Endocrine-related Effects Research Articles

Applying a modified systematic review and integrated assessment framework (SYRINA) - a case study on triphenyl phosphate.

This work presents a case study in applying a systematic review framework (SYRINA) to the identification of chemicals as endocrine disruptors. The suitability and performance of the framework is tested with regard to the widely accepted World Health Organization definition of an endocrine disruptor (ED). The endocrine disrupting potential of triphenyl phosphate (TPP), a well-studied flame retardant reported to exhibit various endocrine related effects was assessed. We followed the 7 steps of the SYRINA framework, articulating the research objective via Populations, Exposures, Comparators, Outcomes (PECO) statements, performed literature search and screening, conducted study evaluation, performed data extraction and summarized and integrated the evidence. Overall, 66 studies, consisting of in vivo, in vitro and epidemiological data, were included. We concluded that triphenyl phosphate could be identified as an ED based on metabolic disruption and reproductive function. We found that the tools used in this case study and the optimizations performed on the framework were suitable to assess properties of EDs. A number of challenges and areas for methodological development in systematic appraisal of evidence relating to endocrine disrupting potential were identified; significant time and effort were needed for the analysis of in vitro mechanistic data in this case study, thus increasing the workload and time needed to perform the systematic review process. Further research and development of this framework with regards to grey literature (non-peer-reviewed literature) search, harmonization of study evaluation methods, more consistent evidence integration approaches and a pre-defined method to assess links between adverse effect and endocrine activity are recommended. It would also be advantageous to conduct more case studies for a chemical with less data than TPP.

SOC-III-09 Comparison of key players involved in endocrine-related effects across different vertebrate species

SOC-III-09 Comparison of key players involved in endocrine-related effects across different vertebrate species

A Systematic Review of the Effects of Equol (Soy Metabolite) on Breast Cancer.

Equol is a soy isoflavone metabolite that can be produced by intestinal bacteria. It is lipophilic and resembles natural oestrogens with an affinity to oestrogen receptors. This review is focused on how equol affects breast cancer, as evidenced by in vivo and in vitro studies. Equol is considered chemoprotective in specific endocrine-related pathologies, such as breast cancer, prostate cancer, cardiovascular diseases, and menopausal symptoms. In humans, not everyone can produce equol from gut metabolism. It is postulated that equol producers benefit more than non-equol producers for all the endocrine-related effects. Equol exists in two enantiomers of R-equol and S-equol. Earlier studies, however, did not specify which enantiomer was being used. This review considers equol’s type and concentration variations, pathways affected, and its outcome in in vivo and in vitro studies.

Organophosphate ester flame retardants have antiandrogenic potential and affect other endocrine related endpoints in vitro and in silico

Organophosphate ester flame retardants (OPFRs) are used to prevent ignition and spreading of fire. They are present in various human matrices suggesting adult, fetal, and neonate exposure. Endocrine related effects have been observed in vivo, but information at the molecular level is lacking for some OPFRs. Also, a better understanding of potential contribution from chemical substructures is needed. The aim of this study was to screen OPFRs for endocrine disruptive potential in vitro and in silico. We selected eleven substances to represent some OPFRs with 1) little information on endocrine activity and others to represent 2) varied chemical substructures. We used in vitro assays for androgen receptor (AR), aryl hydrocarbon receptor (AhR), and Nrf2 activity, effects on steroidogenesis, and transthyretin (TTR) binding, as well as in silico models covering estrogen, thyroid, and CYP3A4 induction related endpoints. Ten OPFRs affected AR and AhR activity, seven affected TTR binding, and five affected 17β-estradiol levels. Several substances had IC50-values below 10 μM and exhibited efficacious effects. These included TPHP, CDP, TMPP, TIPPP, and EHDPP for AR antagonism, suggesting that the degree of arylation and the size of the substance can play a role for the activity. Chlorinated OPFRs had low/no effect on TTR binding. No clear trend was observed for AhR and steroidogenesis, but all arylated OPFRs were predicted to have alert for estrogen receptor binding in an in silico model with metabolism simulator included. Collectively, our data suggest that OPFRs have endocrine disruptive potential warranting further studies to enable human risk assessment.

Populations Collapses in Marine Invertebrates Due to Endocrine Disruption: A Cause for Concern?

In the beginning of the twenty first century, the International Program on Chemical Safety published a document entitled Global Assessment of the State-Of-The-Science of Endocrine Disruptors. The work indicated only weak evidence of endocrine-related effects in human populations, and in wild animal populations. This document was revised in 2012 (State of the Science of Endocrine Disrupting Chemicals−2012) (1). The new document and the extensive scientific evidence it provided showed clearly that ED effects could be a risk to human and wildlife health. These works, however, were focused in human health and related animal models, mainly vertebrates and particularly mammals. It can be argued that invertebrates and many other taxa are important parts of all ecosystems, and, in many instances, have been shown to be also vulnerable to endocrine disruption. Thus, this work is aimed to show some observations on important marine invertebrate taxa, from an ecological point of view. The most important example of endocrine disruption in marine wild populations is the imposex response of marine gastropods, known for more than 40 years, and worldwide used to evaluate marine antifouling pollution. Among the mollusks, other important natural resources are bivalve species, used as human food sources and cephalopods, free-living, highly specialized mollusks, and also human food sources. Effects derived from endocrine disruptors in these species indicate that consumption could bring these compounds to human populations in an almost direct way, sometimes without any form of cooking or preparation. While discussing these questions, this work is also aimed to stimulate research on endocrine disruption among the invertebrate taxa that inhabited our oceans, and on which these effects are poorly known today.

The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax

Azole antifungal drugs are used worldwide to treat a variety of fungal infections such as vulvovaginal candidiasis, particularly in pregnant women who are at increased risk. The aim of this study was to mechanistically investigate the endocrine disrupting potential of four commonly used azole antifungal drugs; clotrimazole, miconazole, ketoconazole and fluconazole in vitro using the H295R cell assay and two recombinant, CYP17A1 and CYP19A1 (aromatase), assays. Steroids were quantified using LC–MS/MS. In both recombinant assays, all four azoles inhibited the CYP enzymes investigated, at therapeutically relevant concentrations. However, responses were much more complex in the H295R cell line. Clotrimazole inhibited steroid production in a dose-dependent manner with IC50 values for CYP17A1 and CYP19A1 in the range 0.017–0.184 μM. Miconazole and ketoconazole increased all steroids on the hydroxylase axis (IC50 MIC: 0.042-0.082 μM, KET: 0.041–1.2 μM), leading to accumulation of progestagens and corticosteroids and suppression of androgens and estrogens, indicating inhibition of CYP17A1, in particular lyase activity. However, ketoconazole suppressed all steroids at higher concentrations, resulting in bell-shaped curves for all steroids on the hydroxylase axis. Fluconazole was found to inhibit CYP17A1-lyase activity, causing suppression of androgens (IC50 = 114–209 μM) and estrogens (IC50 = 28 μM). The results indicate that these four azole drugs are highly potent in vitro and, based on plasma Cmax values, may exert endocrine disrupting effects at therapeutically relevant concentrations. This raises concern for endocrine related effects in patients using azole antifungal drugs, particularly when taken during sensitive periods like pregnancy.

Two-generation exposure to 2-ethylhexyl 4-methoxycinnamate (EHMC) in Japanese medaka (Oryzias latipes) and its reproduction and endocrine related effects

2-Ethylhexyl 4-methoxycinnamate (EHMC) is one of the most widely used UV-filters, and hence has been frequently detected in water environment. EHMC has been reported to induce short-term reproductive toxicity in fish, and thyroid disrupting effects in other animal studies. However, limited information is available for its long-term effects on fecundity, and thyroid disrupting effects in fish. In the present study, effects of EHMC on fecundity, measured as number of eggs, were evaluated in Japanese medaka (Oryzias latipes), and its underlying mechanisms on sex and thyroid hormone disruption were explored. For this purpose, a five-month long (154 d) exposure to F0 generation was conducted on fertilized eggs (<24 h post-fertilization (hpf)), with nominal concentration of 0, 0.05, 0.158, 0.5, 1.58, or 5 mg/L EHMC, followed by a 3-8-d exposure of F1 generation. After >3 months exposure, significant decreases in reproductive performances were observed at all test concentrations as low as 0.05 mg/L. Reproduction effects were not accompanied with sex hormone changes, but up-regulation of vitellogenin gene was observed. Thyroid hormones were decreased by EHMC exposure in F1 fish at -38 day post-fertilization (dpf). In addition, down-regulation of type II iodothyronine deiodinase (dio2) and up-regulation of thyrotropin releasing hormone (trh) were observed in both F0 and F1 juvenile fish, suggesting thyroid disruption potential of EHMC. Our observation suggests that EHMC at the levels one to two orders of magnitude higher than those detected in ambient water may affect reproduction and thyroid hormonal balance of fish.

Biphasic effects of perfluorooctanoic acid on steroidogenesis in mouse Leydig tumour cells

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant, which may possess endocrine disrupting properties. Herein, we investigated the possible mechanism(s) of toxicity and steroidogenesis in mouse Leydig cells. MLTC-1 (mouse Leydig tumour cells) cells were exposed to 0, 50, 100 or 200 μM PFOA for 48 h to ascertain their effects on the nuclear (membrane) receptor responses, steroidogenesis pathway and related regulated gene expression and steroid hormone secretion profiles. Our results reveal that nuclear receptors PXR, SR-B1 and LHR are sensitive to PFOA exposure. PFOA can accumulate in mitochondria and alter cholesterol precursor (fatty acid) mitochondrial transport process-related gene expression and thus inhibit steroid hormone precursor (cholesterol) production. In particular, PFOA exhibits biphasic effects on testosterone and progesterone production at differing levels of exposure. These findings indicate the potential endocrine-related effects of PFOA on steroid hormone secretion in Leydig cells and point to a novel disruption model.

Dietary Phytochemicals and Endrocrine-related Activities: An Update.

Phytochemicals are non-nutrient bioactive compounds occurring in plants and food, which possess the capacity to modulate one or more metabolic processes or pathways in the body, resulting to health benefits and promotion of well-being. The interest of the scientific community continues to grow, powered by progressive research efforts to identify properties and potential applications of bioactive substances, and coupled with public interest and consumer demand. However, the natural derivation of these compounds is not a feature of harmlessness, over that of therapeutic efficacy, to which is also added the absence of post-marketing monitoring which does not allow to evaluate the occurrence of adverse effects related to the use of their related products. The literature is particularly rich of studies concerning phytochemicals as environmental estrogens, which result in infertility, reproductive abnormalities, and tumors but also in some endocrine-related health effects. Nevertheless, further studies have been performed to better understand the bioavailability, pharmacokinetics and mode of action of these compounds which seems to go beyond their ability to bind to oestrogen receptors and either stimulate or inhibit the activity of endogenous oestrogens, highlighting new interesting target molecules and signaling pathways. The present review summarizes the latest developments and knowledge concerning the assessment of endocrine activities of dietary phytochemicals focusing on pharmacological aspects.

Prescribing in pregnancy

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant, which may possess endocrine disrupting properties. Herein, we investigated the possible mechanism(s) of toxicity and steroidogenesis in mouse Leydig cells. MLTC-1 (mouse Leydig tumour cells) cells were exposed to 0, 50, 100 or 200 μM PFOA for 48 h to ascertain their effects on the nuclear (membrane) receptor responses, steroidogenesis pathway and related regulated gene expression and steroid hormone secretion profiles. Our results reveal that nuclear receptors PXR, SR-B1 and LHR are sensitive to PFOA exposure. PFOA can accumulate in mitochondria and alter cholesterol precursor (fatty acid) mitochondrial transport process-related gene expression and thus inhibit steroid hormone precursor (cholesterol) production. In particular, PFOA exhibits biphasic effects on testosterone and progesterone production at differing levels of exposure. These findings indicate the potential endocrine-related effects of PFOA on steroid hormone secretion in Leydig cells and point to a novel disruption model.

Impact of bisphenol A (BPA) on early embryo development in the marine mussel Mytilus galloprovincialis: Effects on gene transcription

Bisphenol A (BPA), a monomer used in plastic manufacturing, is weakly estrogenic and a potential endocrine disruptor in mammals. Although it degrades quickly, it is pseudo-persistent in the environment because of continual inputs, with reported concentrations in aquatic environments between 0.0005 and 12 μg/L. BPA represents a potential concern for aquatic ecosystems, as shown by its reproductive and developmental effects in aquatic vertebrates.In invertebrates, endocrine-related effects of BPA were observed in different species and experimental conditions, with often conflicting results, indicating that the sensitivity to this compound can vary considerably among related taxa. In the marine mussel Mytilus galloprovincialis BPA was recently shown to affect early development at environmental concentrations. In this work, the possible effects of BPA on mussel embryos were investigated at the molecular level by evaluating transcription of 13 genes, selected on the basis of their biological functions in adult mussels. Gene expression was first evaluated in trocophorae and D-veligers (24 and 48 h post fertilization) grown in physiological conditions, in comparison with unfertilized eggs. Basal expressions showed a general up-regulation during development, with distinct transcript levels in trocophorae and D-veligers. Exposure of fertilized eggs to BPA (10 μg/L) induced a general upregulation at 24 h pf, followed by down regulation at 48 h pf. Mytilus Estrogen Receptors, serotonin receptor and genes involved in biomineralization (Carbonic Anydrase and Extrapallial Protein) were the most affected by BPA exposure. At 48 h pf, changes in gene expression were associated with irregularities in shell formation, as shown by scanning electron microscopy (SEM), indicating that the formation of the first shelled embryo, a key step in mussel development, represents a sensitive target for BPA. Similar results were obtained with the natural estrogen 17β-estradiol. The results demonstrate that BPA and E2 can affect Mytilus early development through dysregulation of gene transcription.

A human source for ELF magnetic perturbations

ABSTRACTCurrent models that frame consciousness in terms of electromagnetic field theory carry implications that have yet to be fully explored. Endogenous weak extremely low frequency (ELF) magnetic fields are generated by ionic charge flow in axons, dendrites and synaptic transmitters. Because neural tissues are transparent to such fields, these provide the basis for the globally unifying qualities required to properly describe consciousness as a field. At the same time, however, an electromagnetic approach predicts partial transmission of this 1–100 nT field, suggesting external interactions similar to the various ELF magnetic perturbations that are linked to homeostatic and endocrine-related physiological effects. It follows that humans may represent an additional, previously unrecognized source of weak (1–10 nT) ambient ELF magnetic fields.

Transcriptional changes in steroidogenesis by perfluoroalkyl acids (PFOA and PFOS) regulate the synthesis of sex hormones in H295R cells

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are two of the most widely used perfluoroalkyl acids (PFAAs). Because of their strong persistence, they have become widely distributed throughout the environment and human bodies. PFOA and PFOS are suspected to disrupt the endocrine system based upon many in vivo studies, but the underlying mechanisms are currently unclear. In this study, we investigated the endocrine-related effects of PFOA and PFOS using in vitro estrogen receptor (ER) and androgen receptor (AR) transactivation assays and steroidogenesis assay. The results showed that PFOA and PFOS exhibited weak antagonistic ER transactivation but did not exhibit agonistic ER or AR transactivation. In the steroidogenesis assay, PFOA and PFOS induced 17β-estradiol (E2) level and reduced testosterone level, which would be caused by the induction of aromatase activity. The qPCR analysis of genes involved in steroidogenesis indicates that PFOA and PFOS associate with sex hormone synthesis by the transcriptional induction of two genes, cyp19 and 3β-hsd2. Moreover, the transcriptional induction of cyp11b2 by PFOS suggests that this chemical may underlie the disruption of several physiological functions related to aldosterone. The results of the current study suggest that PFOA and PFOS are potential endocrine disrupting chemicals (EDCs) and provide information for further studies on the molecular events that initiate the adverse endocrine effects.

Concentrations of levonorgestrel and ethinylestradiol in wastewater effluents: Is the progestin also cause for concern?

Synthetic hormones have been widely reported in treated sewage effluents, and consequently receiving aquatic environments. Ethinylestradiol (EE2) is a potent synthetic estrogen commonly used in conjunction with levonorgestrel in oral contraceptive pills. Both EE2 and levonorgestrel have been identified in the aquatic environment, but although there is a significant amount of literature on EE2, there is much less information on levonorgestrel. Using Australian prescription data as well as excretion and predicted wastewater removal rates, the concentrations of EE2 and levonorgestrel in Australian wastewater were calculated at 0.1 ng/L to 0.5 ng/L and 0.2 ng/L to 0.6 ng/L, respectively. Both compounds were analyzed in treated wastewater and surface water grab samples from 3 Southeast Queensland, Australia sites. The predicted no-effect concentration (PNEC) for EE2 of 0.1 ng/L was exceeded at most sites, with EE2 concentrations up to 2 ng/L in treated effluent, albeit quickly diluted to 0.1 ng/L to 0.2 ng/L in the receiving environment. A provisional PNEC for levonorgestrel of 0.1 ng/L derived in the present study was slightly lower than predicted effluent concentrations of 0.2 ng/L to 0.6 ng/L, indicating a potential risk of endocrine-related effects in exposed aquatic species. The detection limit for levonorgestrel in the present study was 2.5 ng/L, and all samples were below detection limit. The present study's results suggest that improvements in analytical capabilities for levonorgestrel are warranted to more accurately quantify the risk of this compound in the receiving environment. Environ Toxicol Chem 2016;35:1378-1385. © 2015 SETAC.

Transcriptomic changes underlie altered egg protein production and reduced fecundity in an estuarine model fish exposed to bifenthrin

Pyrethroid pesticides are a class of insecticides found to have endocrine disrupting properties in vertebrates such as fishes and in human cell lines. Endocrine disrupting chemicals (EDCs) are environmental contaminants that mimic or alter the process of hormone signaling. In particular, EDCs that alter estrogen and androgen signaling pathways are of major concern for fishes because these EDCs may alter reproductive physiology, behavior, and ultimately sex ratio. Bifenthrin, a pyrethroid with escalating usage, is confirmed to disrupt estrogen signaling in several species of fish, including Menidia beryllina (inland silverside), an Atherinid recently established as a euryhaline model. Our main objective was to broadly assess the molecular and physiological responses of M. beryllina to the ng/L concentrations of bifenthrin typically found in the environment, with a focus on endocrine-related effects, and to discern links between different tiers of the biological hierarchy. As such, we evaluated the response of juvenile Menidia to bifenthrin using a Menidia-specific microarray, quantitative real-time polymerase chain reaction (qPCR) on specific endocrine-related genes of interest, and a Menidia-specific ELISA to the egg-coat protein choriogenin, to evaluate a multitude of molecular-level responses that would inform mechanisms of toxicity and any underlying causes of change at higher biological levels of organization. The sublethal nominal concentrations tested (0.5, 5 and 50ng/L) were chosen to represent the range of concentrations observed in the environment and to provide coverage of a variety of potential responses. We then employed a 21-day reproductive assay to evaluate reproductive responses to bifenthrin (at 0.5ng/L) in a separate group of adult M. beryllina. The microarray analysis indicated that bifenthrin influences a diverse suite of molecular pathways, from baseline metabolic processes to carcinogenesis. A more targeted examination of gene expression via qPCR demonstrated that bifenthrin downregulates a number of estrogen-related transcripts, particularly at the lowest exposure level. Choriogenin protein also decreased with exposure to increasing concentrations of bifenthrin, and adult M. beryllina exposed to 0.5ng/L had significantly reduced reproductive output (fertilized eggs per female). This reduction in fecundity is consistent with observed changes in endocrine-related gene expression and choriogenin production. Taken together, our results demonstrate that environmental concentrations of bifenthrin have potential to interfere with metabolic processes, endocrine signaling, and to decrease reproductive output.

Toxic Metal Exposure and Associations with Thyroid and Reproductive Hormone Levels in Pregnant Women Living in Northern Puerto Rico: the PROTECT Study

Toxic metals have been found to be reproductive toxicants as well as suspected endocrine disruptors. Effects on the endocrine and reproductive systems of metals in pregnant women have not yet been thoroughly evaluated. The present exploratory study evaluates the possible relationship between metal exposure and thyroid (thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4)), and sexual hormones (estradiol (E2), progesterone (PROG), sex hormone binding-globulin (SHBG)), among pregnant women participating in a birth cohort study examining the role of environmental toxicants and preterm birth in northern Puerto Rico. Biological samples were collected during two time points in pregnancy (N=133 samples from 84 women). Maternal whole blood samples were analyzed for concentrations of toxic metals (arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb), mercury (Hg), and manganese (Mn) using an inductively coupled plasma-high resolution mass spectrometer. Hormone levels were measured in serum using LC-MS/MS (FT3, FT4) or immunoassay (all others). Linear mixed models were used in preliminary analyses to estimate the association between metals and hormones. After adjusting for maternal age, income, and marital status, Hg concentrations showed statistically significant inverse associations with SHBG (p=0.02). Increases in FT4 and TSH were associated with As exposure (p&lt;0.10); Cd exposure was also associated with increased FT4 (p=0.05). Cr exposure was suggestively associated with decreases in E2, PROG, and SHBG (p&lt;0.10) and As suggested inverse associations with E2 and PROG (p&lt;0.10) but only in unadjusted models. These results may indicate that toxic metals could contribute to endocrine disruption in pregnant women. Given the potential threat of metal exposure from Superfund contaminated sites, associations reported here could indicate a contribution to endocrine-related effects from metals which could lead to adverse reproductive outcomes.

BPA from dental resin material: where are we going with restorative and preventive dental biomaterials?

Since a number of years, the question of the impact of BPA released from dental resins and/or sealants (or other dental materials) is open. These materials contain different monomers and many additives that are used to induce or inhibit the polymerization reaction. The monomers are mainly urethane dimethacrylate, BPA glycidyl dimethacrylate (Bis-GMA), its ethoxylated version (Bis-EMA), and BPA dimethacrylate (Bis-DMA). Comonomers such as triethylene glycol dimethacrylate are used to dilute the thick consistency and provide a higher degree of cure because of their relatively lower molecular weight [1]. BPA is used in the manufacturing process of Bis-GMA, Bis-EMA, and Bis-DMA or other similar molecules, and thus, minute amounts of BPA residuesmay be present in the final material. Interestingly, it has been shown that some patients treated with Bis-DMA containing materials present salivary and urinary BPA concentrations two to tenfold higher than control patients [2], which, however, decreased to almost normal after 24 h. For Bis-GMA materials, very small amounts of BPA could be detected in saliva and only neglectable amounts in urine, which also decreased 24 h after placement. It has been published that BPA may act as an endocrine disruptor (ED), thus being able to alter functions of the endocrine system and cause adverse health effects to an intact organism or its progeny (World Health Organization (WHO) definition 2002). EDs with an estrogenic activity have been proposed to be associated with estrogenic effects such as testicular dysgenesis, inducing testicular, prostate, and mammary gland cancers, impairing semen quality, diabetes, and obesity [3]. Some authors [3–5] claim that a series of diseases including cancer risks, type 2 diabetes, obesity, and developmental impairments are related to exposure towards BPA [3–5]. In human cross-sectional studies, BPA plasma or urine concentrations were reported to be associated among others with prostate dysplasias and abnormal birth weight [4]. A main problem in this context is the correct chemical analysis of BPA, the sensitivity of the analytical methods, and the question of BPA conjugation/glucoronization. Whereas the measurements in urine may be considered reliable, unconjugated BPA is apparently difficult to be measured in plasma because the sensitivity of the methods may not allow the measure the concentrations in the picogram per milliliter range. It is accepted that reported results in plasma/serum may be artifacts due to external contamination of the samples. Experimental studies in animals could not confirm results from reported observational studies in humans and showed general toxicity of BPA of doses above 5 mg/kg bw/day. Proliferation of mammary gland at doses of 400 μg/kg bw/day in monkeys [6] and behavioral effects in rodents at the same dose level. Although there are effects to be noted in in vitro studies on cell and tissue cultures and in vivo animal experiments, which may indicate adverse endocrine related effects due to BPA, it is still difficult to extrapolate these findings to the human clinical situation. Its precise mechanism of action is still not clear, as the signaling pathways seem to be dependent on the BPA concentrations. However, its functional interaction with estrogen receptors has been recently demonstrated and could explain at least in part its endocrine disrupting effects [4]. In the EU, USA, and Canada, BPA was banned from feeding bottles. M. Goldberg (*) : S. Dimitrova-Nakov INSERM UMR-S U747 (Equipe 5) & Faculte des Sciences Fondamentales et Biomedicales, Universite Paris Descartes, 45 rue des Saints Peres, 75270 Paris Cedex 06, France e-mail: mgoldberg.goldberg004@gmail.com

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10–12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The “No Observed Adverse Effect Level” for systemic toxicity was 300 ppm in both males (16.6mg/kg/day) and females (20.6mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science

The Impact of Endocrine Disruption: A Consensus Statement on the State of the Science

Antipsychotic Interventions in Prodromal Psychosis

In recent years, psychopharmacological intervention in prodromal psychosis, also known as the ultra-high risk (UHR) mental state for psychosis, has attracted much attention. Whilst it has been shown that antipsychotic use in UHR individuals may be effective in potentially delaying or even averting progression to frank psychosis, their use in subjects that do not necessarily convert to psychosis has raised considerable ethical concerns because of their adverse effects. Recent treatment guidelines for patients at UHR for psychosis recommend the use of antipsychotics only in exceptional conditions and with great precautions. To date only a few studies have investigated the use of antipsychotic medications in UHR patients and the potential benefits and risks related to their use in prodromal psychosis remain unclear. We review here all published studies that included UHR patients treated with antipsychotics, regardless of study design. These studies were all of second-generation antipsychotics, given that first-generation antipsychotics cannot be recommended because of their adverse drug reactions. We specifically examine the available descriptions of adverse reactions of the individual antipsychotic medication in each study and discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in UHR patients. Clinical trials to date investigating potential benefits of antipsychotic treatments in preventing transition to psychosis were of relatively short duration and have involved a small number of patients. Whilst it appears that pharmacological intervention at this stage may be effective in both reducing the psychopathology and decreasing transition rates, and is potentially safe, in the absence of sufficient evidence-based knowledge to guide treatment, definitive clinical recommendations and guidelines cannot be derived. Certain adverse events take time to develop, such as metabolic syndrome and endocrine-related effects, thus longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events. This can inform the development of timely strategies to prevent serious negative impacts and thus maximize the benefits of antipsychotic intervention in UHR patients that outweigh the risks associated with their use.