Endocrine-disrupting Activity Research Articles

Ambient Exposure to Agricultural Pesticides during Pregnancy and Risk of Cerebral Palsy: A Population-Based Study in California.

Cerebral palsy (CP) is the most common neuro-motor disability in young children. Disruptions of maternal hormone function during pregnancy have been linked to CP risk. We investigated whether prenatal exposure to pesticide compounds with endocrine-disrupting action affect CP risk. We conducted a case-control study of 3905 CP cases and 39,377 controls born between 1998 and 2010 in California to mothers who lived in proximity (within 2 km) to any agricultural pesticide application recorded in the California Pesticide Use Reporting (PUR) system. We focused on 23 pesticides considered endocrine disruptors that are frequently used, and we found that exposure to any of the 23 pesticides in the first trimester was associated with elevated CP risks in female offspring (OR = 1.19; 95% CI: 1.05–1.35) but not males (OR = 0.99; 95% CI: 0.89–1.09) compared to the unexposed offspring. Positive associations were estimated for 15 pesticides suspected to affect the estrogen and 7 pesticides suspected to affect the thyroid hormone system. Our study suggests that first trimester exposure to pesticides that are suspected endocrine disruptors are associated with CP risk in female offspring. Pesticide exposures in early pregnancy may have sex-specific influences on the neuro-motor development of the fetus by interfering with endocrine systems.

Carbendazim-induced androgen receptor expression antagonized by flutamide in male rats

Carbendazim, a widely used fungicide, exhibits reproductive and developmental toxicity. The objective of this study was to investigate the expression of androgen receptor induced by carbendazim and the antagonistic effect of flutamide. Rats were treated with carbendazim, flutamide or a combination of both to measure androgen receptor mRNA, immune activity and protein expression. Carbendazim treatment increased androgen receptor mRNA in a dose-dependent manner, while flutamide, an androgen receptor antagonist, blocked the androgen receptor mRNA. Co-treatment with carbendazim and various flutamide doses decreased the androgen receptor mRNA in a dose-dependent manner. Conversely, co-treatment with flutamide and various carbendazim doses increased the androgen receptor mRNA in a dose-dependent manner. Immunohistochemistry and Western blot analyses showed that carbendazim increased androgen receptor activity (especially in rat testes) in a dose-dependent manner, while flutamide decreased it. Furthermore, carbendazim or flutamide treatment for 7 days increased testosterone and follicular stimulating hormone concentrations in the serum of male rats in a dose-dependent manner, which might involve the disruption of the androgen receptor. Although we need to examine the exact mechanism of androgen receptor involved in the reproductive toxicity and endocrine-disrupting activity induced by carbendazim and its parent, benomyl, we should first discuss how to take advantage of flutamide antagonism on carbendazim-induced reproductive and endocrine-disrupting activity possibly in human. In summary, carbendazim induced androgen receptor expression in mRNA and protein levels, while flutamide antagonized this effect. This is the first report on the antagonistic effect of flutamide on the carbendazim-androgenic effect on mRNA and protein levels. The results would help to clarify the mechanism of carbendazim- and chemical-induced developmental toxicity and endocrine-disrupting activity.

Bacterial community composition and function succession under aerobic and anaerobic conditions impacts the biodegradation of 17β-estradiol and its environmental risk

The widespread detection of 17β-estradiol (E2) in the environment has become an emerging concern worldwide due to its endocrine disrupting effects. This work focuses on the aerobic and anaerobic biodegradations of E2 in various sedimentary environments with different availabilities of electron acceptors, including O2, NO3−, Fe3+, SO42−, or HCO3−. The highest removal efficiency (98.9%) and shortest degradation half-life of E2 (t1/2 = 5.0 d) were achieved under aerobic condition, followed by nitrate-reducing, ferric-reducing, sulfate-reducing and methanogenic conditions. We propose four different degradation pathways of E2 based on the metabolites identified under various redox conditions. Although most of E2 was effectively removed under aerobic condition, the potential environmental risk still needs to be considered due to the residual estrogenic activity induced by estrone (E1) formation. The endocrine-disrupting activities, as indicated by estradiol equivalent (EEQ) values, were related to E2 degradation rate and metabolite formation. We further analyzed the succession of bacterial community compositions and functions using Illumina HiSeq sequencing and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). The findings herein evidenced that bacterial community compositions and metabolic functions associated with different redox conditions impact the biodegradation of E2 and its endocrine-disrupting activity. This knowledge will be useful in predicting the environmental fates of estrogenic hormones in various sedimentary environments and aid in establishing appropriate strategies for eliminating potential environmental risks.

Nonylphenol ethoxylates biodegradation increases estrogenicity of textile wastewater in biological treatment systems

The formation of estrogenic intermediates, i.e. nonylphenol diethoxylate (NP2EO), nonylphenol monoethoxylate (NP1EO), and nonylphenol (NP), following nonylphenol ethoxylates (NPEOs) biodegradation in textile wastewater raises concerns about its endocrine disruptive activity, but the estrogenicity changes of textile wastewater throughout biological treatment processes remain unknown. In the present study, the estrogenicity of textile wastewater sampled from 10 wastewater treatment plants (WWTPs) were investigated using the reporter gene-based T47D-KBluc bioassay. Results showed that the estrogenicity of the textile wastewater significantly increased after either anaerobic or aerobic treatment in all WWTPs, with an average fold change of 3.21, although traditional pollutants were effectively removed. The estradiol equivalents of the effluent (ranging from 1.50 to 4.12 ng-E2/L) were generally higher than published effect based trigger values, indicating an increased risk for the receiving waters. Removal efficiency was high (84.46%) for NPEOs, but was low for NP2EO and NP1EO in the biological treatment processes. Nevertheless, NP had increased concentrations after the treatment. Bioanalytical equivalent concentration of the textile wastewater and that of NP2EO, NP1EO, and NP showed a good linear correlation, of which NP alone contributed more than 70% to the observed estrogenicity. Extending hydraulic retention time was found effective in reducing the estrogenicity as it allows relatively complete degradation of NP, which was further confirmed by running lab-scale A/O reactors fed with NP10EO. The results may extend our knowledge regarding the estrogenicity of textile wastewater and its reduction technologies used in WWTPs.

Structural studies on the endocrine-disrupting role of polybrominated diphenyl ethers (PBDEs) in thyroid diseases.

Polybrominated diphenyl ethers (PBDEs) are synthetic brominated flame retardants with extensive applications in daily-life consumer products. However, PBDEs have become ubiquitous environmental contaminants due to their leach-out capability. The hazardous human health effects and endocrine-disrupting activity of PBDEs have led many governmental organizations to impose ban on their manufacture, causing their gradual phase out from commercial products. However, PBDEs and their metabolites are still being detected from biological and environmental samples owing to their persistence and bioaccumulation. The PDBE metabolites in these samples are present in concentrations often higher and even with higher toxic potential than parent PBDEs. The two commonly detected environmental PBDE congeners, 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47) and 2,2',4,4',5-penta-bromodiphenyl ether (BDE-99), and their HO- and MeO- metabolites were considered in this study for their potential disrupting activity on thyroid hormone transport. Specifically, the study involved structural binding characterization of BDE-47 and BDE-99 including their two HO- and two MeO- metabolites with thyroxine-binding globulin (TBG), which is the main thyroid hormone transport protein in blood. The results showed that the binding pattern and molecular interactions of above two PBDEs and their metabolites exhibited overall similarity to native ligand, thyroxine in dock score, binding energy, and amino acid interactions with TBG. The BDE-99 and its metabolites were predicted to have stronger binding to TBG than BDE-47 with the metabolite 5-MeO-BDE-99 showing equal binding affinity to that of thyroxine. It is concluded that BDE-47 and BDE-99 and their metabolites have the potential to disrupt thyroid hormone transport and interfere in thyroid function.

Exposure to Low Doses of Dechlorane Plus Promotes Adipose Tissue Dysfunction and Glucose Intolerance in Male Mice.

The prevalence of type 2 diabetes (T2D) continues to increase worldwide. It is well established that genetic susceptibility, obesity, overnutrition and a sedentary life style are risk factors for the development of T2D. However, more recently, studies have also proposed links between exposure to endocrine-disrupting chemicals (EDCs) and altered glucose metabolism. Human exposure to environmental pollutants that are suspected to have endocrine disruptor activity is ubiquitous. One such chemical is Dechlorane Plus (DP), a flame retardant, that is now detected in humans and the environment. Here we show that exposure of mice to low, environmentally relevant doses of DP promoted glucose intolerance in mice fed a high-fat diet independent of weight gain. Furthermore, DP had pronounced effects on the adipose tissue, where it induced the development of hypertrophied white adipose tissue (WAT), and increased serum levels of resistin, leptin, and plasminogen activator inhibitor-1. In addition, DP exposure induced "whitening" of brown adipose tissue (BAT), and reduced BAT uncoupling protein 1 expression. Importantly, some of these effects occurred even when the mice were fed a regular, low-fat, diet. Finally, WAT adipogenic markers were reduced with DP treatment in the WAT. We also show that DP directly inhibited insulin signaling in murine adipocytes and human primary subcutaneous adipocytes in vitro. Taken together, our results show that the exposure to low and environmentally relevant levels of DP may contribute to the development of T2D.

Long-term exposure to low 17α-ethinylestradiol (EE2) concentrations disrupts both the reproductive and the immune system of juvenile rainbow trout, Oncorhynchus mykiss

Estrogenic endocrine disrupting compounds (EEDCs), such as ethinylestradiol (EE2), are well studied for their impact on the reproductive system of fish. EEDCs may also impact the immune system and, as a consequence, the disease susceptibility of fish. It is currently not yet known whether the low concentrations of EEDCs that are able to disrupt the reproductive system of trout are effective in disrupting the immune system and the fish host resistance towards pathogens, too, or whether such immunodisruptive effects would occur only at higher EEDC concentrations. Therefore, in the present study we compare the effect thresholds of low 17α-ethinylestradiol concentrations (1.5 and 5.5 EE2 ng/L) on the reproductive system, the immune system, the energy expenditures and the resistance of juvenile rainbow trout (Oncorhynchus mykiss) against the parasite Tetracapsuloides bryosalmonae – the etiological agent of proliferative kidney disease (PKD) of salmonids. The parasite infection was conducted without injection and under low pathogen exposure concentrations. The disease development was followed over 130 days post infection – in the presence or absence of EE2 exposure. The results show that the long-term EE2 exposure affected, at both concentrations, reproductive parameters like the mRNA levels of hepatic vitellogenin and estrogen receptors. At the same concentrations, EE2 exposure modulated the immune parameters: mRNA levels of several immune genes were altered and the parasite intensity as well as the disease severity (histopathology) were significantly reduced in EE2-exposed fish compared to infected control fish. The combination of EE2 exposure and parasite infection was energetically costly, as indicated by the decreased values of the swim tunnel respirometry. Although further substantiation is needed, our findings suggest that EE2 exerts endocrine disruptive and immunomodulating activities at comparable effect thresholds, since reproductive and immune parameters were affected by the same, low EE2 concentrations.

Proteome changes induced by a short, non-cytotoxic exposure to the mycoestrogen zearalenone in the pig intestine

Intestinal epithelial homeostasis is regulated by a complex network of signaling pathways. Among them is estrogen signaling, important for the proliferation and differentiation of epithelial cells, immune signaling and metabolism. The mycotoxin zearalenone (ZEN) is an estrogen disruptor naturally found in food and feed. The exposure of the intestine to ZEN has toxic effects including alteration of the immune status and is possibly implicated in carcinogenesis, but the molecular mechanisms linked with these effects are not clear. Our objective was to explore the proteome changes induced by a short, non-cytotoxic exposure to ZEN in the intestine using pig jejunal explants. Our results indicated that ZEN promotes little proteome changes, but significantly related with an induction of ERα signaling and a consequent disruption of highly interrelated signaling cascades, such as NF-κB, ERK1/2, CDX2 and HIF1α. The toxicity of ZEN leads also to an altered immune status characterized by the activation of the chemokine CXCR4/SDF-1 axis and an accumulation of MHC-I proteins. Our results connect the estrogen disrupting activity of ZEN with its intestinal toxic effect, associating the exposure to ZEN with cell-signaling disorders similar to those involved in the onset and progression of diseases such as cancer and chronic inflammatory disorders. SignificanceThe proteomics results presented in our study indicate that the endocrine disruptor activity of ZEN is able to regulate a cascade of highly inter-connected signaling events essential for the small intestinal crypt-villus cycle and immune status. These molecular mechanisms are also implicated in the onset and progress of intestinal immune disorders and cancer indicating that exposure to ZEN could play an important role in intestinal pathogenesis.

An Aerobic Hybrid Phthalate Degradation Pathway via Phthaloyl-Coenzyme A in Denitrifying Bacteria.

The degradation of the xenobiotic phthalic acid esters by microorganisms is initiated by the hydrolysis to the respective alcohols and ortho-phthalate (hereafter, phthalate). In aerobic bacteria and fungi, oxygenases are involved in the conversion of phthalate to protocatechuate, the substrate for ring-cleaving dioxygenases. In contrast, anaerobic bacteria activate phthalate to the extremely unstable phthaloyl-coenzyme A (CoA), which is decarboxylated by oxygen-sensitive UbiD-like phthaloyl-CoA decarboxylase (PCD) to the central benzoyl-CoA intermediate. Here, we demonstrate that the facultatively anaerobic, denitrifying Thauera chlorobenzoica 3CB-1 and Aromatoleum evansii KB740 strains use phthalate as a growth substrate under aerobic and denitrifying conditions. In vitro assays with extracts from cells grown aerobically with phthalate demonstrated the succinyl-CoA-dependent activation of phthalate followed by decarboxylation to benzoyl-CoA. In T. chlorobenzoica 3CB-1, we identified PCD as a highly abundant enzyme in both aerobically and anaerobically grown cells, whereas genes for phthalate dioxygenases are missing in the genome. PCD was highly enriched from aerobically grown T. chlorobenzoica cells and was identified as an identical enzyme produced under denitrifying conditions. These results indicate that the initial steps of aerobic phthalate degradation in denitrifying bacteria are accomplished by the anaerobic enzyme inventory, whereas the benzoyl-CoA oxygenase-dependent pathway is used for further conversion to central intermediates. Such a hybrid pathway requires intracellular oxygen homeostasis at concentrations low enough to prevent PCD inactivation but sufficiently high to supply benzoyl-CoA oxygenase with its cosubstrate.IMPORTANCE Phthalic acid esters (PAEs) are industrially produced on a million-ton scale per year and are predominantly used as plasticizers. They are classified as environmentally relevant xenobiotics with a number of adverse health effects, including endocrine-disrupting activity. Biodegradation by microorganisms is considered the most effective process to eliminate PAEs from the environment. It is usually initiated by the hydrolysis of PAEs to alcohols and o-phthalic acid. Degradation of o-phthalic acid fundamentally differs in aerobic and anaerobic microorganisms; aerobic phthalate degradation heavily depends on dioxygenase-dependent reactions, whereas anaerobic degradation employs the oxygen-sensitive key enzyme phthaloyl-CoA decarboxylase. We demonstrate that aerobic phthalate degradation in facultatively anaerobic bacteria proceeds via a previously unknown hybrid degradation pathway involving oxygen-sensitive and oxygen-dependent key enzymes. Such a strategy is essential for facultatively anaerobic bacteria that frequently switch between oxic and anoxic environments.

Silver nanoparticles compromise the development of mouse pubertal mammary glands through disrupting internal estrogen signaling

Despite numerous studies on the environmental health and safety (EHS) of silver nanoparticles (AgNPs), most studies looked into their gross toxicities with rather limited understanding on their labyrinthine implicit effects on the target sites, such as the endocrine system. Burgeoning evidence documents the disrupting effects of AgNPs on endocrine functions; however, little research has been invested to recognize the potential impacts on the mammary gland, a susceptible estrogen-responsive organ. Under this setting, we here aimed to scrutinize AgNP-induced effects on the development of pubertal mammary glands at various concentrations that bear significant EHS relevance. We unearthed that AgNPs could accumulate in mouse mammary glands and result in a decrease in the percentage of ducts and terminal ducts in the adult mice after chronic exposure. Strikingly, smaller sized AgNPs showed greater capability to alter the pubertal mammary development than larger sized particles. Intriguingly, mechanistic investigation revealed that the reduction of epithelial proliferation in response to AgNPs was ascribed to reduced ERα expression, which, at least partially, accounted for diseased epithelial morphology in mammary glands. Meanwhile, the decline in fibrous collagen deposition around the epithelium was found to contribute to the compromised development of mammary glands under the exposure of AgNPs. Moreover, as an extension of the mechanism, AgNPs diminished serum levels of estradiol in exposed animals. Together, these results uncovered a novel toxicity feature of AgNPs: compromised development of mouse pubertal mammary glands through the endocrine-disrupting actions. This study would open a new avenue to unveil the EHS impacts of AgNPs.

The impact of endocrine disruptor chemicals on oocyte/embryo and clinical outcomes in IVF.

The negative impact of endocrine-disrupting pesticides on human fertility is now a key issue in reproductive health. There are much fewer literature data about the impact of pesticide exposure on women than on men and very few studies of women participating in an in vitro fertilization (IVF) programme. In the present review, we found that (1) various pesticides with an endocrine-disrupting action are associated with poor oocyte maturation and competency, embryonic defects and poor IVF outcomes, and (2) some pesticide compounds are linked to specific causes of female infertility, such as premature ovarian insufficiency, polycystic ovarian syndrome, and endometriosis. IVF participants living in agricultural regions should be informed about the fertility decline, low ongoing pregnancy rates, and elevated risk of miscarriage associated with exposure to high doses of pesticides.

Innovative Bio-Based Organic UV-A and Blue Light Filters from Meldrum's Acid.

Faced with the ban of some organic UV filters such as octinoxate or avobenzone, especially in Hawaii, it became essential to offer new alternatives that are both renewable and safe for humans and the environment. In this context, a class of bio-based molecules displaying interesting UV filter properties and great (photo)stability has been developed from Meldrum’s acid and bio-based and synthetic p-hydroxycinnamic acids, furans and pyrroles. Moreover, p-hydroxycinnamic acid-based Meldrum’s derivatives possess valuable secondary activities sought by the cosmetic industry such as antioxidant and anti-tyrosinase properties. The evaluation of the properties of mixture of judiciously chosen Meldrum’s acid derivatives highlighted the possibility to modulate secondary activity while maintaining excellent UV protection. Meldrum’s acid derivatives are not only competitive when benchmarked against organic filters currently on the market (i.e., avobenzone), but they also do not exhibit any endocrine disruption activity.

Endocrine disruption: Molecular interactions of environmental bisphenol contaminants with thyroid hormone receptor and thyroxine-binding globulin.

Many bisphenol A (BPA) analogs have been commercially used recently, such as 2,2-bis(4-hydroxyphenyl)butane (BPB), 4,4'-ethylidenebisphenol, 4,4'-methylenediphenol (BPF), 4,4'-(1,4-phenylenediisopropylidene)bisphenol (BPP), 4,4'-dihydroxydiphenyl sulfone (BPS), 4,4'-cyclohexylidenebisphenol (BPZ), 4,4'-(hexafluoroisopropylidene)diphenol (BPAF), 4,4'-(1-phenylethylidene)bisphenol (BPAP), and 2,2-bis(4-hydroxy-3,5-dimethylphenyl)propane (TMBPA), to circumvent adverse effects of BPA. However, their increasing use is also contaminating the environment, which is a potential cause of concern for human health. Thyroid hormone transport and signaling are potential targets for endocrine-disrupting activity of BPA analogs. Thyroxine-binding globulin (TBG) is the major carrier protein for thyroxine (T4) and triiodothyronine (T3) in blood. Thyroid hormones exert their action through thyroid hormone receptors (TRα and TRβ). This report presents the thyroid-disrupting potential of indicated nine BPA analogs from structure-based studies with TBG and TRα. Each BPA analog formed important polar and hydrophobic interactions with a number of residues of TBG and TRα. Majority of TBG residues (77-100%) and TRα residues (70-91%) interacting with BPA analogs were common with those of native ligands T4 and T3, respectively. Majority of BPA analogs interacted with TBG forming a salt bridge interaction at Lys-270. The hydrogen-bonding interaction of T3 with TRα at His-381 was also shared by majority of analogs. The binding energy for BPP, BPB, BPZ, BPAP, and TMBPA with both proteins was closer to binding energy of respective native ligands. The similarity in structural binding characteristics suggested potential disrupting activity of thyroid hormone signaling and transport.

Water Stable Heterometallic Zn-Tb Coordination Polymer for Rapid Detection of the Ultraviolet Filter Benzophenone.

Benzophenone (BP) is an ultraviolet filter (UVF) widely used in personal care products such as sunscreens and cosmetics. Excessive exposure to BP-type UVFs is a potential threat to human's health because of their endocrine-disrupting activity. Water stability of lanthanide compounds is crucial when they serve as luminescent sensors because of the practicality and recyclability. In this study, a water-stable luminescent Zn-Tb heterometallic coordination polymer was rationally designed and synthesized for rapid detection of BP. This material showed a high quenching effect, excellent selectivity, and fast response toward BP.

ALTERATION OF MITOCHONDRIAL MEMBRANE POTENTIAL (ΔΨM): POTENTIAL ROLE IN THE MECHANISM OF MEHP‐INDUCED INHIBITION OF STEROID BIOSYNTHESIS IN MA‐10 LEYDIG CELLS

INTRODUCTION AND OBJECTIVESMono‐(2‐ethylhexyl) phthalate (MEHP) is the active metabolite of di‐(2‐ethylhexyl) phthalate (DEHP), a plasticizer with endocrine disruptor activity that is widely used in the manufacturing industry. MEHP inhibits luteinizing hormone (LH)‐stimulated steroid biosynthesis in Leydig cells by molecular mechanisms that remain unclear. In the present study, using MA‐10 mouse tumor Leydig cells, we examined changes in mitochondrial function caused by MEHP exposures in relationship to possible link to alteration of progesterone biosynthesis.METHODSThe effect of MEHP on LH‐stimulated progesterone production was assessed after treating MA‐10 cells with (0–300 μM) MEHP for 24 hrs. Progesterone production was quantified by enzyme‐linked immunosorbent assay (ELISA). To measure oxygen consumption, cells were treated with MEHP (0–300 μM) for 24 hrs, and oxygen consumption was monitored using a Clarke‐type oxygen electrode. Mitochondrial membrane potential (ΔΨm) was assessed using the JC‐1 dye mitochondrial membrane potential indicator. Mitochondria‐derived superoxide was measured using the MitoSOX™ red mitochondrial superoxide indicator.RESULTSExposures of MA‐10 cells to 0–300 μM MEHP caused inhibition LH‐stimulated progesterone biosynthesis in a dose‐dependent manner. The decrease in the Leydig ability to produce progesterone correlated with a loss in the Leydig cell mitochondrial membrane potential (ΔΨm), and was linked to perturbation of the capacity to energize the mitochondrial membrane. MEHP exposure was suggested to cause a disruption in the electron flow through the electron transport chain, evidenced by a decrease in the ability to consumption molecular oxygen and an increase in the generation of superoxide in the mitochondria.CONCLUSIONSTogether, these observations suggest that MEHP inhibits steroid biosynthesis in MA‐10 cells via a mechanism involving a loss of the mitochondrial membrane potential (ΔΨm) and an increase in the oxidative stress level, two crucial changes known to affect mitochondrial function and cause inhibition of STAR‐mediated cholesterol transport and steroid biosynthesis.Support or Funding InformationThis material is based upon work supported by NIH grant SC2GM099578 and by the North Carolina Biotechnology Center, NCBC grant #2019‐IDG‐1017.

Investigating (anti)estrogenic activities within South African wastewater and receiving surface waters: Implication for reliable monitoring

Natural and synthetic steroid hormones and many persistent organic pollutants are of concern for their endocrine-disrupting activities observed in receiving surface waters. Apart from the demonstrated presence of estrogen- and estrogen-mimicking compounds in surface waters, antagonistic (anti-estrogenic) responses originating from wastewater effluent have been reported but are less known. Estrogenicity and anti-estrogenicity were assessed using recombinant yeast estrogen receptor binding assays (YES/YAES) at ten South African wastewater treatment works (WWTWs) and receiving rivers in two separate sampling campaigns during the summer- and winter periods in the area. Four WWTWs were then further investigated to show daily variation in estrogenic endocrine-disrupting activities during the treatment process. Although estrogenicity was notably reduced at most of the WWTWs, some treated effluent and river water samples were shown to be above effect-based trigger values posing an endocrine-disrupting risk for aquatic life and potential health risks for humans. Furthermore, estrogenicity recorded in samples collected upstream from some WWTW discharge points also exceeded some calculated risk trigger values, which highlights the impact of alternative pollution sources contributing towards endocrine disrupting contaminants (EDCs) in the environment. The YAES further showed variable anti-estrogenic activities in treated wastewater. The current study highlights a variety of factors that may affect bioassay outcomes and conclusions drawn from the results for risk decision-making. For example, mismatches were found between estrogenic and anti-estrogenic activity, which suggests a potential masking effect in WWTW effluents and highlights the complexity of environmental samples containing chemical mixtures having variable endocrine-disrupting modes of action. Although the recombinant yeast assay is not without its limitations to show endocrine-disrupting modulation in test water systems, it serves as a cost-effective tier-1 scoping assay for further risk characterisation and intervention.

Human in vitro percutaneous absorption of bisphenol S and bisphenol A: A comparative study

Bisphenol A (BPA) is widely used in industrial products. Due to the toxicity of this compound, and to comply with restrictions and regulations, manufacturers have progressively replaced it by substitutes. One of the main substitutes used is bisphenol S (BPS). Despite increasing use in many products, the effects of BPS on human health have been little investigated, and studies on percutaneous BPS absorption and particularly toxicokinetic data are lacking. However, the endocrine-disrupting activity of BPA and BPS appears comparable. Dermal contact is a significant source of occupational exposure and is the main route during handling of bisphenol-containing receipts by cashiers. Here, percutaneous BPS absorption was investigated and compared to that of BPA. Experiments were performed according to OECD guidelines. Test compounds dissolved in a vehicle - acetone, artificial sebum or water – were applied in vitro to fresh human skin samples in static Franz diffusion cells. Flux, cumulative absorbed dose and distribution of dose recovered were measured. BPA absorption was vehicle-dependent ranging from 3% with sebum to 41% with water. BPS absorption was much lower than BPA absorption whatever the vehicle tested (less than 1% of applied dose). However, depending on the vehicle 20% to 47% of the applied BPS dose remained in the skin, and was consequently potentially absorbable. Both BPA and BPS were mainly absorbed without biotransformation. Taken together, these results indicate that workers may be exposed to BPS through skin when handling products containing it. This exposure is of concern as its toxicity is currently incompletely understood.

Exclusion of Estrogenic and Androgenic Steroid Hormones from Municipal Membrane Bioreactor Wastewater Using UF/NF/RO Membranes for Water Reuse Application

In the context of water scarcity, domestic secondary effluent reuse may be an option as a reliable source for alleviating acute water shortage. The increasing risks linked with the presence of natural steroid hormones and many emerging anthropogenic micropollutants (MPs) passing through municipal wastewater treatment works (MWWTWs) are of concern for their endocrine-disrupting activities. In this study, domestic wastewater treated by a full-scale membrane bioreactor (MBR) at an MWWTW in the Western Cape Province, South Africa, was used directly as the influent to a reverse osmosis (RO) pilot plant for the removal of selected natural steroid hormones 17β-estradiol (E2) and testosterone (T) as a potential indirect water recycling application. Estrogenicity and androgenicity were assessed using the enzyme-linked immunosorbent assays (ELISA) and the recombinant yeast estrogen receptor binding assays (YES). The influent pH and flux did not influence the rejection of E2 and T, which was most likely due to adsorption, size exclusion, and diffusion simultaneously. RO and nanofiltration (NF) exhibited excellent removal rates (>95%) for E2 and T. All the E2 effluent samples with MBR/ultrafiltration (UF), MBR/NF, and MBR/RO were lower than the US EPA and WHO trigger value of 0.7 ng/L, as well as the predicted no-effect concentration (PNEC) values for fish (1 ng E2/L).

Structural binding interactions of tetrabromobisphenol A with sex steroid nuclear receptors and sex hormone-binding globulin.

Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant owing to its efficient fire-breaking property. However, leaching of TBBPA into the environment has been a global health concern due to the endocrine-disrupting activity (EDA) associated with TBBPA exposure. Limited studies are available on the hazardous effects of TBBPA on reproductive function. The aim of the present study was the structural characterization of potential EDA of TBBPA in reproductive hormone signaling and transport including steroid nuclear receptors, such as estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PR), and the steroid transport protein, sex hormone-binding globulin (SHBG). The structural binding characterization of TBBPA with the sex steroid nuclear receptors and transport protein was performed by induced-fit docking using the Schrödinger 2017 suite. The results revealed that the TBBPA binding pattern and molecular interactions with the indicated receptors and transport protein displayed overall similarity with their respective native ligands. The estimated binding energy value of TBBPA for ERα was similar to the native ligand, estradiol, indicating tight binding and greater potential for TBBPA to disrupt ERα signaling. For ERβ, AR, PR and SHBG, the estimated binding energy values were also close to their respective native ligands, indicating potential for interference in native hormone signaling and transport. In conclusion, TBBPA exposure in humans may potentially cause disruption of sex steroid signaling and transport, and thus lead to reproductive dysfunction.

Endocrine disruptive action of diclofenac and caffeine on Astyanax altiparanae males (Teleostei: Characiformes: Characidae)

Diclofenac (DCF) and caffeine (CAF) are persistent pharmaceuticals that occur in mixtures in the aquatic ecosystems causing effects in the reproductive physiology of aquatic organisms. This study evaluated the physiological reproductive responses of Astyanax altiparanae males exposed to nominal concentrations of DCF (3.08 mg L−1) and CAF (9.59 mg L−1) separately and combined, for 96 h. The steroids profile, estrogenic biomarker vitellogenin (vtgA), testes and liver morphology, and also mortality of males were assessed. DCF and CAF degradation was 5% of the initial concentration for 24 h. The LC50 of the DCF and CAF were 30.8 mg L−1 and 95.9 mg L−1, respectively. Males exposed to DCF and CAF exhibited a reduction of 17β-Estradiol (E2) concentration compared to control (CTL). Similarly, testosterone (T) was also reduced in the DCF treatment, but this response was not observed in 11-Ketotestosterone (11-KT). Males exposed to DCF + CAF combined did not exhibit differences in T, E2 and 11-KT steroids. The vtgA gene expression and the sperm concentration did not change among the treatments. Moreover, acute exposure revealed a hypertrophy of hepatocytes cells in the DCF and DCF + CAF treatments. In conclusion, DCF and CAF, isolated, exhibit an endocrine disruptive activity in A. altiparanae male, an opposite response observed with the mixture of both compounds that abolishes the endocrine disruptive effects. DCF seems to be more toxic for this species, altering also hepatocytes morphology.