Публикации по EDCs

В 2013 г. несколько докладов и публикаций на тему EDCs (химические вещества, вызывающие нарушение работы эндокринной системы) были представлены на 4 съезде токсикологов России в Москве.

В Российской электронной библиотеке  по теме «Химические вещества, вызывающие нарушение работы эндокринной системы» размещено менее 100 публикаций, причем они касаются, в основном, аналитических методов определения этих веществ. В то же время только обзоров по теме EDCs на английском языке опубликовано более 808.

Современные англоязычные публикации

  • Phthalate exposure and childhood obesity
    Shin Hye Kim, MD and Mi Jung Park, MD, PhD (corresponding author)
    Ann Pediatr Endocrinol Metab. Jun 2014; 19(2): 69–75.
    Published online Jun 30, 2014. doi: 10.6065/apem.2014.19.2.69

    В этой публикации произведён обзор возможных механизмов ожирения, вызванного фталатами.

    Abstract:
    Phthalates are commonly used as plasticizers and vehicles for cosmetic ingredients. Phthalate metabolites have documented biochemical activity including activating peroxisome proliferator-activated receptor and antiandrogenic effects, which may contribute to the development of obesity. In vitro and in vivo studies suggest that phthalates have significant effects on the development of obesity, especially after prenatal exposure at low doses. Although few studies have examined the effects of phthalate on obesity development in humans, some work has shown that phthalates affect humans and animals similarly. In this paper, we review the possible mechanisms of phthalate-induced obesity, and discuss evidence supporting the role of phthalates in the development of obesity in humans.

  • Environmental-stress-induced Chromatin Regulation and its Heritability.
    Fang L, Wuptra K, Chen D, Li H, Huang SK, Jin C, Yokoyama KK.
    J Carcinog Mutagen. 2014 Jan 15;5(1). pii: 22058.

    В этой публикации обсуждается влияние окружающей среды на систему регулирования хроматина и эпигенетики клетки.

    Abstract:
    Chromatin is subject to proofreading and repair mechanisms during the process of DNA replication, as well as repair to maintain genetic and epigenetic information and genome stability. The dynamic structure of chromatin modulates various nuclear processes, including transcription and replication, by altering the accessibility of the DNA to regulatory factors. Structural changes in chromatin are affected by the chemical modification of histone proteins and DNA, remodeling of nucleosomes, incorporation of variant histones, noncoding RNAs, and nonhistone DNA-binding proteins. Phenotypic diversity and fidelity can be balanced by controlling stochastic switching of chromatin structure and dynamics in response to the environmental disruptors and endogenous stresses. The dynamic chromatin remodeling can, therefore, serve as a sensor, through which environmental and/or metabolic agents can alter gene expression, leading to global cellular changes involving multiple interactive networks. Furthermore its recent evidence also suggests that the epigenetic changes are heritable during the development. This review will discuss the environmental sensing system for chromatin regulation and genetic and epigenetic controls from developmental perspectives.

  • Disruption of Rat Testis Development Following Combined In Utero Exposure to the Phytoestrogen Genistein and Anti-Androgenic Plasticizer Di-(2-Ethylhexyl) Phthalate.
    Jones S, Boisvert A, Duong TB, Francois S, Thrane P, Culty M.
    Biol Reprod. 2014 Jul 16. pii: biolreprod.114.120907. [Epub ahead of print]

    В этой публикации было показано на крысах, что такие химические вещества, нарушающие работу эндокринной системы (EDCs), как генистейн и DEHP, вызывают долгосрочные изменения в развитии и функциональности яичек.

    Abstract:
    Fetal exposure to environmental endocrine disruptors (EDs) is thought to contribute to reported idiopathic increases in adult male reproductive abnormalities. Although humans are exposed to a myriad of EDs from conception to adulthood, few studies have evaluated the effects of combined EDs on male reproduction. In the present study, we demonstrate that simultaneous gestational exposure to the phytoestrogen genistein and the anti-androgenic plasticizer Di-(2-ethyhexyl) phthalate (DEHP) induces long term alterations in testis development and function. Pregnant Sprague Dawley rats were gavaged from Gestational Day 14 to birth with corn oil, genistein, DEHP or their mixture at 10 mg/kg/day, a dose selected from previous dose-response studies using single chemicals for its lack of long term testicular effects. Hormonal and testicular end-points were examined in adult male offspring. Serum testosterone levels were unchanged. However, significant increases were observed in testis weight and in the expression of mast cell markers in testes from adult rats exposed gestationally to combined compounds. The ED mixture also altered the mRNA expression of Sertoli cell makers Wt1 and Amh, and germ cell markers cKit and Sox17, measured by quantitative real time PCR (qPCR), suggesting long term disruption in testis function and spermatogenesis. Alterations in germ cell markers might reflect direct effects on fetal gonocytes or indirect effects via primary targeting of somatic cells, as suggested by differentially regulated Leydig cell associated genes (Hsd3b, Anxa1, Foxa3 and Pdgfra), determined by gene expression array, qPCR and protein analyses. The two chemicals, when given in combination, induced long term reproductive toxicity at doses not previously reported to produce any conspicuous long term effects. Our study therefore highlights a need for a more comprehensive evaluation of the effects of ED mixtures.

  • First year growth in relation to prenatal exposure to endocrine disruptors — a Dutch prospective cohort study.
    de Cock M, de Boer MR, Lamoree M, Legler J, van de Bor M.
    Int J Environ Res Public Health. 2014 Jul 10;11(7):7001-21. doi: 10.3390/ijerph110707001.

    Это исследование показало, что пренатальное воздействие таких EDCs, как фталаты и DDE, ассоциируется с изменениями в индексе массы тела (BMI) и окружности головы (HC) у грудных детей.

    Abstract:
    Growth in the first year of life may already be predictive of obesity later in childhood. The objective was to assess the association between prenatal exposure to various endocrine disrupting chemicals (EDCs) and child growth during the first year. Dichloro-diphenyldichloroethylene (DDE), mono(2-ethyl-5-carboxypentyl)phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP), mono(2-ethyl-5-oxohexyl)phthalate (MEOHP), polychlorinated biphenyl-153, perfluorooctanesulfonic acid, and perfluoro-octanoic acid were measured in cord plasma or breast milk. Data on weight, length, and head circumference (HC) until 11 months after birth was obtained from 89 mother-child pairs. Mixed models were composed for each health outcome and exposure in quartiles. For MEOHP, boys in quartile 1 had a higher BMI than higher exposed boys (p = 0.029). High DDE exposure was associated with low BMI over time in boys (0.8 kg/m2 difference at 11 m). Boys with high MECPP exposure had a greater HC (1.0 cm difference at 11 m) than other boys (p = 0.047), as did girls in the second quartile of MEHHP (p = 0.018) and DDE (p 0.001) exposure. In conclusion, exposure to phthalates and DDE was associated with BMI as well as with HC during the first year after birth. These results should be interpreted with caution though, due to the limited sample size.

  • Environmental stressors influencing hormones and systems physiology in cattle.
    Bova TL, Chiavaccini L, Cline GF, Hart CG, Matheny K, Muth AM, Voelz BE, Kesler D, Memili E.
    Reprod Biol Endocrinol. 2014 Jul 4;12:58. doi: 10.1186/1477-7827-12-58.

    В этой публикации приведен обзор литературы по влиянию окружающей среды (климат, питание, жизненные условия) на гормоны и физиологию рогатого скота.

    Abstract:
    Environmental stressors undoubtedly influence organismal biology, specifically the endocrine system that, in turn, impact cattle at the systems physiology level. Despite the significant advances in understanding the genetic determinants of the ideal dairy or beef cow, there is a grave lack of understanding of the systems physiology and effects of the environmental stressors that interfere with the endocrine system. This is a major problem because the lack of such knowledge is preventing advances in understanding gene-environment interactions and developing science-based solutions to these challenges. In this review, we synthesize the current knowledge on the nature of the major environmental stressors, such as climate (heat, cold, wind, and humidity), nutrition (feeds, feeding systems, and endocrine disruptors) and management (housing density and conditions, transportation, weaning practices). We summarize the impact of each one of these factors on cattle at the systems level, and provide solutions for the challenges.

  • Should oral gavage be abandoned in toxicity testing of endocrine disruptors?
    Vandenberg LN, Welshons WV, Vom Saal FS, Toutain PL, Myers JP.
    Environ Health. 2014 Jun 25;13(1):46. doi: 10.1186/1476-069X-13-46.

    В этой статье обсуждаются причины для отмены использования желудочного зонда для оценки пероральной экспозиции EDCs.

    Abstract:
    For decades, hazard assessments for environmental chemicals have used intra-gastric gavage to assess the effects of ‘oral’ exposures. It is now widely used—and in some cases required—by US federal agencies to assess potential toxicity of endocrine disrupting chemicals (EDCs). In this review we enumerate several reasons why gavage is not appropriate for the assessment of EDCs using bisphenol A (BPA) as a main example. First, whereas human dietary exposures interact with the oral mucosa, gavage exposures avoid these interactions, leading to dramatic differences in absorption, bioavailability and metabolism with implications for toxicokinetic assumptions and models. Additionally, there are well acknowledged complications associated with gavage, such as perforation of the esophagus that diminish its value in toxicological experiments. Finally, the gavage protocol itself can induce stress responses by the endocrine system and confound the assessment of EDCs. These serious flaws have not been taken into account in interpreting results of EDC research. We propose the exploration of alternatives to mimic human exposures when there are multiple exposure routes/sources and when exposures are chronic. We conclude that gavage may be preferred over other routes for some environmental chemicals in some circumstances, but it does not appropriately model human dietary exposures for many chemicals. Because it avoids exposure pathways, is stressful, and thus interferes with endocrine responses, gavage should be abandoned as the default route of administration for hazard assessments of EDCs.

  • Lifetime-dependent effects of bisphenol A on asthma development in an experimental mouse model.
    Petzold S, Averbeck M, Simon JC, Lehmann I, Polte T.
    PLoS One. 2014 Jun 20;9(6):e100468. doi: 10.1371/journal.pone.0100468. eCollection 2014.

    В этой статье было показано, что бисфенол А (BPA) вызывает процессы, связанные с бронхиальной астмой, если воздействие происходит течении всей жизни, от рождения до последней экспозиции аллергена. Экспозиция BPA в течение внутриутробного развития не влияла на развитие астмы.

    Abstract:
    BACKGROUND:
    Environmental factors are thought to contribute significantly to the increase of asthma prevalence in the last two decades. Bisphenol A (BPA) is a xenoestrogen commonly used in consumer products and the plastic industry. There is evidence and an ongoing discussion that endocrine disruptors like BPA may affect human health and also exert alterations on in the immune system. The aim of this study was to investigate age-dependent effects of BPA on the asthma risk using a murine model to explain the controversial results reported till date.
    METHODS:
    BALB/c mice were exposed to BPA via the drinking water for different time periods including pregnancy and breastfeeding. To induce an asthma phenotype, mice were sensitized to ovalbumin (OVA), followed by an intrapulmonary allergen challenge.
    RESULTS:
    BPA exposure during pregnancy and breastfeeding had no significant effect on asthma development in the offspring. In contrast, lifelong exposure from birth until the last antigen challenge clearly increased eosinophilic inflammation in the lung, airway hyperreactivity and antigen-specific serum IgE levels in OVA-sensitized adult mice compared to mice without BPA exposure. Surprisingly, BPA intake during the sensitization period significantly reduced the development of allergic asthma. This effect was reversed in the presence of a glucocorticoid receptor antagonist.
    CONCLUSIONS:
    Our results demonstrate that the impact of BPA on asthma risk is strongly age-dependent and ranges from asthma-promoting to asthma-reducing effects. This could explain the diversity of results from previous studies regarding the observed health impact of BPA.

  • Exposure to endocrine disrupting chemicals and male reproductive health.
    Jeng HA.
    Front Public Health. 2014 Jun 5;2:55. doi: 10.3389/fpubh.2014.00055. eCollection 2014.

    Обзор эпидемиологической литературы по теме EDC и мужское репродуктивное здоровье.

    Abstract:
    Endocrine disrupting chemicals (EDCs) can interfere with normal hormonal balance and may exert adverse consequences on humans. The male reproductive system may be susceptible to the effects of such environmental toxicants. This review discusses the recent progress in scientific data mainly from epidemiology studies on the associations between EDCs and male reproductive health and our understanding of possible mechanisms associated with the effects of EDCs on male reproductive health. Finally, the review provides recommendations on future research to enhance our understanding of EDCs and male reproductive health. The review highlights the need for (1) well-defined longitudinal epidemiology studies, with appropriately designed exposure assessment to determine potential causal relationships; (2) chemical and biochemical approaches aimed at a better understanding of the mechanism of action of xenoestrogens with regard to low-dose effects, and assessment of identify genetic susceptibility factors associated with the risk of adverse effects following exposure to EDCs.

  • Effects of endocrine disruptors in the development of the female reproductive tract.
    Costa EM, Spritzer PM, Hohl A, Bachega TA.
    Arq Bras Endocrinol Metabol. 2014 Mar;58(2):153-61.

    Обзор эпидемиологической литературы по теме EDC и развитие женской половой системы.

    Abstract:
    Environmental agencies have identified a growing number of environmental contaminants that have endocrine disrupting activity, and these can become a major public health problem. It is suggested that endocrine disruptors could account for the higher-than-expected increase in the prevalence of some non-communicable diseases, such as obesity, diabetes, thyroid diseases, and some cancers. Several endocrine Disrupting Chemicals (EDCs), such as pesticides, bisphenol A, phthalates, dioxins, and phytoestrogens, can interact with the female reproductive system and lead to endocrine disruption. Initially, it was assumed that EDCs exert their effects by binding to hormone receptors and transcription factors, but it is currently known that they may also alter the expression of enzymes involved in the synthesis or catabolism of steroids. Biomonitoring studies have identified these compounds in adults, children, pregnant women, and fetuses. Among the diseases of the female reproductive tract associated with EDCs exposure are the following: precocious puberty, polycystic ovary syndrome, and premature ovarian failure. The different populations of the world are exposed to a great number of chemicals through different routes of infection; despite the various available studies, there is still much doubt regarding the additive effect of a mixture of EDCs with similar mechanisms of action.

  • Effects of quercetin on CYP450 and cytokines in Aroclor 1254 injured endometrial cells of the pregnant rats.
    Xu L1, Sun L1, Lu L1, Zhong X2, Ma Y1, Qin J1.
    Biomed Res Int. 2014;2014:497508. doi: 10.1155/2014/497508. Epub 2014 Mar 10.

    В этой статье показано, что Кверцетин (флаваноид, действующий на рецептор эстрогена) протективно влияет на клетки эндометрия, экспонированные ПХБ.

    Abstract
    Polychlorinated biphenyls (PCBs) are widespread persistent residual environmental pollutants, which affect seriously the growth and reproductive alterations in humans and animals. Aroclor 1254 is a commercial mixture of PCBs. Quercetin is a flavonoid, which acts on estrogen receptors and causes the development of estrogen-related diseases. In this paper, the primary cultured endometrial cells in the pregnant rats were isolated and Aroclor 1254 was used to induce the injured endometrial cells model. The cells were treated with gradient quercetin, the viability of the endometrial cells, the expressions of CYP450, the contents of TNF-α, IL-6, estradiol (E2), and progesterone (P4) were measured. It showed that the viability of the cultured endometrial cells, the expression of CYP1A1 and CYP2B1, and the contents of TNF-α, E2, and IL-6 in the injured endometrial cells increased with the treatment of quercetin. It shows that quercetin has protective effect on the injured endometrial cells in the pregnant rats, this provide a basis on herbal medicine protection for animal reproductive diseases caused by environmental endocrine disruptors.

  • Phthalate and bisphenol A exposure among pregnant women in Canada—results from the MIREC study.
    Arbuckle TE1, Davis K2, Marro L2, Fisher M2, Legrand M3, LeBlanc A4, Gaudreau E4, Foster WG5, Choeurng V2, Fraser WD6; MIREC Study Group.
    Environ Int. 2014 Jul;68:55-65. doi: 10.1016/j.envint.2014.02.010. Epub 2014 Apr 4.

    В этой статье опубликованы уровни метаболитов BPA и фталатов в моче беременных женщин в течении первого триместра (национальное канадское исследование MIREC).

    Abstract:
    Bisphenol A (BPA) and phthalates are endocrine disruptors possibly linked to adverse reproductive and neurodevelopmental outcomes. These chemicals have commonly been measured in urine in population surveys; however, such data are limited for large populations of pregnant women, especially for the critical first trimester of pregnancy. The aim of the study was to measure BPA and phthalate metabolites in first trimester urine samples collected in a large national-scale pregnancy cohort study and to identify major predictors of exposure. Approximately 2000 women were recruited in the first trimester of pregnancy from ten sites across Canada. A questionnaire was administered to obtain demographic and socio-economic data on participants and a spot urine sample was collected and analyzed for total BPA (GC-MS/MS) and 11 phthalate metabolites (LC-MS/MS). The geometric mean (GM) maternal urinary concentration of total BPA, uncorrected for specific gravity, was 0.80 (95% CI 0.76-0.85) μg/L. Almost 88% of the women had detectable urinary concentrations of BPA. An analysis of urinary concentrations of BPA by maternal characteristics with specific gravity as a covariate in the linear model showed that the geometric mean concentrations: (1) decreased with increasing maternal age, (2) were higher in current smokers or women who quit during pregnancy compared to never smokers, and (3) tended to be higher in women who provided a fasting urine sample and who were born in Canada, and had lower incomes and education. Several of the phthalate metabolites analyzed were not prevalent in this population (MCHP, MMP, MiNP, MOP), with percentages detectable at less than 15%. The phthalate metabolites with the highest measured concentrations were MEP (GM: 32.02 μg/L) and MnBP (GM: 11.59 μg/L). MBzP urinary concentrations decreased with maternal age but did not differ by time of urine collection; whereas the DEHP metabolites tended to be higher in older women and when the urine was collected later in the day. This study provides the first biomonitoring results for the largest population of pregnant women sampled in the first trimester of pregnancy. The results indicate that exposure among this population of pregnant women to these chemicals is comparable to or even lower than that observed in a Canadian national population-based survey.

  • Our stolen figures: the interface of sexual differentiation, endocrine disruptors, maternal programming, and energy balance.
    Schneider JE1, Brozek JM2, Keen-Rhinehart E3.
    Horm Behav. 2014 Jun;66(1):104-19. doi: 10.1016/j.yhbeh.2014.03.011. Epub 2014 Mar 28.

    В этом обзоре литературы обсуждаются 3 фактора, связанные с ожирением: сексуальное развитие, химические вещества, нарушающие работу эндокринной системы (EDCs) и материнский программинг (эпигенетические факторы).

    Abstract
    This article is part of a Special Issue «Energy Balance». The prevalence of adult obesity has risen markedly in the last quarter of the 20th century and has not been reversed in this century. Less well known is the fact that obesity prevalence has risen in domestic, laboratory, and feral animals, suggesting that all of these species have been exposed to obesogenic factors present in the environment. This review emphasizes interactions among three biological processes known to influence energy balance: Sexual differentiation, endocrine disruption, and maternal programming. Sexual dimorphisms include differences between males and females in body weight, adiposity, adipose tissue distribution, ingestive behavior, and the underlying neural circuits. These sexual dimorphisms are controlled by sex chromosomes, hormones that masculinize or feminize adult body weight during perinatal development, and hormones that act during later periods of development, such as puberty. Endocrine disruptors are natural and synthetic molecules that attenuate or block normal hormonal action during these same developmental periods. A growing body of research documents effects of endocrine disruptors on the differentiation of adipocytes and the central nervous system circuits that control food intake, energy expenditure, and adipose tissue storage. In parallel, interest has grown in epigenetic influences, including maternal programming, the process by which the mother’s experience has permanent effects on energy-balancing traits in the offspring. This review highlights the points at which maternal programming, sexual differentiation, and endocrine disruption might dovetail to influence global changes in energy balancing traits.

  • Antagonistic effects of a mixture of low-dose nonylphenol and di-n-butyl phthalate (monobutyl phthalate) on the Sertoli cells and serum reproductive hormones in prepubertal male rats in vitro and in vivo.
    Hu Y1, Wang R2, Xiang Z3, Qian W4, Han X1, Li D1.
    PLoS One. 2014 Mar 27;9(3):e93425. doi: 10.1371/journal.pone.0093425. eCollection 2014.

    В этой статье изучены совместные эффекты нонилфенола (влияет на эстрогенный рецептр) и ди-н-бутил фталата (влияет на андрогенный рецептор) на клетки Сертоли в яичках крыс с помощью математической модели и лабораторного анализа. Было показано, что эти химикаты оказывают антагонистическое влияние.

    Abstract:
    The estrogenic chemical nonylphenol (NP) and the antiandrogenic agent di-n-butyl phthalate (DBP) are regarded as widespread environmental endocrine disruptors (EDCs) which at high doses in some species of laboratory animals, such as mice and rats, have adverse effects on male reproduction and development. Given the ubiquitous coexistence of various classes of EDCs in the environment, their combined effects warrant clarification. In this study, we attempted to determine the mixture effects of NP and DBP on the testicular Sertoli cells and reproductive endocrine hormones in serum in male rats based on quantitative data analysis by a mathematical model. In the in vitro experiment, monobutyl phthalate (MBP), the active metabolite of DBP, was used instead of DBP. Sertoli cells were isolated from 9-day-old Sprague-Dawley rats followed by treatment with NP and MBP, singly or combined. Cell viability, apoptosis, necrosis, membrane integrity and inhibin-B concentration were tested. In the in vivo experiment, rats were gavaged on postnatal days 23-35 with a single or combined NP and DBP treatment. Serum reproductive hormone levels were recorded. Next, Bliss Independence model was employed to analyze the quantitative data obtained from the in vitro and in vivo investigation. Antagonism was identified as the mixture effects of NP and DBP (MBP). In this study, we demonstrate the potential of Bliss Independence model for the prediction of interactions between estrogenic and antiandrogenic agents.

  • Human biological monitoring of suspected endocrine-disrupting compounds.
    Hu Y1, Wang R2, Xiang Z3, Qian W4, Han X1, Li D1.
    PLoS One. 2014 Mar 27;9(3):e93425. doi: 10.1371/journal.pone.0093425. eCollection 2014.

    В этом обзоре литературы описаны различные методы мониторинга EDCs и POPs.

    Abstract:
    Endocrine-disrupting compounds are exogenous agents that interfere with the natural hormones of the body. Human biological monitoring is a powerful method for monitoring exposure to endocrine disrupting compounds. In this review, we describe human biological monitoring systems for different groups of endocrine disrupting compounds, polychlorinated biphenyls, brominated flame retardants, phthalates, alkylphenols, pesticides, metals, perfluronated compounds, parabens, ultraviolet filters, and organic solvents. The aspects discussed are origin to exposure, metabolism, matrices to analyse, analytical determination methods, determinants, and time trends.

  • Similar causes of various reproductive disorders in early life.
    Svechnikov K, Stukenborg JB, Savchuck I, Söder O.
    Asian J Androl. 2014 Jan-Feb;16(1):50-9. doi: 10.4103/1008-682X.122199.

    Критический обзор литературы о влияниях EDCs на мужскую половую систему в ранние периоды жизни.

    Abstract:
    During the past few decades, scientific evidence has been accumulated concerning the possible adverse effects of the exposure to environmental chemicals on the well-being of wildlife and human populations. One large and growing group of such compounds of anthropogenic or natural origin is referred to as endocrine-disrupting chemicals (EDCs), due to their deleterious action on the endocrine system. This concern was first focused on the control of reproductive function particularly in males, but has later been expanded to include all possible endocrine functions. The present review describes the underlying physiology behind the cascade of developmental events that occur during sexual differentiation of males and the specific role of androgen in the masculinization process and proper organogenesis of the external male genitalia. The impact of the genetic background, environmental exposures and lifestyle factors in the etiology of hypospadias, cryptorchidism and testicular cancer are reviewed and the possible role of EDCs in the development of these reproductive disorders is discussed critically. Finally, the possible direct and programming effects of exposures in utero to widely use therapeutic compounds, environmental estrogens and other chemicals on the incidence of reproductive abnormalities and poor semen quality in humans are also highlighted.

  • Integrative rodent models for assessing male reproductive toxicity of environmental endocrine active substances.
    Auger J1, Eustache F, Rouiller-Fabre V, Canivenc-Lavier MC, Livera G.
    Asian J Androl. 2014 Jan-Feb;16(1):60-70. doi: 10.4103/1008-682X.122366.

    В этой статье описаны различные методы анализа влияния химических веществ, нарушающих работу эндокринной системы (EDCs), на структуру и функцию мужской половой системы грызунов.

    Abstract:
    In the present review, we first summarize the main benefits, limitations and pitfalls of conventional in vivo approaches to assessing male reproductive structures and functions in rodents in cases of endocrine active substance (EAS) exposure from the postulate that they may provide data that can be extrapolated to humans. Then, we briefly present some integrated approaches in rodents we have recently developed at the organism level. We particularly focus on the possible effects and modes of action (MOA) of these substances at low doses and in mixtures, real-life conditions and at the organ level, deciphering the precise effects and MOA on the fetal testis. It can be considered that the in vivo experimental EAS exposure of rodents remains the first choice for studies and is a necessary tool (together with the epidemiological approach) for understanding the reproductive effects and MOA of EASs, provided the pitfalls and limitations of the rodent models are known and considered. We also provide some evidence that classical rodent models may be refined for studying the multiple consequences of EAS exposure, not only on the reproductive axis but also on various hormonally regulated organs and tissues, among which several are implicated in the complex process of mammalian reproduction. Such models constitute an interesting way of approaching human exposure conditions. Finally, we show that organotypic culture models are powerful complementary tools, especially when focusing on the MOA. All these approaches have contributed in a combinatorial manner to a better understanding of the impact of EAS exposure on human reproduction.

  • Gene-environment interactions in male reproductive health: special reference to the aryl hydrocarbon receptor signaling pathway.
    Hu Y1, Wang R2, Xiang Z3, Qian W4, Han X1, Li D1.
    PLoS One. 2014 Mar 27;9(3):e93425. doi: 10.1371/journal.pone.0093425. eCollection 2014.

    Обзор литературы по механизмам, связанным с Ah-рецептором (воздействие диоксинов, регуляция андрогенов), влияющим на мужскую репродуктивную сферу.

    Abstract:
    Over the last few decades, there have been numerous reports of adverse effects on the reproductive health of wildlife and laboratory animals caused by exposure to endocrine disrupting chemicals (EDCs). The increasing trends in human male reproductive disorders and the mounting evidence for causative environmental factors have therefore sparked growing interest in the health threat posed to humans by EDCs, which are substances in our food, environment and consumer items that interfere with hormone action, biosynthesis or metabolism, resulting in disrupted tissue homeostasis or reproductive function. The mechanisms of EDCs involve a wide array of actions and pathways. Examples include the estrogenic, androgenic, thyroid and retinoid pathways, in which the EDCs may act directly as agonists or antagonists, or indirectly via other nuclear receptors. Dioxins and dioxin-like EDCs exert their biological and toxicological actions through activation of the aryl hydrocarbon-receptor, which besides inducing transcription of detoxifying enzymes also regulates transcriptional activity of other nuclear receptors. There is increasing evidence that genetic predispositions may modify the susceptibility to adverse effects of toxic chemicals. In this review, potential consequences of hereditary predisposition and EDCs are discussed, with a special focus on the currently available publications on interactions between dioxin and androgen signaling.

  • Associations of filaggrin gene loss-of-function variants with urinary phthalate metabolites and testicular function in young Danish Men.
    Joensen UN1, Jørgensen N, Meldgaard M, Frederiksen H, Andersson AM, Menné T, Johansen JD, Carlsen BC, Stender S, Szecsi PB, Skakkebæk NE, De Meyts ER, Thyssen JP.
    Environ Health Perspect. 2014 Apr;122(4):345-50. doi: 10.1289/ehp.1306720. Epub 2013 Dec 23.

    Эта статья изучила экскрецию метаболитов фталатов и функцию яичек молодых мужчин с\без рецессивной мутации в филаггрин гене. Мужчины с рецессивной мутацией имели более высокий уровень метаболитов фталатов в моче.

    Abstract:
    BACKGROUND:
    Filaggrin is an epidermal protein that is crucial for skin barrier function. Up to 10% of Europeans and 5% of Asians carry at least one null allele in the filaggrin gene (FLG). Reduced expression of filaggrin in carriers of the null allele is associated with facilitated transfer of allergens across the epidermis. We hypothesized that these individuals may have increased transdermal uptake of endocrine disruptors, including phthalates.Objectives: We investigated urinary excretion of phthalate metabolites and testicular function in young men with and without FLG loss-of-function variants in a cross-sectional study of 861 young men from the general Danish population.
    METHODS:
    All men were genotyped for FLG R501X, 2282del4, and R2447X loss-of-function variants. We measured urinary concentrations of 14 phthalate metabolites and serum levels of reproductive hormones. We also evaluated semen quality.
    RESULTS:
    Sixty-five men (7.5%) carried at least one FLG-null allele. FLG-null carriers had significantly higher urinary concentrations of several phthalate metabolites, including a 33% higher concentration of MnBP (mono-n-butyl phthalate; 95% CI: 16, 51%). FLG-null variants were not significantly associated with reproductive hormones or semen quality parameters.
    CONCLUSION:
    This study provides evidence that carriers of FLG loss-of-function alleles may have higher internal exposure to phthalates, possibly due to increased transepidermal absorption. FLG loss-of-function variants may indicate susceptible populations for which special attention to transepidermal absorption of chemicals and medication may be warranted.

  • Urinary polycyclic aromatic hydrocarbons and childhood obesity: NHANES (2001-2006).
    Scinicariello F1, Buser MC.
    Environ Health Perspect. 2014 Mar;122(3):299-303. doi: 10.1289/ehp.1307234. Epub 2013 Dec 24.

    Полицикличные ароматические углеводороды (ПАУ) взаимосвязаны с более высоким индексом массы тела, окружностью талии и ожирением по данным поперечного национального американского исследования NHANES.

    Abstract:
    BACKGROUND:
    Polycyclic aromatic hydrocarbons (PAHs) are known carcinogens and suspected endocrine disruptors. Prenatal exposure to PAHs has been associated with obesity in early childhood.
    OBJECTIVE:
    We examined the association of urinary PAH metabolites with adiposity outcomes [body mass index (BMI) z-score, waist circumference (WC), and rate of obesity] in children and adolescents.
    METHODS:
    We performed whole-sample analyses of 3,189 individuals 6-19 years of age who participated in the 2001-2006 National Health and Nutrition Examination Survey. We performed multivariate linear and logistic regression to analyze the association of BMI z-score, WC, and obesity with concentrations of single urinary PAH compounds and the sum of PAHs. Furthermore, the analyses were stratified by developmental stage [i.e., children (6-11 years) and adolescents (12-19 years)].
    RESULTS:
    BMI z-score, WC, and obesity were positively associated with the molecular mass sum of the PAHs and the total sum of naphthalene metabolites. Most associations increased monotonically with increasing quartiles of exposure among children 6-11 years of age, whereas dose-response trends were less consistent for adolescents (12-19 years of age). Neither total PAHs nor total naphthalene metabolites were associated with overweight in either age group, and there was little evidence of associations between the outcomes and individual PAHs.
    CONCLUSIONS:
    Total urinary PAH metabolites and naphthalene metabolites were associated with higher BMI, WC, and obesity in children 6-11 years of age, with positive but less consistent associations among adolescents.

  • Alteration of rat fetal cerebral cortex development after prenatal exposure to polychlorinated biphenyls.
    Naveau E1, Pinson A1, Gérard A1, Nguyen L2, Charlier C3, Thomé JP4, Zoeller RT5, Bourguignon JP1, Parent AS1.
    PLoS One. 2014 Mar 18;9(3):e91903. doi: 10.1371/journal.pone.0091903. eCollection 2014.

    Данная статья показала, что пренатальная экспозиция крыс к ПХБ вызывала изменения в развитии головного мозга и приводила к уменьшению концентрации тироксина в крови.

    Abstract:
    Polychlorinated biphenyls (PCBs) are environmental contaminants that persist in environment and human tissues. Perinatal exposure to these endocrine disruptors causes cognitive deficits and learning disabilities in children. These effects may involve their ability to interfere with thyroid hormone (TH) action. We tested the hypothesis that developmental exposure to PCBs can concomitantly alter TH levels and TH-regulated events during cerebral cortex development: progenitor proliferation, cell cycle exit and neuron migration. Pregnant rats exposed to the commercial PCB mixture Aroclor 1254 ended gestation with reduced total and free serum thyroxine levels. Exposure to Aroclor 1254 increased cell cycle exit of the neuronal progenitors and delayed radial neuronal migration in the fetal cortex. Progenitor cell proliferation, cell death and differentiation rate were not altered by prenatal exposure to PCBs. Given that PCBs remain ubiquitous, though diminishing, contaminants in human systems, it is important that we further understand their deleterious effects in the brain.

  • Zearalenone, an estrogenic mycotoxin, is an immunotoxic compound.
    Hueza IM1, Raspantini PC2, Raspantini LE3, Latorre AO4, Górniak SL5.
    Toxins (Basel). 2014 Mar 13;6(3):1080-95. doi: 10.3390/toxins6031080.

    Эта статья изучила токсичный эффект зеараленона на иммуную систему крыс.

    Abstract:
    The aim of this study was to assess the toxic effects of zearalenone (ZEA) on the immune function. Ovariectomised rats were treated daily by gavage with 3.0 mg/kg of ZEA for 28 days. Body weight gain, food consumption, haemotological parameters, lymphoid organs, and their cellularities were evaluated. Moreover, acquired immune responses and macrophage activity were also assessed. ZEA promoted reduction in body weight gain, which is not fully explained by diminished food consumption. Despite no effect on haematological parameters, ZEA caused thymic atrophy with histological and thymocyte phenotype changes and decrease in the B cell percentage in the spleen. With respect to acquired and innate immune responses, no statistically significant differences in delayed-type hypersensitivity were noticed; however, in the ZEA-treated rats, antibody production and peroxide release by macrophages were impaired. The observed results could be related to ZEA activity on ERs; thus, ZEA is an immunotoxic compound similar to estrogen and some endocrine disruptors.

  • Influence of Genista tinctoria L. or methylparaben on subchronic toxicity of bisphenol A in rats.
    Popa DS1, Bolfa P2, Kiss B1, Vlase L3, Păltinean R4, Pop A1, Cătoi C5, Crişan G3, Loghin F1.
    Biomed Environ Sci. 2014 Feb;27(2):85-96. doi: 10.3967/bes2014.021.

    Genista tinctoria L. herba (GT) уменьшает токсичный эффект BPA, основываясь на данных, полученных на крысах.

    Abstract:
    OBJECTIVE:
    To evaluate the influence of an extract of Genista tinctoria L. herba (GT) or methylparaben (MP) on histopathological changes and 2 biomarkers of oxidative stress in rats subchronicly exposed to bisphenol A (BPA).
    METHODS:
    Adult female Wistar rats were orally exposed for 90 d to BPA (50 mg/kg), BPA+GT (35 mg isoflavones/kg) or BPA+MP (250 mg/kg). Plasma and tissue samples were taken from liver, kidney, thyroid, uterus, ovary, and mammary gland after 30, 60, and 90 d of exposure respectively. Lipid peroxidation and in vivo hydroxyl radical production were evaluated by histological analysis along with malondialdehyde and 2,3-dihydroxybenzoic acid detection.
    RESULTS:
    The severity of histopathological changes in liver and kidneys was lower after GT treatment than after BPA or BPA+MP treatment. A minimal thyroid receptor antagonist effect was only observed after BPA+MP treatment. The abnormal folliculogenesis increased in a time-dependent manner, and the number of corpus luteum decreased. No significant histological alterations were found in the uterus. The mammary gland displayed specific estrogen stimulation changes at all periods. Both MP and GT revealed antioxidant properties reducing lipid peroxidation and BPA-induced hydroxyl radical generation.
    CONCLUSION:
    GT L. extract ameliorates the toxic effects of BPA and is proved to have antioxidant potential and antitoxic effect. MP has antioxidant properties, but has either no effect or exacerbates the BPA-induced histopathological changes.

  • Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors.
    Habert R1, Muczynski V, Grisin T, Moison D, Messiaen S, Frydman R, Benachi A, Delbes G, Lambrot R, Lehraiki A, N’tumba-Byn T, Guerquin MJ, Levacher C, Rouiller-Fabre V, Livera G.
    Reproduction. 2014 Mar 6;147(4):R119-29. doi: 10.1530/REP-13-0497. Print 2014.

    Эта статья показала, что EDCs по-разному влияют на развитие яичек человека и грызунов, что необходимо при интерпретации данных, полученных на грызунах.

    Abstract:
    Fetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk.