

Homologues of c-fos and c-jun from total DNA of Taenia crassiceps and Taenia solium were cloned and sequenced. The amino acid alignment analysis revealed that c-fos DNAs from T. crassiceps and T. solium were highly homologous (96%), and both have high homology compared to several mammalian c-fos proteins (93% to mouse, 96% to rat and 86% to human). The c-jun protein alignment showed higher homology (T. crassiceps and T. solium have 98%), when compared with mouse, rat and human, being 92%, 98% and 93% respectively. RT-PCR amplification of the parasite's total RNA, showed that T. crassiceps expressed both AP-1 complex genes, while T. solium only expressed c-fos. Southern blot hybridization analysis confirmed the true origin of each amplified gene. AP-1 transcription gene expression is regulated by oestradiol in the same fashion as their mammalian counterparts only in T. crassiceps. To study if AP-1 genes are involved in a physiological function of the cyst, reproduction was studied in vitro. Oestradiol treatment stimulated reproduction in T. crassiceps but not in T. solium cysticerci. This is the first report of the detection and functionality of AP-1 transcription factor genes in any species of helminth parasite.

Remote sensing of intraperitoneal parasitism by the host's brain: regional changes of c-fos gene expression in the brain of feminized cysticercotic male mice.

Experimental intraperitoneal Taenia crassiceps cysticercosis in mice exhibits distinct genetical, immunological and endocrinological features possibly resulting from the complex interactive network of their physiological systems. Very notable is the tendency of parasites to grow faster in hosts of the female sex. It is also remarkable in the feminization process that the infection induces in chronically infected male mice, characterized by their estrogenization, deandrogenization and loss of sexual and aggressive patterns of behaviour. The proto-oncogene c-fos is a sex steroid-regulated transcription factor gene, expressed basally and upon stimulation by many organisms. In the CNS of rodents, c-fos is found expressed in association to sexual stimulation and to various immunological and stressful events. Hence, we suspected that changes in c-fos expression in the brain could be involved in the feminization of the infected male mice. Indeed, it was found that c-fos expression increased at different times during infection in the hypothalamus, hippocampus, less so in the preoptic area and cortex, and not in several other organs. The significant and distinctive regional changes of c-fos in the CNS of infected mice indicate that the brain of the host senses intraperitoneal cysticercosis and may also announce its active participation in the regulation of the host-parasite relationship. Possibly, the host's CNS activity is involved in the network that regulates the estrogenization and deandrogenization observed in the chronically infected male mice, as well as in the behavioural and immunological peculiarities observed in this parasitic infection.

Evidence that steroid 5alpha-reductase isozyme genes are differentially methylated in human lymphocytes.

The synthesis of dihydrotestosterone (DHT) is catalyzed by steroid 5alpha-reductase isozymes 1 and 2, and this function determines the development of the male phenotype during embriogenesis and the growth of androgen sensitive tissues during puberty. The aim of this study was to determine the cytosine methylation status of 5alpha-reductase isozymes types 1 and 2 genes in normal and in 5alpha-reductase deficient men. Genomic DNA was obtained from lymphocytes of both normal subjects and patients with primary 5alpha-reductase deficiency due to point mutations in 5alpha-reductase 2 gene. Southern blot analysis of 5alpha-reductase types 1 and 2 genes from DNA samples digested with HpaII presented a different cytosine methylation pattern compared to that observed with its isoschizomer MspI, indicating that both genes are methylated in CCGG sequences. The analysis of 5alpha-reductase 1 gene from DNA samples digested with Sau3AI and its isoschizomer MboI which recognize methylation in GATC sequences showed an identical methylation pattern. In contrast, 5alpha-reductase 2 gene digested with Sau3AI presented a different methylation pattern to that of the samples digested with MboI, indicating that steroid 5alpha-reductase 2 gene possess methylated cytosines in GATC sequences. Analysis of exon 4 of 5alpha-reductase 2 gene after metabisulfite PCR showed that normal and deficient subjects present a different methylation pattern, being more methylated in patients with 5alpha-reductase 2 mutated gene. The overall results suggest that 5alpha-reductase genes 1 and 2 are differentially methylated in lymphocytes from normal and 5alpha-reductase deficient patients. Moreover, the extensive cytosine methylation pattern observed in exon 4 of 5alpha-reductase 2 gene in deficient patients, points out to an increased rate of mutations in this gene.

Cyclic adenosine 3',5'-monophosphate increases pancreatic glucokinase activity and gene expression.

Comparison of the pancreatic and hepatic glucokinase gene transcripts reveals tissue-specific control of expression and the existence of two distinct promoters in a single glucokinase gene. The existence of alternate promoters suggests that separate factors regulate glucokinase transcription in the two tissues. Hepatic glucokinase expression has been shown to be repressed by cAMP; however, in the pancreatic beta-cell it is unlikely that cAMP represses glucokinase activity, as cAMP is known to positively affect glucose-induced insulin secretion, a process that in mature islets requires pancreatic glucokinase activity. In this work we demonstrate that cAMP indeed has a stimulatory effect on pancreatic glucokinase. The cyclic nucleotide stimulates pancreatic glucokinase activity after 3-h incubation, and maximal effects are observed after 6 and 12 h of treatment. Using the bDNA assay, a sensitive signal amplification technique, we detected relative increases in glucokinase messenger RNA levels of 40.5 +/- 7.5% after 3-h incubation with cAMP. This stimulatory effect was increased to 106.3 +/- 22% after 6-h incubation and sustained up to 12 h of incubation. Inhibition of gene transcription by actinomycin D abolishes cAMP-induced glucokinase activity. In transfected fetal islets, cAMP increased the activity of the -1000 bp rat glucokinase promoter by 60 +/- 6%. These data demonstrate that cAMP has a stimulatory effect on pancreatic glucokinase gene expression and that the nucleotide has opposite effects on pancreatic and hepatic glucokinase, supporting the concept that glucokinase transcription in the liver and that in the beta-cell differ.

Tissue damage in the male murine reproductive system during experimental Taenia crassiceps cysticercosis.

Chronic infection with Taenia crassiceps cysticerci in male mice increases the level of estradiol in serum, whereas it reduces that of testosterone. In addition, male mice lose their typical male reproductive behavior. The effects of cysticerci infection on the histomorphology of male reproductive tissues are unknown. The present study was undertaken to determine the histological changes in testes, seminal vesicles, and prostate of male mice infected with T. crassiceps cysticerci. At 16 wk of infection, all tissues exhibited high inflammatory infiltrate. Tissue lesions included marked dilation and peripheral fibrosis. In the testes, a diminution of spermiogenesis was observed. The overall results indicated that the histological changes in chronically parasitized male mice occurred with changes in hormone levels, simultaneously with the high inflammatory immune response.

Modified expression of steroid 5 alpha-reductase as well as aromatase, but not cholesterol side-chain cleavage enzyme, in the reproductive system of male mice during (Taenia crassiceps) cysticercosis.

Infection with Taenia crassiceps cysticerci in male mice produces an increase in serum estradiol levels, whereas serum testosterone is abolished. Concomitantly, complete atrophy of the reproductive tract of infected male mice is observed. The present study was under-taken to determine the expression pattern of three key steroidogenic enzymes in the reproductive tissues of normal and infected male mice. In infected mice, serum estradiol levels were increased 97 times as compared with control mice of the same age. Testosterone and dihydrotestosterone levels were completely inhibited. The expression of 5 alpha-reductase in the reproductive tract was markedly reduced, whereas aromatase mRNA levels were highly elevated in the testes of parasitized mice. No change in the mRNA content for cholesterol side-chain cleavage enzyme was evident. The overall results suggest that the change in the normal production of sex steroids in infected male mice is produced concomitantly by the inhibition of expression of the 5 alpha-reductase enzyme and the activation of aromatase gene expression. This induces a preferential metabolism from testosterone toestradiol instead of the normal metabolism from testosterone to dihydrotestosterone.

Differential expression of the estrogen-regulated proto-oncogenes c-fos, c-jun, and bcl-2 and of the tumor-suppressor p53 gene in the male mouse chronically infected with Taenia crassiceps cysticerci.

Chronic infection with Taenia crassiceps cysticerci produces a 200-fold increase in serum estradiol levels in male mice. The aim of this study was to investigate the expression pattern of c-fos and c-jun, two estradiol-regulated genes, as well as that of p53 and bcl2 in the testes, spleen, and thymus of male mice infected with T. crassiceps cysticerci. In parasitized animals the c-fos mRNA content was significantly increased in all tissues studied, whereas the c-jun mRNA content was increased only in the thymus. The p53 mRNA content was markedly reduced in all tissues of the parasitized animals analyzed, whereas bcl-2 gene expression was abolished in the thymus. On the other hand, thymic cell analysis performed by flow cytometry showed a diminution in the content of CD3+, CD4+, and CD8+ subpopulations in the parasitized mice. Our results suggest that the increase in estradiol levels of the host should change the expression pattern of several genes that participate in apoptosis regulation in the thymus of male mice during chronic infection with T. crassiceps cysticerci.