Alberto Mantovani

In vitro and in vivo activation of endothelial cells by colony-stimulating factors.

This study was designed to identify the set of functions activated in cultured endothelial cells by the hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-colony-stimulating factor (GM-CSF), and to compare them with those elicited by prototypic cytokines active on these cells. Moreover, indications as to the in vivo relevance of in vitro effects were obtained. G-CSF and GM-CSF induced endothelial cells to proliferate and migrate. In contrast, unlike appropriate reference cytokines (IL-1 and tumor necrosis factor, IFN-gamma), G-CSF and GM-CSF did not modulate endothelial cell functions related to hemostasis-thrombosis (production of procoagulant activity and of platelet activating factor), inflammation (expression of leukocyte adhesion molecule-1 and production of platelet activating factor), and accessory function (expression of class II antigens of MHC). Other colony-stimulating factors (IL-3 and macrophage-colony-stimulating factor) were inactive on all functions tested. In comparison to basic fibroblast growth factor (bFGF), G-CSF and GM-CSF induced lower maximal proliferation of endothelial cells, whereas migration was of the same order of magnitude. G-CSF and GM-CSF stimulated repair of mechanically wounded endothelial monolayers. Exposure to both cytokines induced shape changes and cytoskeletal reorganization consistent with a migratory phenotype. To explore the in vivo relevance of the in vitro effects of these cytokines on endothelium, we studied the angiogenic activity of human G-CSF in the rabbit cornea. G-CSF, but not the heat-inactivated molecule, had definite angiogenic activity, without any sign of inflammatory reactions. G-CSF was less active than bFGF. However, the combination of a nonangiogenic dose of bFGF with G-CSF resulted in an angiogenic response higher than that elicited by either individual cytokines. Thus, G-CSF and GM-CSF induce endothelial cells to express an activation/differentiation program (including proliferation and migration) related to angiogenesis.

Metabolism disrupting chemicals and metabolic disorders

The recent epidemics of metabolic diseases, obesity, type 2 diabetes(T2D), liver lipid disorders and metabolic syndrome have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence that other environmental factors may contribute to the rapid increase in the incidence of these metabolic diseases. This review will examine changes to the incidence of obesity, T2D and non-alcoholic fatty liver disease (NAFLD), the contribution of genetics to these disorders and describe the role of the endocrine system in these metabolic disorders. It will then specifically focus on the role of endocrine disrupting chemicals (EDCs) in the etiology of obesity, T2D and NAFLD while finally integrating the information on EDCs on multiple metabolic disorders that could lead to metabolic syndrome. We will specifically examine evidence linking EDC exposures during critical periods of development with metabolic diseases that manifest later in life and across generations.

Environment and women's reproductive health

BACKGROUND There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and womens reproductive health. METHODS Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and womens reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. RESULTS Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). CONCLUSIONS A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect womens reproductive health.

Effect of acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on humoral antibody production in mice☆

The effect of single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1.2, 6 or 30 micrograms/kg i.p.) on primary humoral antibody production was studied in young adult C57 BL/6J mice. TCDD profoundly suppressed the primary response to thymus-dependent (sheep erythrocytes) and independent (type III pneumococcal polysaccharide) antigens. The inhibitory effect of TCDD was still detectable 42 days after treatment. In contrast, under these experimental conditions, in vitro lymphoproliferative responses to Concanavalin A (Con A) and bacterial lypopolysaccharides and the ability to mediate graft versus host reaction were not significantly affected per unit number of lymphoid cells.

Oral, short-term exposure to titanium dioxide nanoparticles in Sprague-Dawley rat: focus on reproductive and endocrine systems and spleen.

Abstract The study explored possible reproductive and endocrine effects of short-term (5 days) oral exposure to anatase TiO2 nanoparticles (0, 1, 2 mg/kg body weight per day) in rat. Nanoparticles were characterised by scanning electron microscopy (SEM) and transmission electron microscopy, and their presence in spleen, a target organ for bioaccumulation, was investigated by single-particle inductively coupled plasma mass spectrometry and SEM/energy-dispersive X-ray. Analyses included serum hormone levels (testosterone, 17-β-estradiol and triiodothyronine) and histopathology of thyroid, adrenals, ovary, uterus, testis and spleen. Increased total Ti tissue levels were found in spleen and ovaries. Sex-related histological alterations were observed at both dose levels in thyroid, adrenal medulla, adrenal cortex (females) and ovarian granulosa, without general toxicity. Altered thyroid function was indicated by reduced T3 (males). Testosterone levels increased in high-dose males and decreased in females. In the spleen of treated animals TiO2 aggregates and increased white pulp (high-dose females) were detected, even though Ti tissue levels remained low reflecting the low doses and the short exposure time. Our findings prompt to comprehensively assess endocrine and reproductive effects in the safety evaluation of nanomaterials.

Environmental risk factors and male fertility and reproduction

Several environmental substances and pesticides exert a direct, cytotoxic effect on male germ cells. However, an increasing concern has been raised by compounds that may act through more subtle mechanisms, for example, specific pesticides that are potentially capable of modulating or disrupting the endocrine system. Overall, exposure to pesticides with endocrine-disrupting potential raise a particular concern for male fertility because of the possible occurrence of both effects at low concentrations and additive interactions with other environmental risk factors. Delayed reproductive problems deserve special attention, since experimental data consistently indicate a high vulnerability in the developing male reproductive system. Epidemiologic studies have confirmed an increased risk of conception delay associated with occupational exposure to pesticides. Moreover, an increased risk of spontaneous abortion has been noted among wives of exposed workers.

Parma consensus statement on metabolic disruptors

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16–18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as “metabolic disruptors”, in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

Long-lasting effects of lindane on mouse spermatogenesis induced by in utero exposure

Long-lasting effects on mouse spermatogenesis induced by prenatal exposure to the insecticide lindane have been investigated by conventional reproductive endpoints complemented by the flow cytometric (FCM) DNA content analysis of testis cells and by the Sperm Chromatin Structure Assay (SCSA). Two lindane dose levels, 15 and 25 mg/kg bw, and diethylstilboestrol (DES, 10 microg/kg bw) as positive control, were administered daily by gavage to pregnant CD1 mice on gestation days (GD) 9-16. Reproductive endpoints were evaluated on F1 male mice on postnatal day (PND) 60; additionally, animals treated with lindane 25 mg/kg per day and DES were examined on PND 100 to evaluate the possible reversibility of the effects. On PND 60, lindane and DES caused a reduction in the sperm head count and concentration, with recovery in older lindane 25 mg/kg per day animals (PND 100). By contrast, the DES group exhibited a greater reduction in the sperm head count on PND 100 than on PND 60. Changes in biochemical parameters in the testes, lactate dehydrogenase-C(4) (LDH-C(4)), and sorbitol dehydrogenase (SDH) activities, were also observed in adult treated F1 mice. Furthermore on PND 60, the FCM analysis revealed changes in the pattern of testicular germ cell distribution, especially in the haploid subcompartment, in the lindane 25 mg/kg per day group. A dose-dependent increase in chromatin abnormalities of the epididymal sperm was also shown by SCSA. These changes recovered on PND 100. Preliminary qualitative examination did not reveal any significant difference in the structure of testicular tissue; however, there were suggestions of a moderate increase in number and size of Leydig cells in both DES- and lindane-treated animals. The partial reversibility of these effects and the lack of structural modification of the testicular tissue as evidenced by histopathologic assessment suggest a functional impairment of sperm production and maturation, possibly associated with changes induced by lindane on factors affecting intratesticular steroidogenesis.

Bisphenol a and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies

Bisphenol A (BPA) is a high production volume monomer used for making a wide variety of polycarbonate plastics and resins. A large body of evidence links BPA to endocrine disruption in laboratory animals, and a growing number of epidemiological studies support a link with health disorders in humans. The aim of this review is to summarize the recent experimental studies describing the effects and mechanisms of BPA on the female genital tract and to compare them to the current knowledge regarding the impact of BPA impact on female reproductive health. In particular, BPA has been correlated with alterations in hypothalamic-pituitary hormonal production, reduced oocyte quality due to perinatal and adulthood exposure, defective uterine receptivity and the pathogenesis of polycystic ovary syndrome. Researchers have reported conflicting results regarding the effect of BPA on premature puberty and endometriosis development. Experimental studies suggest that BPA’s mechanism of action is related to life stage and that its effect on the female reproductive system may involve agonism with estrogen nuclear receptors as well as other mechanisms (steroid biosynthesis inhibition). Notwithstanding uncertainties and knowledge gaps, the available evidence should be seen as a sufficient grounds to take precautionary actions against excess exposure to BPA.

The influence of endocrine disruptors in a selected population of infertile women

Abstract Several studies report that endocrine disrupting chemicals (EDC) able to interfere with endocrine homeostasis may affect women’s reproductive health. We analyzed EDC serum levels and nuclear receptors (NRs) expression in order to have an indication of the internal dose of biologically active compounds and a measurement of indicators of their effects, as a result of the repeated uptake from environmental source. The percentage of patients with detectable bisphenol A (BPA) concentrations was significantly higher in the infertile patients compared with fertile subjects. No significant difference was found between the groups with regard to perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), mono-ethylhexyl phthalate (MEHP) and di-(2-ethylhexyl) phthalate (DEHP) concentrations. Among infertile women, the mean expression of estrogen receptor alpha (ERα) and beta (Erβ), androgen receptor (AR) and pregnane X receptor (PXR) was significantly higher than fertile patients. The mean expression of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) did not show significant differences between two groups. Patients with endometriosis had higher levels of PPARγ than all women with other causes of infertility. This study led further support to EDC exposure as a risk factor for women’s fertility.