Thyroid Disruption Research Articles

Effect of diisobutyl adipate on the expression of biomarker genes that respond to endocrine disruption and on gonadal sexual differentiation in Japanese medaka (Oryzias latipes)

Phthalate and non-phthalate plasticizers are used in polymer materials, such as plastic and rubber. It has recently been found that diisobutyl adipate (DIBA), which is considered an environmentally safe non-phthalate plasticizer, potentially acts as a thyroid disruptor in fish. Here, we investigated the sexual hormone effects of DIBA based on the expression levels of genes that respond to endocrine disruption and sexual hormone activity in the livers and gonads, and on gonadal sexual differentiation in Japanese medaka. Compared with the control group, the mRNA expression of chgH, vtg1, vtg2, and esr1 was significantly suppressed in the livers of DIBA exposed XX individuals. Furthermore, the mRNA expression of gsdf was significantly upregulated and downregulated in the gonads of XX and XY individuals, respectively. The mRNA expressions of esr1 and esr2b were significantly suppressed by DIBA exposure in the gonads of both XX and XY individuals. These observations suggest that DIBA has potential androgenic activity in Japanese medaka. However, normal testes and ovaries were observed in respective XY and XX medaka after DIBA exposure; therefore, these results suggest that DIBA may have weak androgenic activity.

Insights into spirotetramat-induced thyroid disruption during zebrafish (Danio rerio) larval development: An integrated approach with in vivo, in vitro, and in silico analyses

Spirotetramat (SPT), a tetronic acid-derived insecticide, is implicated in reproductive and lipid metabolism disorders, as well as developmental toxicity in fish. While these effects are documented, the precise mechanisms underlying its developmental toxicity are not fully elucidated. In this study, zebrafish embryos (2 h post-fertilization, hpf) were exposed to four concentrations of SPT (0, 60, 120, and 240 μg/L) until 21 dpf (days post-fertilization). We delved into the mechanisms by examining its potential disruption of the thyroid endocrine system, employing in vivo, in vitro, and in silico assays. The findings showed notable developmental disturbances, including reduced hatching rates, shortened body lengths, and decelerated heart rates. Additionally, there was an increase in malformations and a decline in locomotor activity. Detailed analyses revealed that SPT exposure led to elevated thyroid hormone levels, perturbed the hypothalamic-pituitary-thyroid (HPT) axis transcript levels, amplified deiodinase type I (Dio1) and deiodinase type II (Dio2) activities, and both transcriptionally and proteomically upregulated thyroid receptor beta (TRβ) in larvae. Techniques like molecular docking and surface plasmon resonance (SPR) confirmed SPT's affinity for TRβ, consistent with in vitro findings suggesting its antagonistic effect on the T3-TR complex. These insights emphasize the need for caution in using tetronic acid-derived insecticides.

Prenatal Phenol and Paraben Exposures and Adverse Birth Outcomes: A Prospective Analysis of U.S. Births

BackgroundSynthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1–2 spot samples during pregnancy and limited diversity of populations. ObjectiveTo study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program. ResultsWhile many associations were modest and statistically imprecise, a 1-unit increase in log10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: −67%, −2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: −53%, 8%). DiscussionIn a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life.

An In Vitro and In Vivo Study of Thyroid Disruption of 1,2-Bis(2,4,6-tribromophenoxy)ethane (BTBPE)-A Novel Brominated Flame Retardant.

The novel brominated flame retardant, 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), is an emerging environmental pollutant with undetermined toxicity. We investigated how BTBPE causes thyroid endocrine disruption with integrated in silico, in vitro, and in vivo assays. In yeast two-hybrid and T-Screen assays, BTBPE interacted with zebrafish thyroid hormone receptors with binding energies weaker than the TR agonist-3,3',5-Triiodo-l-thyronine (T3), and disrupted thyroid function as a thyroid receptor (TR) agonist. We examined the bioconcentration, developmental toxicity, and thyroid endocrine disruption in zebrafish after a 14-day exposure to BTBPE (1, 3, 10 μg/L). Thyroxine (T4) was lower in BTBPE-treated larvae, whereas corticotropin-releasing hormone (CRH) and thyroid-stimulating hormone (TSH) were higher. The gene transcription alterations along the hypothalamic-pituitary-thyroid (HPT) axis were observed. Furthermore, reduced locomotion suggested that BTBPE imparts developmental neurotoxicity at zebrafish early developmental stage. Establishing that BTBPE has thyroid endocrine-disrupting effects is an important step for understanding and managing BTBPE toxicity.

3 Fluoride Exposure and Hypothyroidism in Pregnant Women: A Potential Mechanism of Fluoride Neurotoxicity

Objective:Fluoride exposure has been associated with thyroid dysfunction, but fluoride's impact on thyroid function in pregnancy is unclear, especially during early gestation when the fetus is dependent on maternal thyroid hormone. We examined the potential thyroid-disrupting effects of maternal fluoride exposure in pregnancy and tested whether thyroid disruption in pregnancy mediates the association between maternal fluoride exposure and child intelligence quotient (IQ) among Canadian mother-child dyads living in areas with optimal fluoridation.Participants and Methods:We measured fluoride concentrations in drinking water and in spot urine samples collected in each trimester from pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals study. We also measured thyroid hormone (thyroid stimulating hormone [TSH], free thyroxine [FT4], and total thyroxine [TT4]) levels during the first trimester of pregnancy and categorized women as euthyroid (n=1301), subclinical hypothyroid (n=100), or primary hypothyroid (n=28). Those categorized as primary hypothyroid were combined with an additional 79 women who reported clinical diagnoses at time of study enrolment (total n=107). In a sample of 1508 women, we used logistic regression to estimate the association between fluoride exposure and risk of either subclinical or primary hypothyroidism, separately, and linear regression to estimate associations between fluoride exposure and women's thyroid hormone levels (TSH, FT4, TT4). We tested effect modification by child sex and thyroid peroxidase (TPO) antibody status. In a subsample of 439 mother-child pairs, we measured child Full-Scale IQ (FSIQ) at 3-4 years of age using the Wechsler Preschool and Primary Scale of Intelligence. We used linear regression to test associations between maternal hypothyroidism or thyroid hormone levels, and children's FSIQ scores. Finally, mediation analysis in the counterfactual framework was used to estimate the proportion of the effect of maternal fluoride exposure on child FSIQ mediated by maternal hypothyroidism, through evaluation of the natural direct (not through hypothyroidism) and indirect (through hypothyroidism) effects.Results:Using categorical measures of thyroid status, a 0.5 mg/L increase in water fluoride concentration was associated with a 1.64 (95% confidence interval [CI], 1.04 to 2.58) increased odds of primary hypothyroidism. This association was stronger among women with normal TPO antibody levels (< 5.61 IU/mL) (odds ratio, 2.80; 95% CI, 1.24 to 6.36). In contrast, we did not find a significant association between maternal urinary fluoride and hypothyroidism. For continuous measures of thyroid hormone levels, a 1 mg/L increase in maternal urinary fluoride was associated with a 35% (p=0.01) increase in TSH among women pregnant with a female fetus. In our subsample analyses, children born to women with primary hypothyroidism had lower FSIQ than children of euthyroid women, especially among boys (B, 8.78; 95% CI, -16.78 to -0.79). In contrast, maternal TSH, FT4, and TT4 levels were not significantly associated with child FSIQ scores. Maternal primary hypothyroidism did not significantly mediate the relationship between maternal water fluoride concentration and child FSIQ (p natural indirect effect= .35).Conclusions:Fluoride in drinking water may increase the risk of hypothyroidism in pregnancy. Thyroid dysfunction in pregnancy may be one mechanism underlying developmental neurotoxicity of fluoride.

Tetrabromobisphenol A exerts thyroid disrupting effects but has little overt impact on postnatal brain development and neurobehaviors in mice

Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant. There is evidence showing that TBBPA can exert thyroid disrupting effects in mammals, but different results were also reported, along with inconsistent reports regarding its neurotoxicity. Here, we investigated thyroid disrupting effects and neurotoxicity of TBBPA (5, 50, 500 µg/(kg·day)) to male mice following maternal and direct exposure through drinking water, with the anti-thyroid drug propylthiouracil (PTU) as the positive control. On postnatal day (PND) 15, we expectedly observed severe thyroid compensatory hyperplasia and cerebellar developmental retardation in PTU-treated pups. The highest dose of TBBPA also caused thyroid histological alteration but had no effects on cerebellar development in terms of Purkinje cell morphology and the thickness of the internal granular layer and the molecular layer of the cerebellum. During puberty and adulthood, the thyroid morphological alterations became more pronounced in the TBBPA-treated animals, accompanied by decreased serum thyroid hormone levels. Furthermore, the 50 and 500 µg/(kg·day) TBBPA groups showed a significant decrease in the serum level of serotonin, a neurotransmitter associated with anxiety behaviors. Correspondingly, the highest dose group displayed anxiety-like behaviors in the elevated plus-maze test on PND 35, but this neurobehavioral alteration disappeared on PND 56. Moreover, no changes in neurobehavioral parameters tested were found in TBBPA-treated animals at puberty and adulthood. Altogether, all observations show that TBBPA can exert thyroid disrupting effects but has little overt impact on brain development and neurobehaviors in mice, suggesting that thyroid disruption does not necessarily cause overtly adverse neurodevelopmental outcomes.

SAT591 Abnormal Levels Of Thyroid Hormones During Development Alters The Migration And Activity Of GnRH Reproductive Neurons

Abstract Disclosure: C. Quignon: None. A. Backer: None. S. Wray: None. Clinical studies have shown that thyroid hormones disorders and alteration of thyroid hormone production by environmental endocrine disruptors, have deleterious effects on reproduction. By acting in the brain on the hypothalamic component of the reproductive axis, abnormal levels of thyroid hormones can disturb sex hormones production, oestrus cycles or puberty onset, possibly leading to subfertility. Moreover, in animal models, endocrine disruptors and thyroid hormones have been shown to have long-lasting transgenerational effects with the maternal hormones influencing the development of foetal reproductive functions. Despite clear evidence of an interaction between the thyroid and reproductive systems, the effect of T3, the active form of thyroid hormones, on the GnRH neurons controlling reproduction, have been poorly studied. In this work we investigated how T3 functionally interacts with GnRH neurons and how abnormal concentration of T3 alters the migration of these neurons during development. Calcium imaging was used to study the direct effect of T3 on GnRH neuronal activity in an ex vivo nasal explants model. Acute administration of T3 (30nM) was found to stimulate the activity of GnRH cells. Dual labelling of GnRH and thyroid hormone receptors (TR) showed that the GnRH neurons express both nuclear and membrane receptors. However, the use of an antagonist that specifically blocks the TR nuclear receptors (1-850), didn’t inhibit the T3 stimulatory effect. In contrast, blockage of integrin αV/β3 membrane receptors (with cilengitide), which have been shown to be activated by T3, prevented the T3-induced increase in GnRH neuronal activity. During development GnRH neurons migrate from the nasal placodes into the brain. Acute administration of T3 for 1hr significatively decreased the migration rate of the GnRH neurons in our ex vivo model. To assess the effect of thyroid disruption during pregnancy on the development of reproductive axis in utero, pregnant females mice have been treated with methimazole to induce hypothyroidism from gestational day 6 to 13. E13 embryos have been collected from treated and control dams and the distribution of migrating GnRH neurons will be compared between both groups. Together these studies are the first to report a direct effect of thyroid hormones on GnRH neuronal activity, through the integrin αV/β3 membrane receptors and show that T3 can modulate the migration of GnRH neurons during development. These results will bring new insights on how thyroid disruption by endocrine disruptor chemicals or thyroid diseases, especially during foetal development, can lead to long term reproductive defects. Presentation: Saturday, June 17, 2023

Maternal exposure to dietary uranium causes oxidative stress and thyroid disruption in zebrafish offspring

The contamination of uranium in aquatic ecosystems has raised growing global concern. However, the understanding of its chronic effects on aquatic organisms is limited, particularly with regards to transgenerational toxicity. In this study, we evaluated the maternal transfer risk of uranium using zebrafish. Sexually mature female zebrafish were exposed to 2 and 20 ng/g of uranium-spiked food for 28 days. The induced bioconcentration, thyroid disruption, and oxidative stress in both the adults (F0) and their embryos (F1) were further investigated. Element analysis showed that uranium was present in both F0 and F1, with higher concentrations observed in F1, indicating significant maternal offloading to the offspring. Meanwhile, an increased malformation and decreased swim speed were observed in the F1. Thyroid hormone analysis revealed significant decreases in the levels of triiodothyronine (T3) in both the F0 adults and F1 embryos, but thyroxine (T4) was not significantly affected. Additionally, the activities of antioxidant defenses, including catalase (CAT) and superoxide dismutase (SOD), and the expression of glutathione (GSH) and malondialdehyde (MDA) were significantly altered in the F0 and F1 larvae at 120 hpf. The hypothalamic-pituitary-thyroid (HPT) axis, oxidative stress, and apoptosis-related gene transcription expression were also significantly affected in both generations. Taken together, these findings highlight the importance of considering maternal transfer in uranium risk assessments.

Association of urinary bisphenols with thyroid function in the general population: a cross-sectional study of an industrial park in China.

Bisphenols (BPs) are potential thyroid disruptors that are widely used in many consumer products, leading to their widespread exposure in the general population. Current cross-sectional and case-control studies have found associations between exposure to BPs and serum thyroid function, but the results were contradictory. The objectives of this study are to describe demographic characteristics, BP exposure levels, and thyroid function measurements in potentially exposed and control districts and to investigate the association of urinary BPs with thyroid function. Data were collected from a general population aged 3-79 years (N = 281) recruited by the Zhejiang Human Biomonitoring Program (ZJHBP). The concentrations of 10 kinds of BPs in urine and serum free triiodothyronine (FT3), total triiodothyronine (TT3), free thyroxine (FT4), total thyroxine (TT4), thyroid-stimulating hormone (TSH), thyroglobulin (Tg), thyroglobulin antibodies (TgAb), thyroid peroxidase antibodies (TPOAb), and thyrotropin receptor antibody (TRAb) in serum were measured. Multiple linear regression and weighted quantile sum (WQS) regression were used to estimate the relationship between single and mixed exposure of BPs and thyroid function. Bisphenol A (BPA), bisphenol S (BPS), and bisphenol P (BPP) were detected, respectively, in 82.73%, 94.24%, and 55.40% of the population in the exposed area and 81.69%, 61.27%, and 43.66% of the population in the control area. Among adult females, serum TT3 was negatively associated with urinary BPA (β = -0.033, 95% CI = -0.071, -0.008, P = 0.021). Among minor females, FT4 and Tg levels were negatively associated with the urinary BPA (β = -0.026, 95% CI = -0.051, -0.002, P = 0.032 for FT4; β = -0.129, 95% CI = -0.248, -0.009, P = 0.035 for Tg), and TPOAb was positively associated with urinary BPA (β = 0.104, 95% CI = 0.006, 0.203, P = 0.039). In WQS models, BPs mixture was positively associated with FT3 (βWQS = 0.022, 95% CI = 0.002, 0.042) and TT3 (βWQS = 0.033, 95% CI = 0.004, 0.062), and negatively associated with FT4 (βWQS = -0.024, 95% CI = -0.044, 0.004). We found widespread exposure to BPA, BPS, and BPP in the general population of Zhejiang province and found an association between BPA and thyroid hormones. This association is gender- and age-dependent and needs to be confirmed in further studies.

P09-28: Mixtures of triazole fungicides and thyroid disruption in vivo and in vitro

P09-28: Mixtures of triazole fungicides and thyroid disruption in vivo and in vitro

P09-11: Towards a qAOP to predict thyroid disruption linked to neurodevelopmental toxicity in rats

P09-11: Towards a qAOP to predict thyroid disruption linked to neurodevelopmental toxicity in rats

A literature Study on Association of Environmental Toxic Compounds with Thyroid Disruption

The literature evidences showed a drastic effect of environmental chemicals compounds on the status of thyroid hormones. Most of the environmental chemical compounds mentioned in study show structural resemblance with thyroid hormones. Therefore, these chemicals can mimic the activity of thyroid hormones. Some chemical compounds also exhibit other mechanism; however, the exact mechanism of action is not cleared yet. Most commonly these chemicals include a dose dependent inhibition of thyroid hormones. No doubt these chemical compounds have beneficial roles at industrial scale where these are used in the preparation of various useful things but we cannot ignore their life-threatening consequences.

Screening for chemicals with thyroid hormone-disrupting effects using zebrafish embryo

Thyroid disruption is an increasingly recognized issue in the use and development of chemicals and new drugs, especially to help toxicologist to complement the reproductive and developmental toxicology information of chemicals. Still, adequate assessment methods are scarce and often suffer a trade-off between physiological relevance and labor- and cost-intensive assays. Here, we present a tiered approach for a medium-throughput screening of chemicals to identify their thyroid disrupting potential in zebrafish embryos as a New Approach Methodology (NAM). After identifying the maximum tolerated concentrations, we exposed zebrafish larvae to sub-adverse effect levels of the reference compounds benzophenone-2, bisphenol A, phenylthiourea, potassium perchlorate, propylthiouracil, and phloroglucinol to exclude any systemic toxicity. Applying the transgenic zebrafish line that carries a gene for the red fluorescence protein (Tg(tg:mCherry)) under the thyroglobulin promoter, we could identify the thyroid disrupting effects of the chemicals by a time and cost-effective image analysis measuring the fluorescence levels in the thyroid glands. Our observations could be confirmed by altered expression patterns of genes involved in the hypothalamus-pituitary-thyroid (HPT) axis. Finally, to anchor the observed thyroid disruption, we determined some changes in the Thyroid hormone levels of triiodothyronine (T3) and Thyroxine (T4) using a newly developed liquid chromatography mass spectrometric (LCMS) method. The presented approach carries the potential to extend the toolbox for legislative authorities and chemical producers for the assessment of thyroid-specific endocrine disruption and to overcome current challenges in the evaluation of endocrine disruptors.

Selenium Nanoparticles mitigating Thyroid Dysfunction in Hexachlorobenzene-Induced Hypothyroid Rats

Hexachlorobenzene (HCB) is a potent endocrine disruptor that targets the thyroid gland and results in thyroid dysfunction. Nano-selenium (SeNP) has attracted attention owing to its antioxidant activity. It can be used to alleviate thyroid disruption by modulating the activity of selenium-containing proteins in the thyroid gland. Our aim is to determine the ability of SeNPs to reverse the effects of the environmental toxicant HCB on thyroid function by assessing thyroid histology, thyroid function tests, lipid profile and antioxidant status. 65-day-old rats were orally administered HCB (50 mg/kg), SeNP (0.05 mg/kg), HCB (50 mg/kg) + SeNP (0.05 mg/kg) or 0.05% aqueous Tween 20 (control) for 90 days. Thyroid function, gland histology and antioxidant levels were evaluated, along with changes in the lipid profile. Experimental data were analyzed using One-way Variance (ANOVA) analysis followed by Tukey’s post-hoc test. Pearson’s correlation analysis assessed the correlation between the various parameters. Results were considered significant at p<0.05. Necrotic lesions and levels of fT3, fT4 and TSH were correlated with the detrimental changes observed due to exposure to HCB. Treatment with SeNP helped in maintaining the normalization of these changes. HCB increases LPO and decreases GSH, CAT, GPx and SOD significantly (p<0.001). A negative correlation between MDA and fT3 (r=−0.86, p= 0.003) was observed in the HCB-treated group. Similarly, GPx and TSH levels were negatively correlated (r=−0.79, p=0.05). TSH levels were negatively and strongly correlated with HDL levels in the SeNP group (r=0.91, p = 0.01). This study suggests that selenium, especially in the nanotized form, can be used to treat thyroid dysfunction caused by exposure to environmental pollutants.

6:2 Chlorinated Polyfluoroalkyl Ether Sulfonates Exert Stronger Thyroid Homeostasis Disruptive Effects in Newborns than Perfluorooctanesulfonate: Evidence Based on Bayesian Benchmark Dose Values from a Population Study.

Growing toxicologic evidence suggests that emerging perfluoroalkyl substances (PFASs), like chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA), may be as toxic or more toxic than perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA). However, further investigations are needed in terms of the human health risk assessment. This study examined the effects of emerging and legacy PFAS exposure on newborn thyroid homeostasis and compared the thyroid disruption caused by 6:2 Cl-PFESA and PFOS using a benchmark dose approach. The health effects of mixture and individual exposure were estimated using the partial least-squares (PLS) model and linear regression, respectively. A Bayesian benchmark dose (BMD) analysis determined the BMD value for adverse effect comparison between 6:2 Cl-PFESA and PFOS. The median (interquartile range) concentrations of 6:2 Cl-PFESA (0.573 [0.351-0.872] ng/mL), PFOS (0.674 [0.462-1.007] ng/mL), and PFOA (1.457 [1.034, 2.405] ng/mL) were found to be similar. The PLS model ranked the PFAS variables' importance in projection (VIP) scores as follows: 6:2 Cl-PFESA > PFOS > PFOA. Linear regression showed that 6:2 Cl-PFESA had a positive association with free triiodothyronine (FT3, P = 0.006) and triiodothyronine (T3, P = 0.014), while PFOS had a marginally significant positive association with FT3 alone (P = 0.042). The BMD analysis indicated that the estimated BMD10 for 6:2 Cl-PFESA (1.01 ng/mL) was lower than that for PFOS (1.66 ng/mL) in relation to a 10% increase in FT3. These findings suggest that 6:2 Cl-PFESA, an alternative to PFOS, has a more pronounced impact on newborns' thyroid homeostasis compared to PFOS and other legacy PFASs.

Assessment of the Predictivity of DIO1-SK Assay to Investigate DIO1 Inhibition in Human Liver Microsomes

Introduction: The European Union Reference Laboratory for alternatives to animal testing (EU RL ECVAM) coordinates the validation of multiple thyroid in vitro assays aiming to set up an in vitro test battery. The validation consists of two independent parts: part 1 (Reproducibility assessment) in which the reproducibility of the method is evaluated by testing a small number of described inhibitors and part 2 (Predictivity assessment) where the predictivity of the method is investigated by testing a blinded set of substances. The deiodinases (DIO) are important regulators of thyroid hormone (TH) metabolism and potential targets for substance-induced thyroid disruption. We previously reported the part 1 results for the Sandell–Kolthoff reaction-based type 1 deiodinase (DIO1-SK) assay and an extensive description of the method. In this study, we report the results of the part 2 testing in the DIO1-SK assay. Methods: A set of 22 test substances consisting of known DIO inhibitors in vitro, as well as substances otherwise interfering with the TH system and substances with no such activities were tested in the standardized DIO1-SK assay. Experiments were performed on blinded substances, which were deblinded after experimental completion, statistically evaluated, and compared to literature data. Finally, an in vitro data interpretation procedure (DIP) was generated. Results and Discussion: Seven test substances produced a maximum DIO1 inhibition >90% and 11 test substances below 20%; they were regarded as inhibitors and noninhibiting substances, respectively. Two test substances, Ketoconazole and Silichristin, were found to be not applicable based on assay interference. Inhibition data were consistent with results of relevant in vitro and computational models. Using the variation of control data, an in vitro DIP was defined categorizing test substances (i) by efficacy using the maximum inhibition data and (ii) by potency using the IC50 data of the test substance.

Associations between endocrine disruptor contamination and thyroid hormone homeostasis in Belgian type 1 diabetic children.

Humans are daily exposed to many environmental pollutants, some of which being suspected to be thyroid disruptors. Some populations could be particularly susceptible to thyroid disruption, such like diabetics due to the well-known relation between the thyroid function and the control of carbohydrate homeostasis by pancreas. Therefore, the aim of this study was to investigate the associations between the exposure to several persistent and non-persistent chemicals and thyroid hormones levels in children with type 1 diabetes. Blood and urine sample were collected from 54 children diagnosed for type 1 diabetes mellitus. The concentrations of 7 phthalate metabolites, 4 parabens, 7 bisphenols, benzophenone 3 and triclosan were measured in urine, while 15 organochlorine pesticides, 4 polychlorinated biphenyls (PCBs) and 7 perfluoroalkyl substances were analyzed in serum samples. In the same time, the blood levels of free thyroxine (fT4), thyroid stimulating hormone (TSH) and glycated hemoglobin (Hb1Ac) were determined. We highlighted positive associations between serum perfluorohexane sulfonate and urinary monoethylphthalate levels, and TSH level in blood. We also found that PCB 138 was positively associated to fT4 while urinary levels of bisphenol F were negatively correlated to this hormone. Finally, we observed positive associations between Hb1Ac levels and the contamination by PCB 153 and two urinary phthalate metabolites: mono-2-ethyl-5-hydroxyhexyl phthalate and mono-2-ethyl-5-oxoxyhexyl phthalate. Our results showed that our small cohort of children with type 1 diabetes mellitus is potentially susceptible to thyroid disruptions by some pollutants. Moreover, for these children, both di-(2-ethylhexyl) phthalate metabolites would potentially hamper the glucose homeostasis. Nevertheless, additional studies are mandatory to further explore these findings.

Chronic poly(l-lactide) (PLA)- microplastic ingestion affects social behavior of juvenile European perch (Perca fluviatilis)

Juvenile perch were exposed to 2 % (w/w) poly(l-lactide) (PLA) microplastic particles (90–150 μm) in food pellets, or 2 % (w/w) kaolin particles, and a non-particle control food over 6 months. Chronic ingestion of PLA microplastics significantly affected the social behavior of juvenile perch, evident as a significantly increased reaction to the vision of conspecifics. PLA ingestion did not alter life cycle parameters, or gene expression levels. In addition to reactions to conspecifics, fish that ingested microplastic particles showed tendencies to decrease locomotion, internal schooling distance, and active predator responses. The ingestion of natural particles (kaolin) significantly downregulated the expression of genes related to oxidative stress and androgenesis in the liver of juvenile perch, and we found tendencies to downregulated expression of genes related to xenobiotic response, inflammatory response, and thyroid disruption. The present study demonstrated the importance of natural particle inclusion and the potential behavioral toxicity of one of the commercially available biobased and biodegradable polymers.

Potential oestrogenic effects (following the OECD test guideline 440) and thyroid dysfunction induced by pure cyanotoxins (microcystin-LR, cylindrospermopsin) in rats

Potential endocrine-disrupting properties of cyanotoxins, such as microcystin-LR (MC-LR) and cylindrospermopsin (CYN) are of concern due to their increasing occurrence, the scarcity of reports on the topic (particularly for CYN) and the impact of human's health at different levels. Thus, this work performed for the first time the uterotrophic bioassay in rats, following the Organization for Economic Cooperation and Development (OECD) Test Guideline 440, to explore the oestrogenic properties of CYN and MC-LR (75, 150, 300 μg/kg b.w./day) in ovariectomized (OVX) rats. Results revealed neither changes in the wet and blotted uterus weights nor in the morphometric study of uteri. Moreover, among the steroid hormones analysed in serum, the most remarkable effect was the dose-dependent increase in progesterone (P) levels in rats exposed to MC-LR. Additionally, a histopathology study of thyroids and serum levels of thyroids hormones were determined. Tissue affectation (follicular hypertrophy, exfoliated epithelium, hyperplasia) was observed, as well as increased T3 and T4 levels in rats exposed to both toxins. Taken together, these results point out that CYN and MC-LR are not oestrogenic compounds at the conditions tested in the uterotrophic assay in OVX rats, but, however, thyroid disruption effects cannot be discarded.

Adverse thyroid hormone and behavioral alterations induced by three frequently used synthetic musk compounds in embryo-larval zebrafish (Danio rerio)

Synthetic musk compounds (SMCs) have been extensively used in numerous consumer products, such as perfumes, cosmetics, soap, and fabric softener. Due to their bioaccumulative nature, these compounds have often been detected in the aquatic ecosystem. However, their effects on endocrine and behavioral effects in freshwater fish have rarely been investigated. In the present study, thyroid disruption and neurobehavioral toxicity of SMCs were investigated using embryo-larval zebrafish (Danio rerio). Three frequently used SMCs, i.e., musk ketone (MK), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta [g]- benzopyran (HHCB), and 6-acetyl-1,1,2,4,4,7-hexamethyltetralin (AHTN), were chosen. Experimental concentrations for HHCB and AHTN were selected to include the maximum levels reported in the ambient water. The 5-day exposure to either MK or HHCB led to significant decrease of T4 concentration in the larval fish at the levels as low as 0.13 μg/L, even though compensatory transcriptional changes, e.g., up-regulation of hypothalamic crhβ gene and/or down-regulation of ugt1ab gene, were taken place. In contrast, AHTN exposure resulted in up-regulation of crhβ, nis, ugt1ab, and dio2 genes but did not alter T4 level, suggesting its lesser thyroid disrupting potential. All tested SMCs caused hypoactivity of the larval fish. Several genes related to neurogenesis or development, e.g., mbp and syn2a, were down-regulated, but the patterns of transcriptional changes were different among the tested SMCs. The present observations demonstrate that MK and HHCB can decrease T4 levels and cause hypoactivity of the larval zebrafish. It requires attention that HHCB and AHTN could influence thyroid hormone or behavior of the larval fish even at the levels close to those observed in the ambient environment. Further studies on potential ecological consequences of these SMCs in freshwater environment are warranted.