Bulletin de Veille n°5 BPA

Ce 5e bulletin de veille met en évidence 4 études complémentaires sur les troubles du comportement, la confirmation de la contamination au bisphénol A via les biberons, le lait maternel et donc d’autres supports alimentaires type canettes et boites de conserve. A noter également l’étude de Melzer qui met en avant un accroissement de la propension aux maladies coronariennes suite à exposition au BPA.

 

RISQUES LIES AU BISPHENOL A :

ARTICLES PARUS EN JANVIER-FEVRIER 2010

DANS LA LITTERATURE SCIENTIFIQUE (Source Medline)

ANALYSE GÉNÉRALE


Effets chez l’homme :

● Effets sanitaires : Confirmation sur un échantillon de population adulte représentatif de la population américaine recruté dans le grand programme de surveillance biologique NHANES d’un lien entre les niveaux d’imprégnation élevés en BPA et la survenue de maladies coronariennes et, dans une moindre mesure, de diabète.

● Effets sur cellules : Confirmation de la diminution par le BPA de l’efficacité des traitements de chimiothérapie et mise en évidence d’un impact sur un mécanisme de défense sur la génération de vaisseaux sanguins (mécanisme impliqué dans la croissance des cellules cancéreuses).

Effets chez l’animal :

● Troubles du comportement : nouvelles études chez les animaux traités au stade fœtal et pendant la lactation :

- Rats : à 40 µg/kg/j : les femelles ont une perturbation du comportement de type anxieux. Chez les 2 sexes, diminution de la capacité de reconnaissance spatiale).

- Aucun effet observé chez des rats de souche SD, mais cette souche est peu sensible aux oestrogènes (voir ci-dessous)

- Souris :

1) effets anxiolytiques et déficits cognitifs à des doses de l’ordre de la DJA

2) atteinte de mémoire spatiale, mémoire d’évitement à des doses > DJA

3) Stimulation de la différenciation neuronale à des doses > DJA)

● Action sur le système reproducteur mâle chez le rat (diminution des cellules de Leydig) et atteinte de l’hypophyse (mais à dose élevée de 20 à 200 mg/kg/j)

● Effets sur le porc (sur les cellules de la granulosa) et le mouton (baisse du poids à la naissance)Ø Effets chez les batraciens : perturbation des hormones thyroïdiennes, impliquées dans la métamorphose. Ce système étant conservé chez les vertébrés, ces résultats peuvent avoir des implications pour l’espèce humaine.

Exposition :

● Lait maternel : confirmation de la présence de BPA (chez la femme et chez la rate)

● Eau : Mise en évidence dans le Danube et ses affluents ; explication possible : le traitement en station est peu efficace (22%) en comparaison d’autres perturbateurs endocriniens (99% DEHP )

● 4 études sur les sources de contamination : confirmation d’une migration lors du chauffage au micro-onde, très supérieure à la dose générée par un chauffage à l’eau bouillante ; présence dans les boîtes de conserve (exposition prédominante pour les adultes et les adolescents ; Dose Maximum 1,5 µg/kg/j), les biberons (Moyenne à 0,8 µg/kg/j) et les produits liquides pour nourrissons (Maximum à 22 µg/kg/j). Ces contaminations induisent des doses inférieures à la DJA actuelle (50 µg/kg/j), mais très supérieures à la DJA qui devrait être calculée selon les règles de bonne pratique (au minimum 5 ng/kg/j par rapport aux troubles du comportement). Par ex pour les formules pour nourrissons, le ratio maximal est de 4400.

Déontologie :

● Débat contradictoire à propos de l’étude de Ryan (Etude citée dans le bulletin d’Octobre-Novembre et publiée en version papier en Mars ; voir abstract ci-dessous). Ryan ne met en évidence aucun impact à faible dose du BPA chez le rat en comparaison de l’éthinyl oestradiol, hormone de synthèse utilisée dans les contraceptifs. Sharpe considère en conséquence que l’étude de Ryan devrait clore le débat sur les risques liés au BPA. A l’inverse, Vom Saal critique la méthodologie suivie qui a consisté à utiliser une souche de rat peu sensible aux estrogènes (Souche Long Evans). En effet, la dose la plus faible induisant un effet chez le rat se situe entre 5 et 50 µg/kg/j, or la dose utilisée dans les contraceptifs humains est < 0,5 µg/kg/j. Il n’y a donc pas d’effet sur cette souche de rat à une dose qui induit une stérilité temporaire chez 99 ,7% des femmes. Pour que la comparaison ait un sens, il aurait donc fallu tester une dose de BPA au minimum de 500 µg/kg/j, ce qui n’a pas été le cas. Les auteurs considèrent que l’étude de Ryan n’a pas respecté les recommandations du National Toxicology Program considérant que les études sur les faibles doses de perturbateurs endocriniens utilisent des contrôles positifs ou des doses appropriées.

 

ANALYSE DE CHAQUE ARTICLE

 

Effets chez l’homme :

● Effets sanitaires

- Maladies coronariennes

Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS. Association of urinary bisphenol a concentration with heart disease: evidence from NHANES 2003/06. PLoS One. 2010 Jan 13;5(1):e8673.

Epidemiology and Public Health Group, Peninsula Medical School, University of Exeter, Exeter, United Kingdom. david.melzer@pms.ac.uk

→ En bref :

L’étude a étudié un échantillon de population adulte représentatif de la population américaine recruté dans le grand programme de surveillance biologique NHANES à 2 périodes différentes 2003/04 (n = 1455) et 2005/06 (n = 1493). Elle met en évidence un lien entre les niveaux d’imprégnation élevés en BPA et la survenue de maladies coronariennes et, dans une moindre mesure, de diabète. Le taux d’imprégnation a diminué entre les deux périodes. Cet article confirme les résultats publiés en 2008 par Lang sur un échantillon de population provenant de la même étude. L’aspect le plus important est le fait que ces résultats concernent une population adulte, alors que les données animales portent sur les effets liés à l’exposition fœtale. Autre aspect important : bien que le BPA soit éliminé par l’organisme humain quotidiennement, l’imprégnation est suffisamment constante pour induire des effets chroniques comme les maladies coronariennes. Les auteurs recommandent des études pour mieux comprendre le mécanisme d‘action.

Abstract :

BACKGROUND:

Bisphenol A (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years.

METHODOLOGY AND FINDINGS:

A cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18-74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant.

CONCLUSIONS:

Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.

- Inégalités

Ranjit N, Siefert K, Padmanabhan V. Bisphenol-A and disparities in birth outcomes: a review and directions for future research. J Perinatol. 2010 Jan;30(1):2-9. Epub 2009 Jul 9.

Michael and Susan Dell Center for Advancement of Healthy Living, University of Texas School of Public Health, Austin Regional Campus, Austin, TX, USA.

→ En bref :

Les auteurs s’interrogent sur le lien entre les disparités ethniques de santé et les disparités d’exposition au BPA.

Abstract :

Racial disparities in pregnancy outcome in the United States are significant, persistent and costly, but the causes are poorly understood. We propose that disproportionate exposure of African-American women to environmental endocrine disrupting compounds (EDCs) may contribute to birth outcome disparities. Marked racial segregation, as well as health behaviors associated with poverty could result in differences in exposure to particular EDCs. One EDC that has aroused concern in recent years is bisphenol-A (BPA), a widely used industrial plasticizer with known estrogenic properties. Published studies indicate that excessive BPA exposure is associated with reduced fetal survival, as well as reductions in maternal weight and fetal body weight. Related findings include adverse effects of BPA exposure on ovarian function, mammary gland development, earlier age of puberty onset and some metabolic parameters. However, these findings are largely limited to experimental animal studies, and need to be validated in human populations. Our review supports the need to move beyond the currently dominant toxicological approach to examining the effects of BPA exposure, and rely more on observational human studies and epidemiological methods. Many of the risk factors for racial disparities in pregnancy outcome are global or difficult to modify, but exposure to BPA is a potentially malleable risk factor. If BPA contributes to racial disparities in pregnancy outcome, there are important implications for prevention. It is our hope that this review will stimulate further research in this important and neglected area.

- Cellules humaines

Traitements Médicaux

Lapensee E, Ben-Jonathan N. Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy. Endocr Relat Cancer. 2010 Jan 13. [Epub ahead of print]

Cancer and Cell Biology, University of Cincinnati, Cincinnati, United States.

→ En Bref :

Article analysant les mécanismes de résistance à la chimiothérapie (cisplatine, doxorubicine, taxol, vinblastine) générée entre autres par le BPA.

Abstract :

Resistance to chemotherapy is a major complication in the treatment of advanced breast cancer. Estrogens and prolactin (PRL) are implicated in the pathogenesis of breast cancer but their roles in chemoresistance have been overlooked. A common feature to the two hormones is activation of their receptors by diverse compounds which mimic or antagonize their actions. The PRL receptor (PRLR) is activated by lactogens (PRL, growth hormone or placental lactogen) originating from the pituitary, breast, adipose tissue or the placenta. Estrogen receptors (ERs) exist in multiple membrane-associated and cytoplasmic forms that can be activated by endogenous estrogens, man-made chemicals, and phytoestrogens. Here we review evidence that low doses of PRL, estradiol (E2), and bisphenol A (BPA) antagonize multiple anti-cancer drugs that induce cell death by different mechanisms. Focusing on cisplatin, a DNA-damaging drug which is effective in the treatment of many cancer types but not breast cancer, we compare the abilities of PRL, E2 and BPA to antagonize its cytotoxicity. Whereas PRL acts by activating the glutathione-S-transferase detoxification enzyme, E2 and BPA act by inducing the anti-apoptotic protein Bcl-2. The implications of these findings to patients undergoing chemotherapy are discussed.

Cellules endothelium

Scoditti E, Massaro M, Carluccio MA, Distante A, Storelli C, De Caterina R. PPAR{gamma} agonists inhibit angiogenesis by suppressing PKC{alpha}- and CREB-mediated COX-2 expression in the human endothelium. Cardiovasc Res. 2009 Dec 23. [Epub ahead of print] C.N.R. Institute of Clinical Physiology, Lecce, Italy.

→ En Bref :

Le BPA diminue un mécanisme de défense contre l’angiogénèse, décrivant la croissance de nouveaux vaisseaux et jouant un rôle majeur dans la croissance des tumeurs malignes et le développement des métastases.

Abstract :

AIMS: The activation of Peroxisome Proliferator-Activated Receptor(PPAR)gamma is known to inhibit angiogenesis. As a potential mechanism for this, we aimed at examining the effects of PPARgamma agonists on the pro-angiogenic enzyme cyclooxygenase(COX)-2 in human endothelium. Methods and Results Cultured endothelial cells were pre-incubated with the PPARgamma agonists rosiglitazone (RSG) or GW1929 before stimulation with vascular endothelial growth factor (VEGF) or phorbol myristate acetate (PMA). RSG and GW1929 attenuated VEGF- and PMA-stimulated COX-2 activity, as well as protein and mRNA expression. This effect was abolished by the PPARgamma antagonists bisphenol A diglycidyl ether and GW9662 as well as by PPARgamma small interfering RNAs. Transient transfection experiments revealed that the induction of COX-2 promoter was significantly inhibited by RSG through an interference with the cAMP response element (CRE) site. COX-2 downregulation after siRNA targeting CRE binding protein (CREB) confirmed the role of CREB in mediating COX-2 transcription. Correspondingly, PPARgamma agonists attenuated CREB activation. Since both Protein Kinase C (PKC) alpha and beta are involved in VEGF-induced COX-2 expression and CREB activation, we investigated which isoform(s) of PKC was affected by RSG. RGS only reduced VEGF- and PMA-stimulated PKCalpha membrane translocation. CONCLUSIONS: VEGF induces CREB-mediated COX-2 expression through a PKCalpha-dependent pathway in human endothelium. The anti-angiogenic effect of PPARgamma agonists is due, at least in part, to an interference with the VEGF-stimulated PKCalpha-mediated activation of CREB and the related expression of COX-2.

 

Effets chez l’animal :

● Porc

Grasselli F, Baratta L, Baioni L, Bussolati S, Ramoni R, Grolli S, Basini G. Bisphenol A disrupts granulosa cell function. Domest Anim Endocrinol. 2010 Feb 11. [Epub ahead of print]

Dipartimento di Produzioni Animali, Biotecnologie Veterinarie, Qualità e Sicurezza degli Alimenti, Italy.

→ En Bref :

Le BPA perturbe le fonctionnement des cellules de la granulosa ovarienne chez le porc via un effet de promotion du processus d’angiogénèse ovarien.

Abstract :

Because of its widespread use and potential adverse biological effects, bisphenol A (BPA) represents one of the most studied endocrine-disrupting compounds. Within the reproductive system, ovarian granulosa cells have been documented as a target of BPA action, but no consensus has been reached about functional modifications induced by BPA. On these bases, we studied the potential disrupting effects of BPA on the main granulosa cell functional activities, also taking into account a potential interference with the ovarian angiogenic process. Ovarian granulosa cells were isolated from porcine follicles and cultured in the presence or absence of BPA at different concentrations for 48h. Cell proliferation was studied by measuring adenosine triphosphate content. Progesterone (P4) and estradiol 17beta (E2) production was determined by radioimmunoassay. Vascular endothelial growth factor (VEGF) output was quantified by an enzyme-linked immunosorbent assay. Redox status was monitored by measuring superoxide anion and hydrogen peroxide, and by determining the activities of the scavenging enzymes superoxide dismutase, catalase, and peroxidase by colorimetric methods. Granulosa cell proliferation as well as redox status resulted unaffected by BPA. Concentrations of E2 were stimulated by the lower BPA concentration, whereas they were inhibited by the larger doses tested. P4 output was decreased by all BPA concentrations. To the contrary, VEGF production was stimulated. Data indicate that BPA can interfere with reproductive activity by affecting granulosa cell steroidogenesis in vitro; furthermore, BPA can exert a promoting effect on the ovarian angiogenic process by increasing VEGF output in pigs. A disruption of this finely tuned process seems particularly relevant because of the risk of uncontrolled neovascularization.

● Mouton

Padmanabhan V, Sarma HN, Savabieasfahani M, Steckler TL, Veiga-Lopez A. Developmental reprogramming of reproductive and metabolic dysfunction in sheep: native steroids vs. environmental steroid receptor modulators.Int J Androl. 2010 Jan 12. [Epub ahead of print]

Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, MI, USA.

→ En Bref :

L’exposition au BPA à un niveau d’imprégnation maternelle de 30-50 ng/mL BPA se traduit par un impact hormonal (Baisse de l’hormone LH) et un faible poids à la naissance.

Abstract :

Summary The inappropriate programming of developing organ systems by exposure to excess native or environmental steroids, particularly the contamination of our environment and our food sources with synthetic endocrine disrupting chemicals that can interact with steroid receptors, is a major concern. Studies with native steroids have found that in utero exposure of sheep to excess testosterone, an oestrogen precursor, results in low birth weight offspring and leads to an array of adult reproductive/metabolic deficits manifested as cycle defects, functional hyperandrogenism, neuroendocrine/ovarian defects, insulin resistance and hypertension. Furthermore, the severity of reproductive dysfunction is amplified by excess postnatal weight gain. The constellation of adult reproductive and metabolic dysfunction in prenatal testosterone-treated sheep is similar to features seen in women with polycystic ovary syndrome. Prenatal dihydrotestosterone treatment failed to result in similar phenotype suggesting that many effects of prenatal testosterone excess are likely facilitated via aromatization to oestradiol. Similarly, exposure to environmental steroid imposters such as bisphenol A (BPA) and methoxychlor (MXC) from days 30 to 90 of gestation had long-term but differential effects. Exposure of sheep to BPA, which resulted in maternal levels of 30-50 ng/mL BPA, culminated in low birth weight offspring. These female offspring were hypergonadotropic during early postnatal life and characterized by severely dampened preovulatory LH surges. Prenatal MXC-treated females had normal birth weight and manifested delayed but normal amplitude LH surges. Importantly, the effects of BPA were evident at levels, which approximated twice the highest levels found in human maternal circulation of industrialized nations. These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals.

● Rat

Troubles du comportement

Poimenova A, Markaki E, Rahiotis C, Kitraki E. Corticosterone – regulated actions in the rat brain are affected by perinatal exposure to low dose of bisphenol A. Neuroscience. 2010 Feb 25. [Epub ahead of print]Department of Operative Dentistry, School of Dentistry, University of Athens, Greece.

→ En Bref :

Troubles du comportement sur la descendance de rates traitées au BPA (40 µg/kg/j) pendant la gestation et la lactation. Les femelles ont une perturbation du comportement de type anxieux. Chez les 2 sexes, diminution de la capacité de reconnaissance spatiale. Le mécanisme passe par la corticostérone, hormone secrétée par les glandes surrénales.

Abstract :

The estrogen – mimicking endocrine disrupter bisphenol A (BPA) which is used in the manufacture of plastic and epoxy resins, is one of the world’s most heavily produced synthetic chemicals. BPA is detected in animal tissues, and its bio-accumulation has shown to be higher in the fetus than the mother. Exposure to doses below the daily safe limit has been reported to affect the sexual differentiation of the brain and modify the behavior of the exposed rodent offspring. The aim of the present study was to investigate in the rat the possible organizational effects of low BPA exposure on glucocorticoid – regulated responses. Female breeders were exposed to 40 microg/kg bw BPA daily throughout pregnancy and lactation. Plasma corticosterone levels and the two types of hippocampal corticosteroid receptors (GR and MR) were determined in mid-adolescent offspring under basal conditions and following a Y-maze task. BPA treated females had higher corticosterone levels than control females and BPA males and lower GR levels than BPA males, under basal conditions. Following the mildly stressful experience of Y-maze, corticosterone levels were increased in BPA-treated animals of both sexes, compared to the controls. GR levels were also increased in BPA- treated females compared to males. No effect of BPA was observed on MR levels, whereas the Y-maze experience significantly decreased receptors’ levels in both female groups. The animals’ performance in the task was also evaluated. BPA exposure significantly impaired the spatial recognition memory in both sexes, and modified the behavioural coping in a sex-dependent manner. Female BPA-treated offspring exhibited increased ‘anxiety-like’ behaviour and dramatic loss of exploration attitude during the task, in comparison to males. This study provides for the first time evidence that corticosterone and its actions in the brain are sensitive to the programming effects of BPA at a dose below the currently acceptable daily intake.

 

Stump DG, Beck MJ, Radovsky A, Garman RH, Freshwater LL, Sheets LP, Marty MS, Waechter JM Jr, Dimond SS, Van Miller JP, Shiotsuka RN, Beyer D, Chappelle AH, Hentges SG. Developmental Neurotoxicity Study of Dietary Bisphenol A in Sprague-Dawley Rats.Toxicol Sci. 2010 Feb 17. [Epub ahead of print]

WIL Research Laboratories, LLC (DStump@WILresearch.com; MBeck@WILresearch.com; ARadovsky@WILresearch.com).

→ En Bref :

Aucun effet mis en évidence sur souche de rat SD exposé pendant la gestation et la lactation.Cette étude conforte la DJA actuelle. Il faut noter que l’usage de cette souche de rat est critiquée pour sa faible sensibilité aux oestrogènes.

Abstract :

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F(1) offspring from dietary exposure during gestation and lactation according to OECD and U.S. EPA guidelines for the study of developmental neurotoxicity. BPA was offered to female Crl:CD(SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day (GD) 0 through lactation day (LD) 21. F(1) offspring were evaluated using the following tests: detailed clinical observations (DCO) (post-natal day (PND) 4, 11, 21, 35, 45, and 60); auditory startle (PND 20 and 60); motor activity (PND 13, 17, 21, and 61); learning and memory using the Biel water maze (PND 22 and 62); brain and nervous system neuropathology and brain morphometry (PND 21 and 72). For F(1) offspring, there were no treatment-related neurobehavioral effects nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 mg/kg/day and 13.1 mg/kg/day during gestation and lactation, respectively) with no treatment-related effects at lower doses or non-monotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 mg/kg/day and 410 mg/kg/day during gestation and lactation, respectively).

 

Reproduction

Nakamura D, Yanagiba Y, Duan Z, Ito Y, Okamura A, Asaeda N, Tagawa Y, Li C, Taya K, Zhang SY, Naito H, Ramdhan DH, Kamijima M, Nakajima T. Bisphenol A may cause testosterone reduction by adversely affecting both testis and pituitary systems similar to estradiol. Toxicol Lett. 2010 Feb 5. [Epub ahead of print]

Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.

→ En Bref :

Mise en évidence d’une diminution des cellules de Leydig (ces cellules sont des cellules interstitielles situées dans le testicule et produisent la testostérone) et affecte l’hypophyse (glande endocrine stimulant les autres glandes endocrines) . Les doses utilisées sont supérieures aux doses d’exposition humaines (de 20 à 200 mg/kg/j) .

Abstract :

Bisphenol A (BPA) causes reproductive toxicities, but the mechanisms are still unclear. In the present study, we sought to clarify these mechanisms in comparison with those of 17beta-estradiol (E2). Prepubertal Wistar/ST male rats (4 week-old) were subcutaneously administered BPA (0, 20, 100 and 200mg/kg/day) or E2 (10 and 100mug/kg/day) for 6 weeks. Both BPA and E2 treatments decreased plasma and testicular testosterone levels, and plasma luteinizing hormone (LH), but not E2 and follicle-stimulating hormone levels, though E2 treatment increased its plasma level. In relation to the decreased testosterone levels, BPA and E2 decreased expressions of steroidogenic enzymes and cholesterol carrier protein in Leydig cells. Thus, decreased testosterone levels in plasma might have resulted from decreased expressions of these enzymes and protein as well as from decreased plasma LH levels. Interestingly, the changes in steroidogenic enzymes and carrier protein were observed at lower levels of exposure to BPA or E2 than those inhibiting plasma LH levels. Microscopically, 200mg/kg BPA and 100mug/kg E2 significantly decreased Leydig cell numbers in the testis. In addition, BPA and E2 also decreased expression of estrogen receptor alpha-mRNA, which might be related to the decreased numbers of Leydig cells. Thus, BPA directly affects not only Leydig cells but also the pituitary gland, but the former may be impaired at lower exposure concentrations than the latter. Copyright © 2010. Published by Elsevier Ireland Ltd.

Métabolisme

Verner MA, Magher T, Haddad S. High concentrations of commonly used drugs can inhibit the in vitro glucuronidation of bisphenol A and nonylphenol in rats. Xenobiotica. 2010 Feb;40(2):83-92.Département des sciences biologiques, Université du Québec à Montréal, Montréal, Quebec, Canada.

→ En Bref :

Diminution de la conjugaison du BPA par des médicaments usuels.

Abstract :

4-n-Nonylphenol and bisphenol A are endocrine disrupting chemicals that are mainly detoxified through glucuronidation. A factor that may modulate their glucuronidation rates is co-exposure to pharmaceuticals. This study aimed to identify and characterize the potential metabolic interactions between 14 drugs and these two endocrine disruptors. Nonylphenol and bisphenol A were co-incubated in freshly isolated rat hepatocytes with, drugs at a high concentration. Statistically significant metabolic inhibition of bisphenol A and nonylphenol biotransformation was observed with nine drugs (>50% inhibition by naproxen, salicylic acid, carbamazepine and mefenamic acid). Inhibition assays of UGT activity in rat liver microsomes revealed: 1) competitive inhibition by naproxen (K(i)(app) = 848.3 muM) and carbamazepine (K(i)(app) = 1023.1 muM), 2) no inhibition by salicylic acid suggesting another mechanism of inhibition. Detoxification of nonylphenol and bisphenol A was shown to be impaired by excessive concentrations of many drugs and health risk assessment should therefore address this issue.

● Souris

Troubles du comportement

Xu XH, Zhang J, Wang YM, Ye YP, Luo QQ Perinatal exposure to bisphenol-A impairs learning-memory by concomitant down-regulation of N-methyl-d-aspartate receptors of hippocampus in male offspring mice. Horm Behav. 2010 Mar 3. [Epub ahead of print].Chemistry and Life Sciences College, Zhejiang Normal University, PR China; Psychology Research Center, Zhejiang Normal University, PR China; The Key Laboratory for Ecology of Zhejiang Province, PR China.

→ En Bref :

Troubles du comportement consécutifs à une exposition au stade foetal touchant la mémoire spatiale et la mémoire d’évitement. Les doses utilisées supérieures à la DJA (de 0,05 à 50 mg/kg/j) limitent l’intérêt de l’étude.

Abstract :

Bisphenol-A (BPA) has been shown to influence development of the brain and behaviors. The purpose of the present report was to investigate the effects of perinatal exposure to BPA on learning/memory and its mechanism of action, especially focusing on N-methyl-d-aspartate receptor (NMDAR). Perinatal maternal exposure to BPA at 0.5, 5, and 50mg/kg/d significantly extended the escape length to find the hidden platform in Morris water maze, and BPA at 0.5 or 5mg/kg/d markedly decreased the percentage of time spent in the quadrant where the platform had been during training both in postnatal day (PND) 21 and PND 56 mice. The results of passive avoidance test showed that the error frequency to step down from a platform after received footshock was significantly increased, and the latency of the step-down response onto the grid floor 24h after received footshock was obviously reduced by exposure to BPA at 5 and 50mg/kg/d (P<0.01) in the PND 21 offspring or at 50mg/kg/d in the PND 56 offspring (P<0.01). Furthermore, perinatal exposure to BPA significantly inhibited the expressions of NMDAR subunits NR1, NR2A, and 2B in the hippocampus during the development stage, especially in PND 56 mice. The expressions of estrogen receptor beta (ERbeta) in both PND 21 and PND 56 mice were markedly down-regulated by BPA at 0.5, 5, and 50mg/kg/d. These results indicate that perinatal exposure to BPA affects normal behavioral development in both spatial memory and avoidance memory, and also permanently influences the behavior of offspring in adulthood. The inhibition of expressions of NMDAR subunits and ERbeta in hippocampus during postnatal development stage may be involved.

 

Tian YH, Baek JH, Lee SY, Jang CG. Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice. Synapse. 2010 Feb 18;64(6):432-439. [Epub ahead of print]

Department of Pharmacology, College of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.

→ En Bref :

Les animaux ont été exposés pendant la période périnatale à des doses de 100 et 500 µg/kg/j. Observation d’effets anxiolytiques et de déficits cognitifs.

Abstract :

Bisphenol A (BPA), an environmental endocrine-disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine-disrupting chemical, bisphenol A [(BPA); 100 mug/kg/day or 500 mug/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA-treated mice using two anxiety-related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 mug/kg/day) increased movement in the central zone. BPA treatment (500 mug/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y-maze test and novel object test. BPA-treated mice showed decreased alternation behavior in the Y-maze at both of doses, indicating working memory impairment. BPA-treated mice (100 mug/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D(1) and D(2) receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D(2) receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long-term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems.

 

Kim K, Son TG, Park HR, Kim SJ, Kim HS, Kim HS, Kim TS, Jung KK, Han SY, Lee J. Potencies of bisphenol A on the neuronal differentiation and hippocampal neurogenesis.J Toxicol Environ Health A. 2009;72(21-22):1343-51.

Department of Pharmacy, College of Pharmacy and Longevity Life Science and Technology Institutes, Pusan National University, Geumjeong-gu, Busan, Korea.

→ En Bref :

Le BPA stimule la différenciation neuronale et pourrait perturber le développement néonatal du cerveau (Animaux exposés du jour 14,5 au jour 18,5 de la gestation de 5 à 20 mg/kg/j).

Abstract :

Endocrine-disrupting chemicals (EDC) produce adverse effects on reproductive and immune function or neurological behavior, and may also induce cancer. The environmental EDC bisphenol A (BPA) is widely used in the manufacture of plastics and epoxy resins. BPA affects reproductive organ growth and development, but the potential adverse effects of BPA on neuronal development are not fully understood. Here, BPA concentration-dependently decreased proliferation of murine-derived multipotent neural progenitor cells (NPC), and high concentrations produced cytotoxicity. In contrast, low concentrations of BPA, which possess estrogenic activity, stimulated NPC differentiation into a neuronal phenotype. BPA treatment did not affect neonatal brain development in F1 mice. However, BPA treatment (20 mg/kg) accelerated formation of the dentate gyrus in postnatal day 1 mice. Prenatal and postnatal BPA treatment did not affect adult hippocampal neurogenesis in the dentate gyrus in 8-wk-old mice. Data indicate that BPA stimulates neuronal differentiation and might disrupt neonatal brain development.

● Batraciens

Heimeier RA, Shi YB. Amphibian metamorphosis as a model for studying endocrine disruption on vertebrate development: effect of bisphenol A on thyroid hormone action.Gen Comp Endocrinol. 2010 Feb 20. [Epub ahead of print]

Institute of Environmental Medicine (IMM), Karolinska Institutet (KI), Nobels väg 13, S-171 77, Stockholm, Sweden.

→ En Bref :

Mise en évidence d’une perturbation des hormones thyroïdiennes, impliquées dans la métamorphose. Ce système étant conservé chez les vertébrés, ces résultats peuvent avoir des implications pour l’espèce humaine.

Abstract :

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.

 

Exposition

Environnement

- Données générales

Halden RU. Plastics and Health Risks. Annu Rev Public Health. 2010 Jan 13. [Epub ahead of print]

Center for Environmental Biotechnology, The Biodesign Institute at Arizona State University, Tempe, AZ 85287-1501; Center for Water and Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205; email: halden@asu.edu.

→ En Bref :

La production annuelle de plastique est de 300 Millions de tonnes (Note : sur un total de 400 MT de substances chimiques, dont 3 MT de BPA) . Le BPA et le DEHP sont les molécules les plus mises en cause pour leurs effets toxiques.

Abstract :

By 2010, the worldwide annual production of plastics will surpass 300 million tons. Plastics are indispensable materials in modern society, and many products manufactured from plastics are a boon to public health (e.g., disposable syringes, intravenous bags). However, plastics also pose health risks. Of principal concern are endocrine-disrupting properties, as triggered for example by bisphenol A and di-(2-ethylhexyl) phthalate (DEHP). Opinions on the safety of plastics vary widely, and despite more than five decades of research, scientific consensus on product safety is still elusive. This literature review summarizes information from more than 120 peer-reviewed publications on health effects of plastics and plasticizers in lab animals and humans. It examines problematic exposures of susceptible populations and also briefly summarizes adverse environmental impacts from plastic pollution. Ongoing efforts to steer human society toward resource conservation and sustainable consumption are discussed, including the concept of the 5 Rs-i.e., reduce, reuse, recycle, rethink, restrain-for minimizing pre-and postnatal exposures to potentially harmful components of plastics. Expected final online publication date for the Annual Review of Public Health Volume 31 is March 17, 2010. Please see http://…@asu.edu.

→ En Bref :

Analyse du pourcentage retenu par le traitement en station pour 33 substances : de 22 % pour le bisphénol A diglycidyl ether (BADGE) à 99% for di-(2-ethylhexyl)phthalate (DEHP).

Abstract :

Accurate quantification of organic wastewater compounds (OWCs) is essential for assessing their removal efficiency in wastewater treatment plants (WWTPs) and for calculating discharge rates into effluent-receiving surface waters. In this study, we undertook a theoretical evaluation of the effect of sorption and sample filtration on data quality. Filtration of samples, while commonly practiced, may preclude a potentially significant fraction of chemical mass from both chemical measurements and mass flow analyses for WWTPs. Sorption theory dictates that analyte losses from sample filtration are notable for hydrophobic organic compounds (HOCs) featuring a pH-dependent logarithmically transformed organic carbon-water distribution coefficient (log D(OC)) of >/=3.0. Among a total of 33 organic wastewater compounds considered, the extent of sorption to filterable materials ranged from 22% for bisphenol A diglycidyl ether (BADGE) to 99% for di-(2-ethylhexyl)phthalate (DEHP). Sample filtration also was demonstrated to have a profound impact on the outcome of chemical fate and behavior studies. When the chemical mass residing on filterable particulates was considered, the concentration spread (range) doubled between maximum and minimum concentrations reported for raw wastewater. Furthermore, removal efficiencies of WWTPs calculated for HOCs increased by as much as 62% just by changing the method of accounting. We conclude that some of the data spread reported in the literature concerning chemical mass loadings, contaminant concentrations in raw sewage, and removal efficiencies of similarly designed WWTPs is driven not by actual differences in sewage composition, geographic locations and treatment units but by sample processing protocols and the method of mass accounting.

 

Loos R, Locoro G, Contini S. Occurrence of polar organic contaminants in the dissolved water phase of the Danube River and its major tributaries using SPE-LC-MS(2) analysis. Water Res. 2010 Jan 4. [Epub ahead of print]

European Commission, Joint Research Centre, Institute for Environment and Sustainability, Via Enrico Fermi, 21020 Ispra, Italy.

→ En Bref :

Analyse du BPA dans les eaux de surfaces du Danube et de ses affluents. Le BPA est présent dans 29 % des prélèvements (Conc maxi 68 ng/l soit une Dose quotidienne chez l’homme de 2,2 ng/kg/j sur la base d’une consommation quotidienne de 2 l). A comparer avec la DJA de 5 ng/kg/j qui devrait être retenue sur la base des données sur le trouble du comportement. A rapprocher de l’étude précédente qui montre un % faible de rétention par le traitement. L’enjeu du BPA est aussi environnemental. Vor les études sur les invertébrés.

Abstract :

Polar water-soluble organic contaminants were analysed in the dissolved liquid water phase of river water samples from the Danube River and its major tributaries (within the Joint Danube Survey 2). Analyses were performed by solid-phase extraction (SPE) followed by triple-quadrupole liquid chromatography mass spectrometry (LC-MS(2)). In total, 34 different polar organic compounds were screened. Focus was given on pharmaceutical compounds (such as ibuprofen, diclofenac, sulfamethoxazole, carbamazepine), pesticides and their degradation products (e.g. bentazone, 2,4-D, mecoprop, atrazine, terbutylazine, desethylterbutylazine), perfluorinated acids (PFOS; PFOA), and endocrine disrupting compounds (nonylphenol, NPE(1)C, bisphenol A, estrone). The most relevant polar compounds identified in the Danube River basin in terms of frequency of detection, persistency, and concentration levels were 1H-benzotriazole (median concentration 185 ng/L), caffeine (87 ng/L), tolyltriazole (73 ng/L), nonylphenoxy acetic acid (49 ng/L), carbamazepine (33 ng/L), 4-nitrophenol (29 ng/L), 2,4-dinitrophenol (19 ng/L), PFOA (17 ng/L), sulfamethoxazole (16 ng/L), desethylatrazine (11 ng/L), and 2,4-D (10 ng/L). The highest contamination levels were found in the area around Budapest and in the tributary rivers Arges (Romania), Timok (Bulgaria), Rusenski Lom (Bulgaria), and Velika Morava (Serbia).

● Emballages alimentaires

Lim DS, Kwack SJ, Kim KB, Kim HS, Lee BM. Potential risk of bisphenol A migration from polycarbonate containers after heating, boiling, and microwaving. J Toxicol Environ Health A. 2009;72(21-22):1285-91.

Division of Toxicology, College of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, South Korea.

→ En Bref :

Pas de détection de BPA à la limite de 1 µg/L dans des bouteilles de polycarbonate remplies de riz ou de porc à température ambiante ou chauffée dans de l’eau bouillante. Par contre le passage au micro-onde (100 °C 9mn) induit une migration respectivement de 6 à 18 et 5 à 15 µg/l. BPA est détecté aussi dans des bouteilles remplies d’eau bouillante avec une concentration croissante en fonction du temps (jusqu’à 3h).

Abstract :

The migration levels of bisphenol A (BPA) were analyzed in food samples by high-performance liquid chromatography (HPLC) from polycarbonate (PC) bottles subjected to simulated use by heating with microwave, heating in a boiling water bath, or filling them with boiling hot water (100 degrees C). Migration testing performed in PC bottles filled with steamed rice or hot cooked pork, standing at room temperature, or heated in a boiling water bath (100 degrees C) showed that BPA was not detected at the limit of detection (LOD) of 1 microg/L (ppb). In contrast, heating by microwaving to 100 degrees C for 9 min increased BPA migration levels from 6 to 18 ppb and from 5 to 15 ppb for steamed rice or for cooked pork, respectively. In addition, 3 different PC bottles were tested by filling them with boiling hot water (100 degrees C) and leaving them to stand at room temperature for up to 3 h. The mean BPA levels from the bottles increased in a time-dependent manner, with the range of not detected (ND) to 2.5 ppb after 60 min. However, none of the PC bottles released BPA at levels that exceed the recently established specific migration limits (SML) of 600 ppb established by European Union and Korea Food and Drug Administration (KFDA). Data suggest that the use of PC plastic bottles in our daily life is considered safe in Korea.

 

Lim DS, Kwack SJ, Kim KB, Kim HS, Lee BM. Risk assessment of bisphenol A migrated from canned foods in Korea. J Toxicol Environ Health A. 2009;72(21-22):1327-35.

Division of Toxicology, College of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-Do, South Korea.

→ En Bref :

Dosage du BPA dans les boîtes de conserve. Exposition humaine maximum de 1,5 µg/kg, < DJA européenne de 50 µg/kg/j mais celle-ci n’est pas calculée selon les règles de bonne pratique. La DJA déduite des études sur le troubles du comportement serait au minimum de 5 ng/kg/j soit une exposition humaine pouvant aller jusqu’à 300 fois le DJA. Cela confirme que les boîtes de conserve sont une source de contamination majeure de la population humaine.

Abstract :

Exposure and risk assessment of bisphenol A (BPA) was conducted on consumption of canned foods in Korean adults. Sixty-one canned food items with different brands purchased from retail outlets in markets were analyzed for BPA concentration by high-performance liquid chromatography (HPLC) coupled with fluorescence detection. Limits of detection (LOD) were 3 microg/kg for solid and 2 microg/kg for liquid foods. BPA was detected from 7 groups of food items, such as tuna (n = 8), fish (n = 11), fruits (n = 9), vegetables (n = 12), meats (n = 13), coffee (n = 5), and tea (n = 3) in the range from not detected (ND) to 136.14 microg/kg. Mean concentrations of BPA were 3.1 microg/kg (ND-21.5 microg/kg) for vegetables, 8.3 microg/kg (ND-14.26) for tea, 8.6 microg/kg (ND-54.56 microg/kg) for fruits, 24.49 microg/kg (ND-98.30 microg/kg) for meats, 39.78 microg/kg (ND-125.25 microg/kg) for fish, 43.7 microg/kg (ND-116.88 microg/kg) for tuna, and 45.51 microg/kg (ND-136.14 microg/kg) for coffee, in the order of magnitude. Based on daily dietary intake of canned food items and concentrations of BPA, human exposure level to BPA was estimated to be 1.509 microg/kg body weight (bw)/d, well below the tolerable daily intake (TDI) or reference dose (RfD) of 50 microg/kg, bw/d set by the European Commission, U.S.EPA, and South Korea. Therefore, the potential risk for BPA contamination due to consumption of each canned food items was calculated to be (1.509 microg/kg bw/d)/(50 microg/kg bw/d) = 0.03, which is the hazard index [HI = exposure level/(RfD or TDI)]. Evidence indicates that the levels of BPA levels in canned foods are not likely to constitute a safety concern for consumers in Korea.

 

Cao XL, Dufresne G, Clement G, Bélisle S, Robichaud A, Beraldin F. Levels of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE) in canned liquid infant formula products in Canada and dietary intake estimates. AOAC Int. 2009 Nov-Dec;92(6):1780-9.

Health Canada, Food Research Division, Bureau of Chemical Safety, Food Directorate, 251 Frederick Banting Driveway, AL: 2203D, Ottawa, ON, Canada K1A 0K9. Xu-Liang_Cao@hc-sc.gc.ca

→En Bref :

Contamination des liquides pour nourrissons (Maximum à 22 µg/kg/j) .

Abstract :

A method based on solid-phase extraction followed by HPLC analysis with fluorescence detection was developed for the determination of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE) in liquid infant formula. In this method, instead of trying to isolate and measure each individual form of the molecules, hydrolysis of BADGE, BFDGE, BADGE x H2O, and BFDGE x H2O was forced to completion to their stable forms, BADGE x 2H2O and BFDGE x 2H2O, before extraction. The method LODs were 2.0 ng/g for BADGE and 3.0 ng/g for BFDGE. Extraction recoveries were 61-91% for BADGE, and 55-82% for BFDGE over the concentration range of 10 to 50 ng/g. The method was used to analyze samples of 21 canned liquid infant formula products for BADGE and BFDGE. BADGE was detected in samples of all products at levels ranging from as low as 2.4 ng/g to as high as 262 ng/g. BFDGE was detected in only one product (40 ng/g), and this product also had the highest BADGE level (262 ng/g). HPLC/MS/MS with a similar LOD was also used to confirm the results. The probable daily intakes (PDI) of BADGE and BFDGE due to consumption of canned liquid infant formula were estimated for infants from premature to 12-18 months of age. The maximum PDI of BADGE was 22 microg/kg body weight/day for the 12-18 months old with the maximum formula intake. The maximum PDI of BFDGE was < 3.4 microg/kg body weight/day.

 

von Goetz N, Wormuth M, Scheringer M, Hungerbühler K. Bisphenol A: How the Most Relevant Exposure Sources Contribute to Total Consumer Exposure.Risk Anal. 2010 Jan 29. [Epub ahead of print] Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.

→ En Bref :

Analyse des différentes sources d’exposition de la population humaine au BPA. La plus importante pour les nourrissons et les enfants est celle des biberons (Dose moyenne de 0,8 µg/kg/j) et pour les adolescents et les adultes celle des canettes et boîtes de conserve. Les auteurs rappellent que cette dose est inférieure à la DJA européenne, mais correspond à l’ordre de grandeur des expositions induisant des effets chez l’animal.

Abstract :

Bisphenol A (BPA) is an endocrine disrupting chemical that is found in human urine throughout industrial societies around the globe. Consumer exposure pathways to BPA include packaged food, household dust, air, and dental fillings. To date, information on the relative contribution of the different pathways to total consumer exposure is lacking, but is key for managing substance-associated risks. We investigated the relative contributions of the pathways known to be most relevant for nine different consumer groups. Our results suggest that the most important pathways for infants and children are the use of polycarbonate (PC) baby bottles and for adults and teenagers the consumption of canned food. Dental surgery can also considerably contribute over a short time directly after the surgery. For infants fed with PC baby bottles with mean dose rates of 0.8 mug/kg(bw)/d the highest exposure dose rate was calculated. This dose rate is far below the tolerable daily intake of 50 mug/kg(bw)/d. However, it is of the same order of magnitude as recently reported concentrations that caused low-dose health effects in rodents. We find a pattern of falling exposure levels with rising age that is supported by urinary concentrations of BPA available for selected consumer groups. Similarly, the exposure levels we predict are confirmed by the levels reported in these studies.

 

DEONTOLOGIE

Sharpe RM. Is it time to end concerns over the estrogenic effects of bisphenol A? Toxicol Sci. 2010 Mar;114(1):1-4.

Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. r.sharpe@hrsu.mrc.ac.ukComment on : Toxicol Sci. 2010 Mar;114(1):133-48.

Vom Saal FS. Flawed Experimental Design Reveals the Need for Guidelines Requiring Appropriate Positive Controls in Endocrine Disruption Research.Toxicol Sci. 2010 Feb 17. [Epub ahead of print]; Lettre signée par 23 autres scientifiques impliqués dans les recherches sur les perturbateurs endocriniens.

→ En Bref :

Critique de la méthodologie suivie par Ryan (Etude citée dans le bulletin d’Octobre – Novembre et publiée en version papier en Mars ; voir abstract ci-dessous). Ryan ne met en évidence aucun impact à faible dose du BPA chez le rat en comparaison de l’éthinyl oestradiol, hormone de synthèse utilisée dans les contraceptifs. Sharpe considère en conséquence que l’étude de Ryan devrait clore le débat sur les risques liés au BPA. Vom Saal critique la méthodologie suivie qui a consisté à utiliser une souche de rat peu sensible aux estrogènes (Souche Long Evans). En effet, la dose la plus faible induisant un effet chez le rat se situe entre 5 et 50 µg/kg/j, or la dose utilisée dans les contraceptifs humains est < 0,5 µg/kg/j. Donc Il n’y a pas d’effet sur cette souche de rat à une dose qui induit une stérilité temporaire chez 99 ,7% des femmes. Pour que la comparaison ait un sens, il aurait donc fallu tester une dose de BPA au minimum de 500 µg/kg/j, ce qui n’a pas été le cas. Les auteurs considèrent que l’étude de Ryan n’a pas respecté les recommandations du National Toxicology Program considérant que les études sur les faibles doses de perturbateurs endocriniens utilisent des contrôles positifs ou des doses appropriées. Aucun

Abstract :

· Ryan BC, Hotchkiss AK, Crofton KM, Gray LE Jr. In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats. Toxicol Sci. 2010 Mar;114(1):133-48. Epub 2009 Oct 28.

Reproductive Toxicology Branch, TA Division, National Health and Environmental Effects Research Laboratory, ORD, U.S. Environmental Protection Agency Office of Research and Development, Research Triangle Park, North Carolina 27711, USA.Comment in: Toxicol Sci. 2010 Mar;114(1):1-4.

Many chemicals released into the environment display estrogenic activity including the oral contraceptive ethinyl estradiol (EE2) and the plastic monomer bisphenol A (BPA). EE2 is present in some aquatic systems at concentrations sufficient to alter reproductive function of fishes. Many concerns have been raised about the potential effects of BPA. The National Toxicology Program rated the potential effects of low doses of BPA on behavior and central nervous system (CNS) as an area of « some concern, » whereas most effects were rated as of « negligible » or « minimal » concern. However, the number of robust studies in this area was limited. The current study was designed to determine if maternal exposure to relatively low oral doses of EE2 or BPA in utero and during lactation would alter the expression of well-characterized sexually dimorphic behaviors or alter the age of puberty or reproductive function in the female Long-Evans rat offspring. Pregnant rats were gavaged with vehicle, EE2 (0.05-50 microg/kg/day), or BPA (2, 20, and 200 microg/kg/day) from day 7 of gestation to postnatal day (PND) 18, and the female offspring were studied. EE2 (50 microg/kg/day) increased anogenital distance and reduced pup body weight at PND2, accelerated the age at vaginal opening, reduced F1 fertility and F2 litter sizes, and induced malformations of the external genitalia (5 microg/kg). F1 females exposed to EE2 also displayed a reduced (male-like) saccharin preference (5 microg/kg) and absence of lordosis behavior (15 microg/kg), indications of defeminization of the CNS. BPA had no effect on any of the aforementioned measures. These results demonstrate that developmental exposure to pharmacologically relevant dosage levels of EE2 can permanently disrupt the reproductive morphology and function of the female rat.me to end concerns over the estrogenic effects of bisphenol A? Toxicol Sci. 2010 Mar;114(1):1-4.

Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. r.sharpe@hrsu.mrc.ac.ukComment on : Toxicol Sci. 2010 Mar;114(1):133-48.

Vom Saal FS. Flawed Experimental Design Reveals the Need for Guidelines Requiring Appropriate Positive Controls in Endocrine Disruption Research.Toxicol Sci. 2010 Feb 17. [Epub ahead of print]; Lettre signée par 23 autres scientifiques impliqués dans les recherches sur les perturbateurs endocriniens.

→ En Bref :

Critique de la méthodologie suivie par Ryan (Etude citée dans le bulletin d’Octobre – Novembre et publiée en version papier en Mars ; voir abstract ci-dessous). Ryan ne met en évidence aucun impact à faible dose du BPA chez le rat en comparaison de l’éthinyl oestradiol, hormone de synthèse utilisée dans les contraceptifs. Sharpe considère en conséquence que l’étude de Ryan devrait clore le débat sur les risques liés au BPA. Vom Saal critique la méthodologie suivie qui a consisté à utiliser une souche de rat peu sensible aux estrogènes (Souche Long Evans). En effet, la dose la plus faible induisant un effet chez le rat se situe entre 5 et 50 µg/kg/j, or la dose utilisée dans les contraceptifs humains est < 0,5 µg/kg/j. Donc Il n’y a pas d’effet sur cette souche de rat à une dose qui induit une stérilité temporaire chez 99 ,7% des femmes. Pour que la comparaison ait un sens, il aurait donc fallu tester une dose de BPA au minimum de 500 µg/kg/j, ce qui n’a pas été le cas. Les auteurs considèrent que l’étude de Ryan n’a pas respecté les recommandations du National Toxicology Program considérant que les études sur les faibles doses de perturbateurs endocriniens utilisent des contrôles positifs ou des doses appropriées. Aucun

Abstract :

· Ryan BC, Hotchkiss AK, Crofton KM, Gray LE Jr. In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats. Toxicol Sci. 2010 Mar;114(1):133-48. Epub 2009 Oct 28.

Reproductive Toxicology Branch, TA Division, National Health and Environmental Effects Research Laboratory, ORD, U.S. Environmental Protection Agency Office of Research and Development, Research Triangle Park, North Carolina 27711, USA.Comment in: Toxicol Sci. 2010 Mar;114(1):1-4.

Many chemicals released into the environment display estrogenic activity including the oral contraceptive ethinyl estradiol (EE2) and the plastic monomer bisphenol A (BPA). EE2 is present in some aquatic systems at concentrations sufficient to alter reproductive function of fishes. Many concerns have been raised about the potential effects of BPA. The National Toxicology Program rated the potential effects of low doses of BPA on behavior and central nervous system (CNS) as an area of « some concern, » whereas most effects were rated as of « negligible » or « minimal » concern. However, the number of robust studies in this area was limited. The current study was designed to determine if maternal exposure to relatively low oral doses of EE2 or BPA in utero and during lactation would alter the expression of well-characterized sexually dimorphic behaviors or alter the age of puberty or reproductive function in the female Long-Evans rat offspring. Pregnant rats were gavaged with vehicle, EE2 (0.05-50 microg/kg/day), or BPA (2, 20, and 200 microg/kg/day) from day 7 of gestation to postnatal day (PND) 18, and the female offspring were studied. EE2 (50 microg/kg/day) increased anogenital distance and reduced pup body weight at PND2, accelerated the age at vaginal opening, reduced F1 fertility and F2 litter sizes, and induced malformations of the external genitalia (5 microg/kg). F1 females exposed to EE2 also displayed a reduced (male-like) saccharin preference (5 microg/kg) and absence of lordosis behavior (15 microg/kg), indications of defeminization of the CNS. BPA had no effect on any of the aforementioned measures. These results demonstrate that developmental exposure to pharmacologically relevant dosage levels of EE2 can permanently disrupt the reproductive morphology and function of the female rat.