Assessment of endocrine disruptor impacts on lipid metabolism in a fatty acid-supplemented HepaRG human hepatic cell line.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. This disease encompasses several stages, from steatosis to steatohepatitis and, eventually, to fibrosis and cirrhosis. Exposure to environmental contaminants is one of the risk factors and an increasing amount of evidence points to a role for endocrine disrupting compounds (EDCs). This study assesses the impact of selected EDCs on the formation of lipid droplets, the marker for steatosis in a hepatic model. The mechanisms underlying this effect are then explored. Ten compounds were selected according to their obesogenic properties: bisphenol A, F and S, butyl-paraben, cadmium chloride, p,p'-DDE, DBP, DEHP, PFOA and PFOS. Using a 2D or 3D model, HepaRG cells were exposed to the compounds with or without fatty acid supplementation. Then, the formation of lipid droplets was quantified by an automated fluorescence-based method. The expression of genes and proteins involved in lipid metabolism and the impact on cellular respiration was analyzed. The formation of lipid droplets, which is revealed or enhanced by oleic acid supplementation, was most effectively induced by p,p'-DDE and DEHP. Experiments employing either 2D or 3D culture conditions gave similar results. Both compounds induced the expression of PLIN2. p,p'-DDE also appears to act by decreasing in fatty acid oxidation. Some EDCs were able to induce the formation of lipid droplets, in HepaRG cells, an effect which was increased after supplementation of the cells with oleic acid. A full understanding of the mechanisms of these effects will require further investigation. The novel automated detection method described here may also be useful in the future as a regulatory test for EDC risk assessment.

The Austrian children's biomonitoring survey 2020 Part B: Mycotoxins, phytotoxins, phytoestrogens and food processing contaminants.

This study assessed the levels of environment and food-related exposures in urine of Austrian school children aged six to ten (n = 85) focusing on mycotoxins, phytoestrogens, and food processing by-products using two multi-analyte LC-MS/MS methods. Out of the 55 biomarkers of exposure reported in this study, 22 were quantified in the first void urine samples. Mycotoxins frequently quantified included zearalenone (detection rate 100%; median 0.11 ng/mL), deoxynivalenol (99%; 15 ng/mL), alternariol monomethyl ether (75%; 0.04 ng/mL), and ochratoxin A (19%; 0.03 ng/mL). Several phytoestrogens, including genistein, daidzein, and its metabolite equol, were detected in all samples at median concentrations of 22 ng/mL, 43 ng/mL, and 14 ng/mL, respectively. The food processing by-product 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was detected in 4% of the samples (median 0.016 ng/mL). None of the investigated samples contained the tested phytotoxins that were rarely considered for human biomonitoring previously (pyrrolizidine alkaloids, tropane alkaloids, aristolochic acids). When relating estimated exposure to current health-based guidance values, 22% of the children exceeded the tolerable daily intake for deoxynivalenol, and the estimated MOE for OTA indicates possible health risks for some children. The results clearly demonstrate frequent low-level (co-)exposure and warrant further exposome-scale exposure assessments, especially in susceptible sub-populations and longitudinal settings.

Estrogens and endocrine-disrupting chemicals differentially impact the bioenergetic fluxes of mammary epithelial cells in two- and three-dimensional models.

Due to its sensitivity to hormonal signaling, the mammary gland is often referred to as a sentinel organ for the study of endocrine-disrupting chemicals (EDCs), environmental pollutants that can interfere with the estrogen signaling pathway and induce mammary developmental defects. If and how EDCs impact mammary epithelial cell metabolism has not yet been documented. Herein, to study how estrogens and EDCs modulate mammary gland metabolism, we performed bioenergetic flux analyses using mouse mammary epithelial organoids compared to cells grown in monolayer culture. Several EDCs were tested, including bisphenol A (BPA), its close derivative BPS, a new BPA replacement copolyester called TritanTM, and the herbicide glyphosate. We report that estrogens reprogrammed mammary epithelial cell metabolism differently when grown in two- and three-dimensional models. Specific EDCs were also demonstrated to alter bioenergetic fluxes, thus identifying a new potential adverse effect of these molecules. Notably, organoids were more sensitive to low EDC concentrations, highlighting them as a key model for screening the impact of various environmental pollutants. Mechanistically, transcriptomic analyses revealed that EDCs interfered with the regulation of estrogen target genes and the expression of metabolic genes in organoids. Furthermore, co-treatment with the anti-estrogen fulvestrant blocked these metabolic impacts of EDCs, suggesting that, at least partially, they act through modulation of the estrogen receptor activity. Finally, we demonstrate that mammary organoids can be used for long-term studies on EDC exposure to study alterations in organogenesis/morphogenesis and that past pregnancies can modulate the sensitivity of mammary epithelial organoids to specific EDCs. Overall, this study demonstrates that estrogens and EDCs modulate mammary epithelial cell metabolism in monolayer and organoid cultures. A better understanding of the metabolic impacts of EDCs will allow a better appreciation of their adverse effects on mammary gland development and function.

Long exposure to a mixture of endocrine disruptors prediposes the ventral prostate of rats to preneoplastic lesions.

Endocrine disruptors (ED) are compounds dispersed in the environment that modify hormone biosynthesis, affecting hormone-dependent organs such as the prostate. Studies have only focused on evaluating the effects of ED alone or in small groups and short intervals and have not adequately portrayed human exposure. Therefore, we characterized the prostate histoarchitecture of rats exposed to an ED mixture (ED Mix) mimicking human exposure. Pregnant females of the Sprague-Dawley strain were randomly distributed into two experimental groups: Control group (vehicle: corn oil, by gavage) and ED Mix group: received 32.11 mg/kg/day of the ED mixture diluted in corn oil (2 ml/kg), by gavage, from gestational day 7 (DG7) to post-natal day 21 (DPN21). After weaning at DPN22, the male pups continued to receive the complete DE mixture until they were 220 days old when they were euthanized. The ED Mix decreased the epithelial compartment, increased the fractal dimension, and decreased glandular dilation. In addition, low-grade prostatic intraepithelial neoplasia was observed in addition to regions of epithelial atrophy in the group exposed to the ED Mix. Exposure to the mixture decreased both types I and III collagen area in the stroma. We concluded that the ED Mix was able to cause alterations in the prostatic histoarchitecture and induce the appearance of preneoplastic lesions.

Heavy Metals and Essential Elements in Association with Oxidative Stress in Women with Polycystic Ovary Syndrome-A Systematic Review.

Altered levels of heavy metals and essential elements have been associated with oxidative stress (OS) and metabolic and hormonal changes in women with polycystic ovary syndrome (PCOS). We aimed to summarize the knowledge on the association of heavy metals and essential elements with OS in PCOS. An electronic literature search using PubMed for studies published between January 2008 and April 2023 was conducted. We evaluated heavy metals and essential elements in relation to OS in PCOS in 15 articles. PCOS women had increased antimonium (Sb), cadmium (Cd), lead (Pb), mercury (Hg), arsenic (As), tellurium (Te), thallium (Tl) and osmium (Os) blood levels and decreased zinc (Zn) blood levels; the results of copper (Cu) blood levels were conflicting. Some studies showed a significant correlation between heavy metals (Sb, Cd, Pb, Hg, As, Te and Tl) and essential elements (Se, Zn, Cr, Ca, Mg and Cu) and markers of OS and chronic inflammation. Heavy metals (Sb, Cd, Pb and Hg) and essential elements (Zn, Cr, Se, Ca, Mg and Cu) were associated with metabolic and hormonal characteristics in PCOS. There might be a possible benefit from supplementation therapy in reducing OS and endocrinological problems related to PCOS. Our review confirmed an association between heavy metals and essential elements with OS in PCOS women. This systematic review is registered in PROSPERO under number CRD42023418453.

Calcium supplementation and body mass index modify associations between prenatal phthalate exposure and perinatal bone ultrasound measures among pregnant women.

Phthalates have endocrine activity that may interfere with bone health, particularly during pregnancy and the early postpartum period, when bone resorption increases. We evaluated associations between prenatal phthalate exposure and perinatal bone health among 289 mothers in the ELEMENT birth cohort in Mexico City who were randomized upon recruitment to receive 1,200 mg daily calcium supplementation or placebo throughout pregnancy. Spot urine samples at up to three timepoints during pregnancy were assayed for 9 phthalate metabolites. Bone integrity was assessed by quantitative ultrasound speed of sound (SOS) measurements of the phalange and distal radius at 3, 6, and 8 months of pregnancy and 1, 3, 7, and 12 months postpartum. Geometric means of specific gravity-corrected phthalate concentrations were used as overall measures of prenatal exposure. Linear mixed effect models estimated associations between phthalate exposure and repeated perinatal bone SOS measures, adjusting for age, pre-pregnancy body mass index (BMI), education, parity, calcium supplementation, and month of pregnancy/postpartum. Effect modification by calcium supplementation and BMI were assessed in sensitivity analyses. An interquartile range increase in MEP and MiBP increased pregnancy phalange z-scores (ß: 0.11; 95%CI: 0.003, 0.31 and ß: 0.15; 95%CI: 0.00,0.42, respectively). Higher concentrations of several phthalate metabolites resulted in lower SOS measures among women who received calcium supplements (compared to placebo group) but higher SOS measures among women with a BMI≥25 (compared to BMI<25). These results suggest that phthalate exposure may interfere with bone remodeling during pregnancy, and that consideration of effect modifiers is paramount to fully understand the effects of environmental exposures on bone health.

Iodine Deficiency, Maternal Hypothyroxinemia and Endocrine Disrupters Affecting Fetal Brain Development: A Scoping Review.

This scoping review critically discusses the publications of the last 30 years on the impact of mild to moderate iodine deficiency and the additional impact of endocrine disrupters during pregnancy on embryonal/fetal brain development. An asymptomatic mild to moderate iodine deficiency and/or isolated maternal hypothyroxinemia might affect the development of the embryonal/fetal brain. There is sufficient evidence underlining the importance of an adequate iodine supply for all women of childbearing age in order to prevent negative mental and social consequences for their children. An additional threat to the thyroid hormone system is the ubiquitous exposure to endocrine disrupters, which might exacerbate the effects of iodine deficiency in pregnant women on the neurocognitive development of their offspring. Ensuring adequate iodine intake is therefore essential not only for healthy fetal and neonatal development in general, but it might also extenuate the effects of endocrine disruptors. Individual iodine supplementation of women of childbearing age living in areas with mild to moderate iodine deficiency is mandatory as long as worldwide universal salt iodization does not guarantee an adequate iodine supply. There is an urgent need for detailed strategies to identify and reduce exposure to endocrine disrupters according to the "precautional principle".

Estrogenic in vitro evaluation of zearalenone and its phase I and II metabolites in combination with soy isoflavones.

Humans and animals are exposed to multiple substances in their food and feed that might have a negative health impact. Among these substances, the Fusarium mycoestrogen zearalenone (ZEN) and its metabolites α-zearalenol (α-ZEL) and α-zearalanol (α-ZAL) are known to possess endocrine disruptive properties. In a mixed diet or especially animal feed, these potential contaminants might be ingested together with naturally occurring phytoestrogens such as soy isoflavones. So far, risk assessment of potential endocrine disruptors is usually based on adverse effects of single compounds whereas studies investigating combinatorial effects are scarce. In the present study, we investigated the estrogenic potential of mycoestrogens and the isoflavones genistein (GEN), daidzein (DAI) and glycitein (GLY) as well as equol (EQ), the gut microbial metabolite of DAI, in vitro alone or in combination, using the alkaline phosphatase (ALP) assay in Ishikawa cells. In the case of mycoestrogens, the tested concentration range included 0.001 to 10 nM with multiplication steps of 10 in between, while for the isoflavones 1000 times higher concentrations were investigated. For the individual substances the following order of estrogenicity was obtained: α-ZEL > α-ZAL > ZEN > GEN > EQ > DAI > GLY. Most combinations of isoflavones with mycoestrogens enhanced the estrogenic response in the investigated concentrations. Especially lower concentrations of ZEN, α-ZEL and α-ZAL (0.001-0.01 nM) in combination with low concentrations of GEN, DAI and EQ (0.001-0.1 µM) strongly increased the estrogenic response compared to the single substances.

Forskolin Induces Endocrine Disturbance in Human JEG-3 Placental Cells.

Forskolin, used in folk medicine since ancient times, is now available as a dietary supplement, with an indication as a fat burner and appetite suppressant. However, the safety of forskolin is poorly documented especially for pregnant women. The question that we raised is what about the safety of forskolin in pregnant women? As the placenta, an endocrine organ, is the key organ of pregnancy, we evaluated the in vitro placental toxicity of forskolin. We focused first on the activation of a P2X7 degenerative receptor as a key biomarker for placental toxicity, and second on steroid and peptide hormonal secretion. We observed that forskolin activated P2X7 receptors and disturbed estradiol, progesterone, hPL and hyperglycosylated hCG secretion in human placental JEG-Tox cells. To the best of our knowledge, we highlighted, for the first time, that forskolin induced endocrine disturbance in placental cells. Forskolin does not appear to be a safe product for pregnant women and restrictions should be taken.

Fish and the Thyroid: A Janus Bifrons Relationship Caused by Pollutants and the Omega-3 Polyunsaturated Fatty Acids.

Benefits of the omega-3 polyunsaturated fatty acids (PUFA) on a number of clinical disorders, including autoimmune diseases, are widely reported in the literature. One major dietary source of PUFA are fish, particularly the small oily fish, like anchovy, sardine, mackerel and others. Unfortunately, fish (particularly the large, top-predator fish like swordfish) are also a source of pollutants, including the heavy metals. One relevant heavy metal is mercury, a known environmental trigger of autoimmunity that is measurable inside the thyroid. There are a number of interactions between the omega-3 PUFA and thyroid hormones, even at the level of the thyroid hormone transport proteins. Concerning the mechanisms behind the protection from/amelioration of autoimmune diseases, including thyroiditis, that are caused by the omega-3 PUFA, one can be the decreased production of chemokines, a decrease that was reported in the literature for other nutraceuticals. Recent studies point also to the involvement of resolvins. The intracellular increase in resolvins is associated with the tissue protection from inflammation that was observed in experimental animals after coadministration of omega-3 PUFA and thyroid hormone. After having presented data on fish consumption at the beginning, we conclude our review by presenting data on the market of the dietary supplements/nutraceuticals. The global omega-3 products market was valued at USD 2.10 billion in 2020, and was projected to go up at a compound annual growth rate of 7.8% from 2020 to 2028. Among supplements, fish oils, which are derived mainly from anchovies, are considered the best and generally safest source of omega-3. Taking into account (i) the anti-autoimmunity and anti-cancer properties of the omega-3 PUFA, (ii) the increasing incidence of both autoimmune thyroiditis and thyroid cancer worldwide, (iii) the predisposing role for thyroid cancer exerted by autoimmune thyroiditis, and (iv) the risk for developing metabolic and cardiovascular disorders conferred by both elevated/trendwise elevated serum TSH levels and thyroid autoimmunity, then there is enough rationale for the omega-3 PUFA as measures to contrast the appearance and/or duration of Hashimoto's thyroiditis as well as to correct the slightly elevated serum TSH levels of subclinical hypothyroidism.

Comprehending the Role of Endocrine Disruptors in Inducing Epigenetic Toxicity.

Endocrine disruptors are natural or man-made chemicals that interfere with the body's endocrine system leading to hormone synthesis and production defects. These chemicals are categorized as plasticizers and cosmetic chemicals, heavy metals, phytoestrogens, pesticides, detergents, surfactants, and flame retardants. Some of the most common endocrine disruptors are dioxins, bisphenol A, phthalates, perchlorate, perfluoroalkyl, and poly-fluoroalkyl substances (PFAs), phytoestrogens, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCB), triclosan, atrazine, lead, arsenic, mercury, organophosphate pesticides, and glycol ethers. Epigenetic alterations such as DNA methylation, histone modification, and miRNA regulation have been observed to play a major role in many diseases such as cancer, neurodegenerative diseases, PCOS, cardiovascular diseases, and various other disorders. In recent times, there has been a focus on endocrine-disrupting chemicals in epigenetic alterations. This review concentrates on estrogen and androgen disrupting effects, placental, and fetal effects, thyroid disrupting effects, and transgenerational effects of endocrine disruptors.

Nutritional interventions to ameliorate the effect of endocrine disruptors on human reproductive health: A semi-structured review from FIGO.

BACKGROUND: Endocrine disrupting chemicals have harmful effects on reproductive, perinatal, and obstetric outcomes. OBJECTIVE: To analyze the evidence on nutritional interventions to reduce the negative effects of endocrine disruptors on reproductive, perinatal, and obstetric outcomes. SEARCH STRATEGY: A search of MEDLINE (PubMed), Allied Health Literature (CINAHL), EMBASE, Web of Science, and the Cochrane Database was conducted from inception to May 2021. SELECTION CRITERIA: Experimental studies on human populations. DATA COLLECTION AND ANALYSIS: Data were collected from eligible studies. Risk of bias assessment was completed using the Cochrane risk of bias tool and the ROBINS-I Tool. RESULTS: Database searches yielded 15 362 articles. Removing 11 181 duplicates, 4181 articles underwent abstract screening, 26 articles were eligible for full manuscript review, and 16 met full inclusion criteria. Several interventions were found to be effective in reducing exposure to endocrine disruptors: avoidance of plastic containers, bottles, and packaging; avoidance of canned food/beverages; consumption of fresh and organic food; avoidance of fast/processed foods; and supplementation with vitamin C, iodine, and folic acid. There were some interventional studies examining therapies to improve clinical outcomes related to endocrine disruptors. CONCLUSION: Dietary alterations can reduce exposure to endocrine disruptors, with limited data on interventions to improve endocrine-disruptor-related clinical outcomes. This review provides useful instruction to women, their families, healthcare providers, and regulatory bodies.

Association of Early Pubertal Onset in Female Rats With Inhalation of Lavender Oil.

BACKGROUND: Central precocious puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis but its major cause remains unclear. Studies have indicated an association between chronic environmental exposure to endocrine-disrupting chemicals and pubertal onset. Essential oil is widely used in homes worldwide for relief of respiratory symptoms, stress, and/or sleep disturbance. METHODS: To evaluate this association, we compared the hormone levels and timing of vaginal opening (VO) in female rats exposed to lavender oil (LO) through different routes (study groups: control, LO nasal spray [LS], and indoor exposure to LO [LE]) during the prepubertal period. The body weights of the animals were also compared every 3 days until the day of VO, at which time gonadotropin levels and internal organ weights were assessed. RESULTS: The LS group showed early VO at 33.8 ± 1.8 days compared with the control (38.4 ± 2.9 days) and LE (36.6 ± 1.5 days) groups. Additionally, luteinizing hormone levels were significantly higher in the LE and LS groups than those in the control group. Body weights did not differ significantly among the groups. CONCLUSION: Inhalation exposure to an exogenic simulant during the prepubertal period might trigger early pubertal onset in female rats. Further evaluation of exposure to other endocrine-disrupting chemicals capable of inducing CPP through the skin, orally, and/or nasally is warranted.

Intrauterine exposure to di(2-ethylhexyl) phthalate (DEHP) disrupts the function of the hypothalamus-pituitary-thyroid axis of the F1 rats during adult life.

Introduction: DEHP is an endocrine disruptor widely used in the production of malleable plastics. DEHP exposure was associated with altered hypothalamic-pituitary-thyroid (HPT) axis function. Although previous studies reported deleterious effects of DEHP exposure during the intrauterine period, few studies have evaluated the direct effects triggered by this endocrine disruptor on the offspring animals' thyroid function. This study aimed to investigate the impact of intrauterine exposure to DEHP on the HPT axis function programming of the offspring animals during adulthood. Methods: Pregnant Wistar rats were orally treated with corn oil or corn oil supplemented with DEHP (0.48 or 4.8 mg/kg/day) throughout the gestational period. The offspring rats were euthanized on the 90th postnatal day. Hypothalamus, pituitary, thyroid, and liver were collected to analyze gene expression and protein content through qPCR and Western Blot. Blood was collected to determine TSH and thyroid hormone levels through fluorometric or chemiluminescence immunoassays. Results: In the adult F1 female rats, the highest dose of DEHP decreased TSH serum levels. In the thyroid, DEHP reduced the gene expression and/or protein content of NIS, TSHR, TG, TPO, MCT8, NKX2.1, PAX8, and FOXE1. These data are consistent with the reduction in T4 serum levels of the F1 DEHP-exposed female rats. In the liver, DEHP exposure increased the mRNA expression of Dio1 and Ttr, while the highest dose of DEHP reduced the mRNA expression of Ugt1a1 and Ugt1a6. Conversely, in the F1 male adult rats, TSHB expression and TSH serum levels were increased in DEHP-exposed animals. In the thyroid, except for the reduced protein content of TSHR, none of the evaluated genes/proteins were altered by DEHP. TH serum levels were not changed in the DEHP-exposed F1 male rats compared to the control group. Additionally, there were no significant alterations in the expression of hepatic enzymes in these animals. Discussion/Conclusions: Our results demonstrated, for the first time, that intrauterine exposure to DEHP disrupts the HPT axis function in male and female offspring rats and strongly suggest that DEHP exposure increases the susceptibility of the offspring animals to develop thyroid dysfunctions during adulthood.

Endocrine disruptors on and in fruits and vegetables: Estimation of the potential exposure of the French population.

Fruits and vegetables are considered to be healthy compared to fats, carbohydrates, and meats. However, their production involves plant protection products (PPPs) or they can contain phytoestrogens which may exhibit endocrine effects. Thus, the exposure to the main PPPs and to phytoestrogens known as endocrine disruptors (EDs) is estimated. PPPs include fungicides, growth substances, herbicides, and insecticides authorised in France. ED-PPPs exposure is estimated from the maximum residue limits (MRLs) of 70 potential ED-PPPs used in France on 64 fruits and vegetables. The estimated exposure to potential ED-PPPs is 509 µg/d and involves agonist and antagonist substances in complex mixtures. Anti-androgens are preeminent, at 353 µg/d. Exposure to genistein and daidzein is calculated from 140 measurements in 9 categories of food-items containing soy. The global exposure to isoflavones in France is evaluated at 6700 µg/d. Phytoestrogen exposure is much higher than that of ED-PPPs. Their endocrine effects should be considered.

In Utero Chlordecone Exposure and Thyroid, Metabolic, and Sex-Steroid Hormones at the Age of Seven Years: A Study From the TIMOUN Mother-Child Cohort in Guadeloupe.

Background: Chlordecone is an endocrine-disrupting chemical with well recognized estrogenic and progestagenic properties. This organochlorine insecticide was extensively used in the French West Indies from 1973 to 1993 to control the banana root borer. Due to its poor degradation in the environment, permanently polluted soil is responsible for the current contamination of the food chain and human beings. We aimed to examine the relationship of in utero exposure to chlordecone and thyroid (thyroid stimulating hormone [TSH], free tri-iodothyronine [FT3], free thyroxine [FT4]), metabolic (insulin growth-factor 1, leptin, adiponectin), and sex-steroid (dehydroepiandrosterone [DHEA], total testosterone [TT], dihydrotestosterone [DHT], estradiol [E2]) hormone levels in children at the age of seven years who participated in TIMOUN, an ongoing birth cohort in Guadeloupe. Methods: Chlordecone concentrations were measured in cord-blood at delivery. Thyroid, metabolic, and sex-steroid hormone levels were determined in the blood of children at seven years of age. Associations between in utero chlordecone exposure and hormone levels at seven years of age were assessed by multiple linear or logistic regression, controlling for confounding factors. Results: Among the study population (210 boys and 228 girls), chlordecone and hormone measurements were available for 124 boys and 161 girls. We found the third quartile of in utero chlordecone exposure relative to the lowest quartile to be associated with elevated TSH levels in girls and elevated DHEA, TT, and DHT levels in both sexes. Complementary non-linear analysis (spline regression) confirmed a significant non-linear trend for TSH in girls and DHEA and DHT in boys. Conclusion: In utero chlordecone exposure was associated with elevated levels of selected thyroid (TSH) and sex-steroid (DHEA, TT, and DHT) hormones at seven years in a non-monotonic dose response (inverted U) relationship. The implications for future health and reproductive function in puberty and adulthood should be determined.

[What do we know about effects of the endocrine disruptors on metabolism and obesity?] / Que sait-on de l'action des perturbateurs endocriniens sur le métabolisme et l'obésité?

WHAT DO WE KNOW ABOUT EFFECTS OF THE ENDOCRINE DISRUPTORS ON METABOLISM AND OBESITY? Some endocrine disruptors (EDs) are suspected to be involved in the increase of the prevalence of obesity and metabolic diseases. Data from epidemiological, in vivo, in vitro and in silico studies suggest that EDs may exert their effects on numerous tissues involved in energy metabolism and in the regulation of appetite: adipose tissue, liver, muscle, pancreas, gut and hypothalamus. Their effects are due to: disruptions of the carbohydrate and lipid homeostasis in these organs, via the activation of specific nuclear receptors or transcriptional factors, disturbances in communication between these organs, and epigenetic mechanisms, involved for example in intergenerational effects. The characterization of the effects of EDs on endocrine systems is still under investigations in several European and international projects and initiatives, with the aim to establish new validated regulatory tests for ED identification.

QUE SAIT-ON DE L'ACTION DES PERTURBATEURS ENDOCRINIENS SUR LE MÉTABOLISME ET L'OBÉSITÉ ? Certains perturbateurs endocriniens (PE) semblent être impliqués dans l'augmentation de la prévalence de l'obésité et des maladies métaboliques. Les données provenant d'études épidémiologiques, in vivo, in vitro et in silico suggèrent que les PE exerceraient leurs effets sur de nombreux tissus impliqués dans le métabolisme énergétique ou la régulation de l'appétit : tissu adipeux, foie, muscle, pancréas, intestin et hypothalamus. Les effets sont liés : aux perturbations de l'homéostasie glucido-lipidique dans ces organes, via l'activation de récepteurs nucléaires ou facteurs transcriptionnels spécifiques ; aux perturbations de la communication entre ces organes et aux mécanismes épigénétiques, impliqués par exemple dans les effets intergénérationnels. La caractérisation des effets des PE sur les systèmes endocriniens se poursuit, au sein d'initiatives et de projets européens et internationaux qui, à terme, mèneront à la mise en place de tests réglementaires validés pour l'identification des perturbateurs endocriniens.

Transient central precocious puberty: a new entity among the spectrum of precocious puberty?

OBJECTIVE: Recently, we observed some cases of Precocious Puberty (PP) with a partial central activation of hypothalamic-pituitary-gonadal (HPG) axis that tended to normalized in 6-12 months. To evaluate the frequency of this form within the spectrum of forms of PP, we retrospectively assessed the clinical, hormonal and ultrasound characteristics of patients attending to our Center for signs of PP, between 2007 and 2017. To hypothesize some causes of this "pubertal poussée" a questionnaire about environmental data was provided to patients. METHODS: 96 girls were recruited for the study and divided into three Groups. Group 1: 56 subjects with Central PP (CPP) requiring treatment with GnRH analogue; Group 2: 22 subjects with transient activation of pubertal axis, that tended to normalize, "Transient CPP"(T-CPP); Group 3: 18 subjects with Isolated Thelarche (IT). RESULTS: Mean age at diagnosis was 6.8 ± 1.0 years in Group 1, 5.9 ± 1.3 years in Group 2 and 5.6 ± 1.5 years in Group 3. A significant increase of diagnosis of T-CPP was observed over the study period. Significantly higher use of some homeopathic medicines and potential exposure to pesticides was reported in Group 2 vs Group 1. CONCLUSIONS: To our knowledge, we first reported a form defined as T-CPP, characterized by partial activation in the HPG axis normalizing over time. An increased use of homeopathic medicines and exposure to environmental pollutants in these patients was evidenced.

Fighting Bisphenol A-Induced Male Infertility: The Power of Antioxidants.

Bisphenol A (BPA), a well-known endocrine disruptor present in epoxy resins and polycarbonate plastics, negatively disturbs the male reproductive system affecting male fertility. In vivo studies showed that BPA exposure has deleterious effects on spermatogenesis by disturbing the hypothalamic-pituitary-gonadal axis and inducing oxidative stress in testis. This compound seems to disrupt hormone signalling even at low concentrations, modifying the levels of inhibin B, oestradiol, and testosterone. The adverse effects on seminal parameters are mainly supported by studies based on urinary BPA concentration, showing a negative association between BPA levels and sperm concentration, motility, and sperm DNA damage. Recent studies explored potential approaches to treat or prevent BPA-induced testicular toxicity and male infertility. Since the effect of BPA on testicular cells and spermatozoa is associated with an increased production of reactive oxygen species, most of the pharmacological approaches are based on the use of natural or synthetic antioxidants. In this review, we briefly describe the effects of BPA on male reproductive health and discuss the use of antioxidants to prevent or revert the BPA-induced toxicity and infertility in men.

Changes in the Population Size of Calbindin D-28k-Immunoreactive Enteric Neurons in the Porcine Caecum under the Influence of Bisphenol A: A Preliminary Study.

Calbindin D-28k (CB) is a calcium-binding protein widely distributed in living organisms that may act as a calcium buffer and sensory protein. CB is present in the enteric nervous system (ENS) situated in the gastrointestinal tract, which controls the majority of activities of the stomach and intestine. The influence of various doses of bisphenol A (BPA)-a chemical compound widely used in plastics production-on the number and distribution of CB-positive enteric neuronal cells in the porcine caecum was investigated with an immunofluorescence technique. The obtained results showed that low dosages of BPA resulted in an increase in the number of CB-positive neuronal cells in the myenteric (MP) and inner submucous (ISP) plexuses, whereas it did not alter the number of such neuronal cells in the outer submucous plexus (OSP). High dosages of BPA caused the increase in the amount of CB-positive perikarya in all the above-mentioned kinds of the caecal neuronal plexuses. These observations strongly suggest that CB in the ENS participates in the processes connected with the toxic activity of BPA. Most likely, the changes noted in this experiment result from the adaptive and protective properties of CB.