Endocrine-disrupting Activity Research Articles

Effect of the Metabolic Modification of Environmental Chemicals on Endocrine-disrupting Activity

The endocrine-disrupting activities of various environmental chemicals are metabolically activated. For example, diphenyls, styrene oligomers, chalcones, trans-stilbene and 2-nitrofluorene are not estrogens, but after incubation with liver microsomes, their metabolites show estrogenic activities. Thus, these chemicals are estrogenically activated by the cytochrome P450 system. In contrast, the antiandrogenic activity of fenthion, an organophosphorus insecticide, is abolished after metabolism to sulfoxide and sulfone derivatives. Structural requirements of twenty bisphenol A related compounds, as well as various benzophenones, for estrogenic and antiandrogenic activities have been investigated. The estrogenic and antiandrogenic activities of Benzophenone 3, a representative UV absorbant, are activated by oxidative metabolism. Parabens (used as antimicrobial agents) exhibit estrogenic activity, and their potency shows a bell-shaped curve between C1 (methylparaben) and C12 (dodecylparaben) parabens. The AhR ligand activity of indirubin is decreased by metabolism. Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDE) are activated by hydroxylation to show estrogenic and thyroid hormone-disrupting activities. Halogen adjacent to a hydroxyl group is essential for thyroid hormone-disrupting activity. Tetrabromobisphenol A, tetrachlorobisphenol A and tetramethylbisphenol A also exhibit thyroid hormone-disrupting activity. Amphibian metamorphosis of tadpoles to frogs is affected by hydroxylated PCB, hydroxylated PBDE and bisphenol A derivatives. These chemicals suppress thyroid hormone-dependent metamorphosis, acting as antagonists of thyroid hormone. Thus, metabolic modification can have a dramatic impact on the endocrine-disrupting activities of environmental chemicals.

Endocrine-Disrupting Activities and Organic Contaminants Associated with Oil and Gas Operations in Wyoming Groundwater.

Unconventional oil and natural gas (UOG) operations couple horizontal drilling with hydraulic fracturing to access previously inaccessible fossil fuel deposits. Hydraulic fracturing, a common form of stimulation, involves the high-pressure injection of water, chemicals, and sand to fracture the target layer and release trapped natural gas and/or oil. Spills and/or discharges of wastewater have been shown to impact surface, ground, and drinking water. The goals of this study were to characterize the endocrine activities and measure select organic contaminants in groundwater from conventional oil and gas (COG) and UOG production regions of Wyoming. Groundwater samples were collected from each region, solid-phase extracted, and assessed for endocrine activities (estrogen, androgen, progesterone, glucocorticoid, and thyroid receptor agonism and antagonism), using reporter gene assays in human endometrial cells. Water samples from UOG and conventional oil areas exhibited greater ER antagonist activities than water samples from conventional gas areas. Samples from UOG areas tended to exhibit progesterone receptor antagonism more often, suggesting there may be a UOG-related impact on these endocrine activities. We also report UOG-specific contaminants in Pavillion groundwater extracts, and these same chemicals at high concentrations in a local UOG wastewater sample. A unique suite of contaminants was observed in groundwater from a permitted drinking water well at a COG well pad and not at any UOG sites; high levels of endocrine activities (most notably, maximal estrogenic activity) were noted there, suggesting putative impacts on endocrine bioactivities by COG. As such, we report two levels of evidence for groundwater contamination by both UOG and COG operations in Wyoming.

Effects of tributyltin on early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes)

Tributyltin, an organotin compound, was used worldwide as an antifouling agent in aquatic environments and there has been much concern about the toxicological and ecotoxicological properties of organotin compounds. Even though it has been prohibited worldwide, tributyltin is still detected at low concentrations in aquatic environments. Here we investigated the effects of tributyltin on the early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes). In adults, exposure to tributyltin at 3.82 μg/L suppressed fecundity and fertility and increased mortality. At 10.48 μg/L all medaka died by the sixth day of exposure. Exposure to tributyltin during early life-stages induced no significant differences in mortality or embryonic development, but growth was suppressed in groups exposed to 0.13 and 0.68 μg/L. Furthermore, there was no abnormal gonadal development in Japanese medaka exposed to tributyltin. These results provide evidence of the negative effects of tributyltin on reproduction in a teleost fish. Tributyltin did not affect gonadal sex differentiation in Japanese medaka, but fecundity and fertility were suppressed, although it is not clear whether this suppression resulted from the endocrine-disrupting action of tributyltin or its toxicity.

Molecular Mechanism of Alternative P450-Catalyzed Metabolism of Environmental Phenolic Endocrine-Disrupting Chemicals.

Understanding the bioactivation mechanisms to predict toxic metabolites is critical for risk assessment of phenolic endocrine-disrupting chemicals (EDCs). One mechanism involves ipso-substitution, which may contribute to the total turnover of phenolic EDCs, yet the detailed mechanism and its relationship with other mechanisms are unknown. We used density functional theory to investigate the P450-catalyzed ipso-substitution mechanism of the prominent xenoestrogen bisphenol A. The ipso-substitution proceeds via H-abstraction from bisphenol A by Compound I, followed by essentially barrierless OH-rebound onto the ipso-position forming a quinol, which can spontaneously decompose into the carbocation and hydroquinone. This carbocation can further evolve into the highly estrogenic hydroxylated and dimer-type metabolites. The H-abstraction/OH-rebound reaction mechanism has been verified as a general reaction mode for many other phenolic EDCs, such as bisphenol analogues, alkylphenols and chlorophenols. The identified mechanism enables us to effectively distinguish between type I (eliminating-substituent as anion) and type II (eliminating-substituent as cation) ipso-substitution in various phenolic EDCs. We envision that the identified pathways will be applicable for prediction of metabolites from phenolic EDCs whose fate are affected by this alternative type of P450 reactivity, and accordingly enable the screening of these metabolites for endocrine-disrupting activity.

New Research about the Effect of Octylphenol (4-tOP) on Histological Structure of Testis in Mice

The reproductive system of the vertebrates - mainly of the adult males -seems to be vulnerable to the action of endocrine disruptors. The aim of this study was to evaluate the effect of octylphenol (OP) on histological structure of testis in NMRI mice. The mice were divided in three groups (5 mice for each group) such as: control group (C - untreated); vehicle group (V - treated with a mixture of ethanol and corn oil 1:10) and experimental group (E � treated with OP in concentration of 160 mg/kg body weight). The solution of OP was prepared in ethanol, administered by subcutaneous injection in the thigh region (1 ml total volume), for seven consecutive days. For histological examination, after slaughtering, the testes were fixed in 10% neutral formalin, embedded in paraffin, sectioned to a thickness of 5 �m and stained with Mallory�s trichrome method. Microscopic analysis reveals in the individuals from the C and V groups, the normal morphology of the seminiferous tubules. In the case of individuals in the E group, treated with OP, in the testicular parenchyma occurs changes consisting in: detachment of the seminiferous tubule epithelium, mild proliferation of germ cells, the presence of apoptotic bodies among the cells of seminal line, diffuse hyperplasia of the Leydig interstitial cells and hypertrophy of the peritubular capillary. Experimental data obtained in this study demonstrated that the treatment with octylphenol induces irreversible changes in the testicular parenchyma with the disruption of spermatogenesis process.

Environmental mixture with estrogenic activity increases Hsd3b1 expression through estrogen receptors in immature rat granulosa cells.

Humans are exposed not only to single endocrine disruptors, but also to chemical mixtures that can adversely affect their reproductive health. Steroidogenesis in reproductive tissues is emerging as the key target of endocrine disruptor action. Here, we analyzed the effect of environmental chemical mixtures with estrogenic activity on steroidogenic processes in immature rat granulosa cells and whether the observed steroidogenic effects were mediated through estrogen receptors. Extracts from untreated wastewater were prepared by solid-phase extraction and silica gel fractionation. ER-CALUX assay showed that the polar fractions of wastewater exerted different levels of estrogenic activity. Exposure of immature granulosa cells to the polar fraction exerting 9ng of 17β-estradiol equivalents per liter of water of estrogenic activity increased mRNA expression of the key enzymes of progesterone biosynthetic pathway Star and Hsd3b1, but did not alter the level of Cyp19a1 and Lhr. Addition of estrogen receptor inhibitor ICI 182 780 prevented the estrogenic mixture-induced increase in Hsd3b1, but not Star mRNA level in immature granulosa cells. These results indicate that the environmental chemical mixtures with estrogenic activity exert endocrine disrupting effects by augmenting the progesterone biosynthetic pathway in immature rat granulosa cells, which is an effect achieved in part through activation of the estrogen receptors.

Endocrine Disruption Activity of 30-day Dietary Exposure to Decabromodiphenyl Ethane in Balb/C Mouse

ObjectiveThis study aimed to evaluate the hepatotoxicity, metabolic disturbance activity and endocrine disrupting activity of mice treated by Decabromodiphenyl ethane (DBDPE). MethodsIn this study, Balb/C mice were treated orally by gavage with various doses of DBDPE. After 30 days of treatment, mice were sacrificed; blood, livers and thyroid glands were obtained, and hepatic microsomes were isolated. Biochemical parameters including 8 clinical chemistry parameters, blood glucose and hormone levels including insulin and thyroid hormone were assayed. The effects of DBDPE on hepatic cytochrome P450 (CYP) levels and activities and uridinediphosphate-glucuronosyltransferase (UDPGT) activities were investigated. Liver and thyroid glands were observed. ResultsThere were no obvious signs of toxicity and no significant treatment effect on body weight, or liver-to-body weight ratios between treatment groups. The levels of ALT and AST of higher dose treatment groups were markedly increased. Blood glucose levels of treatment groups were higher than those of control group. There was also an induction in TSH, T3, and fT3. UDPGT, PROD, and EROD activities were found to have been increased significantly in the high dose group. Histopathologic liver changes were characterized by hepatocyte hypertrophy and cytoplasmic vacuolization. Our findings suggest that DBDPE can cause a certain degree of mouse liver damage and insufficiency. ConclusionDBDPE has the activity of endocrine disruptors in Bal/C mice, which may induce drug-metabolizing enzymes including CYPs and UDPGT, and interfere with thyroid hormone levels mediated by AhR and CAR signaling pathways. Endocrine disrupting activity of DBDPE could also affect the glucose metabolism homeostasis.

Bisphenol A (BPA) modulates the expression of endocrine and stress response genes in the freshwater snail Physa acuta

Bisphenol A (BPA), a known endocrine disrupting chemical (EDC) that can mimic the action of oestrogens by interacting with hormone receptors, is potentially able to influence reproductive functions in vertebrates and invertebrates. The freshwater pulmonate Physa acuta is a sensitive organism to xenobiotics appropriate for aquatic toxicity testing in environmental studies. This study was conducted to explore the effects of BPA on the Gastropoda endocrine system. The effects following a range of exposure times (5–96h) to BPA in P. acuta were evaluated at the molecular level by analysing changes in the transcriptional activity of the endocrine-related genes oestrogen receptor (ER), oestrogen-related receptor (ERR), and retinoid X receptor (RXR), as well as in genes involved in the stress response, such as hsp70 and hsp90. Real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis showed that BPA induced a significant increase in the mRNA levels of ER, ERR, and RXR, suggesting that these receptors could be involved in similar pathways or regulation events in the endocrine disruptor activity of this chemical at the molecular level in Gastropoda. Additionally, the hsp70 expression was upregulated after 5 and 72h of BPA exposures, but hsp90 was only upregulated after 5h of BPA exposure. Finally, we assessed the glutathione-S-transferase (GST) activity after BPA treatment and found that it was affected after 48h. In conclusion, these data provide, for the first time, evidences of molecular effects produced by BPA in the endocrine system of Gastropoda, supporting the potential of ER, ERR and RXR as biomarkers to analyse putative EDCs in ecotoxicological studies. Moreover, our results suggest that P. acuta is an appropriate sentinel organism to evaluate the effect of EDCs in the freshwater environment.

The hypothalamic-pituitary-testicular axis and the testicular function are modulated after silver nanoparticle exposure.

Silver nanoparticles (AgNPs) are widely used in industrial and medical applications and humans may be exposed through different routes, increasing the risk of toxicity. We investigated the transcript expression of genes involved in the regulation of the hypothalamic-pituitary-testicular (HPT) axis and the parameters associated with sperm functionality after prepubertal exposure. AgNPs modulated the transcript expression of genes involved in the control of the HPT axis and spermatogenesis in the groups treated with lower doses, while the functional parameters related to sperm and puberty were affected in the groups administered higher doses. These results suggest that the HPT axis is disrupted by AgNPs during the prepubertal and pubertal periods, which are highly susceptible windows for the endocrine-disrupting chemical activity.

Importance of Two Birth Cohorts (n=20,926 and n=514): 15 Years' Experience of the Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy

Since "Our Stolen Future" by Theo Colborn was published in 1996, global interest on the impact of chemical substances, such as the endocrine-disrupting action of chemicals, has increased. In Japan, "The Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy" was launched in 2001. It was a model of Japan Environment and Children's Study of the Ministry of the Environment. In a large-scale, Hokkaido cohort, we obtained the consent of 20,926 mothers at the organogenesis stage with the cooperation of 37 obstetrics clinics in Hokkaido. We tracked the effects of endocrine disruptors on developmental disorders. In a small-scale Sapporo cohort, we observed in detail the neuropsychiatric development of children with the consent of 514 mothers in their late pregnancy. We examined how prenatal exposure to low concentrations of environmental chemicals affect the development of organs and the postnatal development of children. Maternal exposure to POPs, such as PCB/dioxins and perfluorinated alkyl substances, has affected not only children's birth size, thyroid functions, and sex hormone levels, but also postnatal neurodevelopment, infection, and allergy among others. The associations of short-half-life substances, such as DEHP and BPA, with obesity, ASD, and ADHD have been investigated. Gene-environment interactions have been found for smoking, caffeine, folic acid, and PCB/dioxin. In 2015, our center was officially designated as the WHO Collaborating Centre for Environmental Health and Prevention of Chemical Hazards, and we continue to the contribute to the global perspectives of child health.

Occurrence and Partitioning of Bisphenol Analogues in Adults’ Blood from China

Widespread human exposure and associated adverse health effects led to regulations on the usage of bisphenol A (BPA). Several bisphenol analogues (BPs) have been introduced as BPA alternatives in various applications. However, these BPs have been shown to exhibit similar or even stronger endocrine-disrupting activities compared with that of BPA. Currently, information on the human exposure to BPA alternatives remains limited. In this study, nine BPs were quantified in 81 pairs of plasma and red blood cell (RBC) samples from Chinese participants. In human plasma, the predominant BPs was BPA, bisphenol S (BPS), and bisphenol AF (BPAF), with the mean concentrations of 0.40, 0.15, and 0.073 ng/mL, respectively. BPA (accounting for 63% of total BPs) and BPS (18%) were the major BPs in the RBC fraction. Mass fractions in plasma (Fp) were found to be highest for BPS (mean, 0.78), followed by BPAF (0.71) and BPA (0.67), indicating strong partitioning to the plasma fraction. However, bisphenol AP was more frequently detected in the RBC fraction. Estimated total daily intake (EDI) of BPA was in the range of 0.0048-0.75 μg/kg bw/day for the participants, and adults aged >50 years had comparatively lower EDI. To our knowledge, this is the first study to assess the occurrence and partitioning of BPA alternatives in paired human plasma and RBCs from the Chinese general population.

Ultraviolet filters and heat shock proteins: effects in Chironomus riparius by benzophenone-3 and 4-methylbenzylidene camphor.

Benzophenone-3 (BP3) and 4-methylbenzylidene camphor (4MBC) are common ultraviolet filters (UV filters), compounds considered as emergent contaminants, used in different products like plastics and personal care products. The levels of these compounds are rising in the wild, but the effects they have on invertebrates are poorly understood. Chironomus riparius is a benthic insect widely used in toxicology, and several studies have been previously performed in our laboratory to determine the effects these compounds have on this organism at the molecular level. We have shown that UV filters can alter the mRNA levels of heat shock protein 70 (Hsp70), one of the most studied heat shock proteins. Although these proteins are crucial for the survival of organisms, little data is available on the effects these emergent contaminants have on them, especially in invertebrates. Here, we analyzed the transcriptional activity of 12 genes covering the different groups of heat shock protein [Hsp10, Hsp17, Hsp21, Hsp22, Hsp23, Hsp24, Hsp27, Hsp34, Hsp40, Hsp60, Hsc70 (3), and Hsc70 (4)] in response to 0.1 and 1mg/L concentrations of BP3 and 4MBC at 8 and 24h. The results showed that some small Hsp (sHsp) genes were altered by these compounds, while the genes of proteins present in mitochondria, Hsp10 and Hsp60, did not change. sHsps are also involved in developmental processes, so the observed variations could be due to the endocrine disruption activity described for these compounds rather than to a stress response.

Monotonic Dose Effect of Bisphenol-A, an Estrogenic Endocrine Disruptor, on Estrogen Synthesis in Female Sprague-Dawley Rats.

Bisphenol-A (BPA) is a ubiquitous environmental chemical that produces adverse effect on reproduction system due to its potent estrogenic endocrine disruptive activity. The present study was aimed to investigate the monotonic dose effect of BPA on estrogen synthesis in female Sprague-Dawley rats. For this purpose, we administered three different doses of BPA (10, 50, 100µg/kg bw/day) into rats and analyzed various biochemical, hormonal, molecular and histological parameters. 10µg BPA treated rats showed significantly decreased levels of phase I detoxification agents (CYP450, Cyt-b5). Overexpression of eNOS with decreased expression of StAR and steroidogenic enzymes (CYP11A1, aromatase) indicate decreased production of estrogen. Increased levels of serum gonadotropins (FSH, LH) and decreased levels of estradiol suggest mimetic action of BPA and its feedback inhibition. Increased body weight, lipid profile status of 10µg BPA treated rats and histological analysis of ovary and mammary tissue support the study. Overall, our results suggest that BPA exerts its estrogen mimetic effects in a monotonic manner.

Exposure to pesticide as a risk factor for depression: A population-based longitudinal study in Korea

BackgroundExposure to pesticides is associated with mental disorders, including depression, especially among occupationally exposed populations, such as farmers. The results of experimental studies ascribed the negative effects of pesticides on mental health to their neurotoxic and endocrine-disrupting activities. PurposeThis study aimed to investigate the association between the risk of depression and high- or low-level exposure to pesticides in a rural population. MethodsThis longitudinal study was performed in 2005–2008 (baseline) and 2008–2012 (follow-up) to evaluate the risk of depression among 2151 Korean adults. A standardized questionnaire was used to obtain information on depression upon self-reported exposure to pesticide based on the Center for Epidemiologic Studies Depression Scale. Logistic regression analysis was performed to evaluate the association between pesticide exposure and depression. We adjusted the data for age, cigarette smoking status, current alcohol use, monthly income, educational level, marriage status, and religion. ResultsAmong the individuals who reported depression, the number of participants who used pesticides was significantly higher than that who did not (N=61 [7.2%] vs. N=54 [4.2%], P=0.003). A positive association was noted between >20-year period of pesticide use and depression (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.41–3.88). Individuals who reported depression showed greater odds of being exposed to higher pesticide concentrations (OR, 2.33; 95% CI, 1.40–3.88) and experiencing pesticide poisoning (OR, 5.83; 95% CI, 1.80–18.86) than those who did not. ConclusionExposure to pesticides at a high concentration was found to be associated with depressive symptoms among Korean adults.

Conifer Diterpene Resin Acids Disrupt Juvenile Hormone-Mediated Endocrine Regulation in the Indian Meal Moth Plodia interpunctella.

Diterpene resin acids (DRAs) are important components of oleoresin and greatly contribute to the defense strategies of conifers against herbivorous insects. In the present study, we determined that DRAs function as insect juvenile hormone (JH) antagonists that interfere with the juvenile hormone-mediated binding of the JH receptor Methoprene-tolerant (Met) and steroid receptor coactivator (SRC). Using a yeast two-hybrid system transformed with Met and SRC from the Indian meal moth Plodia interpunctella, we tested the interfering activity of 3704 plant extracts against JH III-mediated Met-SRC binding. Plant extracts from conifers, especially members of the Pinaceae, exhibited strong interfering activity, and four active interfering DRAs (7α-dehydroabietic acid, 7-oxodehydroabietic acid, dehydroabietic acid, and sandaracopimaric acid) were isolated from roots of the Japanese pine Pinus densiflora. The four isolated DRAs, along with abietic acid, disrupted the juvenile hormone-mediated binding of P. interpunctella Met and SRC, although only 7-oxodehydroabietic acid disrupted larval development. These results demonstrate that DRAs may play a defensive role against herbivorous insects via insect endocrine-disrupting activity.

Endocrine-disrupting activity of per- and polyfluoroalkyl substances: Exploring combined approaches of ligand and structure based modeling

Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited. In this study, experimental data for T4-TTR competing potency of 24 PFASs obtained in a radioligand-binding assay were modeled using classification- and regression-based quantitative structure-activity relationship (QSAR) tools with simple molecular descriptors obtained from chemical structure of these compounds in order to identify the responsible structural features and fragments of the studied PFASs for endocrine disruption activity. Additionally, docking studies were performed employing the crystal structure complex of TTR with bound 2′, 6′-difluorobiphenyl-4-carboxylic acid (PDB: 2F7I) in order to constitute the receptor model for human TTR. The results corroborate evidence for these binding interactions and indicate multiple high-affinity modes of binding. The developed in silico models therefore advance our understanding of important structural attributes of these chemicals and may provide important information for the design of future synthesis of PFASs as well as may serve as an efficient query tool for virtual screening of large PFAS databases to check their endocrine toxicity profile.

Effects of low doses of carbendazim or iprodione either separately or in mixture on the pubertal rat seminiferous epithelium: An ex vivo study

It has been shown that non-cytotoxic doses of Carbendazim (CBZ), a broad-spectrum benzimidazole fungicide, possess endocrine-disrupting (androgen-like) actions, ex vivo, on the pubertal rat seminiferous epithelium. Iprodione (IPR), a dicarboximide fungicide, is also known to be an endocrine-disrupter (anti-androgen). The effect of a mixture of these two pesticides was investigated in the validated rat seminiferous tubule culture model. Cultures were performed in the absence or presence of CBZ 50nM or IPR 50nM either alone or in mixture (Mix), over a 3-week period. Mix exerted a dramatic effect on two proteins (Connexin 43 and Claudin-11) of the blood-testis barrier and possessed similar effects to IPR on some germ cell populations. The presence of IPR together with CBZ (Mix) cancelled the effect of CBZ on the increase of the androgen-dependent TP1 and TP2 mRNAs and on the decrease of ERα, ERβ mRNAs. Nevertheless, CBZ alone or IPR alone or Mix induced toxicity on spermatogenesis resulting in a decrease of round spermatids (the precursors of spermatozoa). These results strongly suggest that, even at these low concentrations, the effects of IPR and of CBZ are not solely dependent on their respective anti-androgenic and androgen-like effects and should involve several mechanisms of action.

High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose-dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits.

The endocrine disruption potential of betamethasone using Japanese medaka as a fish model

ABSTRACTThe presence of synthetic glucocorticosteroids (GCs) in surface water and their potential endocrine disruption (ED) activity at environmental concentrations has not been fully investigated. Synthetic GCs may interfere with endogenous receptors within the hypothalamic-pituitary-gonadal (HPG) axis and disruptions of this pathway can result in decreased reproduction and/or adverse developmental effects. Betamethasone, a synthetic GC, has been on the market in the United States since the 1980's. The Pharmaceutical Assessment and Transport Evaluation model estimated betamethasone concentrations to be <0.6 ng/L in 95% of all U.S. surface waters. Concentrations of 0.01, 0.1, and 1.0 µg betamethasone/L were used in a two-generation fish full life cycle study with Japanese medaka. Gross endpoints, secondary sexual characteristics, and vitellogenin expression were evaluated. The highest concentration at which ED outcomes are not anticipated was determined to be 0.1 µg/L. The ratio of the predicted environmental concentration to the no effect concentration for ED is less than one, indicating no risk to aquatic life from environmentally relevant concentrations of betamethasone.

Endocrine disrupting compounds modulates adiponectin secretion, expression of its receptors and action on steroidogenesis in ovarian follicle

We determined the effect of dioxin-like polychlorinated naphtalenes (PCN) (Halowax 1051) (100pg/ml), benzo(a)pyrene [B(a)P] (2.5ng/ml), hexachlorobenzene (HCBz) (0.2ng/ml) and non-dioxin like polybrominated diphenyl ether (BDE-47) (25ng/ml) and bisphenol A (BPA) (20ng/ml) on ovarian adiponectin secretion (ELISA) and its receptors expression (Western blot). Ovarian cells co-culture was used to examine action of endocrine disruptors (EDCs) on adiponectin (10μg/ml) stimulated steroidogenesis. B(a)P, HCBz, testosterone (T) decreased adiponectin secretion and receptors expression, BPA, BDE-47, estradiol (E2) had the opposite effect, while PCN had inhibitory effect only on adiponectin secretion. In adiponectin stimulated cells dioxin-like compounds decreased E2 and except of PCN had no effect on T, while non-dioxin like increased E2 and decreased T secretion. Results indicated to modulatory role of EDCs on adiponectin and its receptor and its action on ovarian steroidogenesis, suggest that dioxin- like compounds may contribute to the ovarian dysfunction in obesity-related disorders.