Exposure to MEHP during Pregnancy and Lactation Impairs Offspring Growth and Development by Disrupting Thyroid Hormone Homeostasis.

Mono(2-ethylhexyl) phthalate (MEHP), as a highly toxic and biologically active phthalate metabolite, poses considerable risks to the environment and humans. Despite the existence of in vitro studies, there is a lack of in vivo experiments assessing its toxicity, particularly thyroid toxicity. Herein, we investigated the thyroid-disrupting effects of MEHP and the effects on growth and development of maternal exposure to MEHP during pregnancy and lactation on the offspring modeled by SD rats. We found that thyroid hormone (TH) homeostasis was disrupted in the offspring, showing a decrease in total TH levels, combined with an increase in free TH levels. Nonhomeostasis ultimately leads to weight loss in female offspring, longer anogenital distance in male offspring, prolonged eye-opening times, and fewer offspring. Our findings indicate that maternal exposure to MEHP during pregnancy and lactation indirectly influences the synthesis, transport, transformation, and metabolism of THs in the offspring. Meanwhile, MEHP disrupted the morphology and ultrastructure of the thyroid gland, leading to TH disruption. This hormonal disruption might ultimately affect the growth and development of the offspring. This study provides a novel perspective on the thyroid toxicity mechanisms of phthalate metabolites, emphasizing the health risks to newborns indirectly exposed to phthalates and their metabolites.

Thyroid-Disrupting Effects of Exposure to Fipronil and Its Metabolites from Drinking Water Based on Human Thyroid Follicular Epithelial Nthy-ori 3-1 Cell Lines.

Fipronil is a broad-spectrum insecticide used for plants and poultry. Owing to its widespread use, fipronil and its metabolites (fipronil sulfone, fipronil desulfinyl, and fipronil sulfide), termed FPM, can be frequently detected in drinking water and food. Fipronil can affect the thyroid function of animals, but the effects of FPM on the human thyroid remain unclear. We employed human thyroid follicular epithelial Nthy-ori 3-1 cells to examine combined cytotoxic responses, thyroid-related functional proteins including the sodium-iodide symporter (NIS), thyroid peroxidase (TPO), deiodinases I-III (DIO I-III), and the nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) pathway induced by FPM of 1-1000-fold concentrations detected in school drinking water collected from a heavily contaminated area of the Huai River Basin. Thyroid-disrupting effects of FPM were evaluated by examining biomarkers of oxidative stress and thyroid function and tetraiodothyronine (T4) levels secreted by Nthy-ori 3-1 cells after FPM treatment. FPM activated the expression of NRF2, HO-1 (heme oxygenase 1), TPO, DIO I, and DIO II but inhibited NIS expression and increased the T4 level of thyrocytes, indicating that FPM can disrupt the function of human thyrocytes through oxidative pathways. Given the adverse impact of low FPM concentrations on human thyrocytes, supportive evidence from rodent studies, and the critical importance of thyroid hormones on development, the effects of FPM on the neurodevelopment and growth of children warrant priority attention.

Evaluation of thyroid-disrupting effects of bisphenol F and bisphenol S on zebrafish (Danio rerio) using anti-transthyretin monoclonal antibody-based immunoassays.

The thyroid disrupting chemicals (TDCs) have raised great concerns due to their adverse impacts on thyroid hormones (THs). In this study, we investigated the thyroid-disrupting effects of bisphenol F (BPF) and bisphenol S (BPS), two major BPA substitutes, on adult zebrafish (Danio rerio). Firstly, anti-transthyretin (TTR) monoclonal antibody (anti-TTR mAb) was prepared and used to establish an indirect ELISA, which had a working range of 15.6∼1000 ng/mL of a detection limit of 6.1 ng/mL. The immunoassays based on anti-TTR mAb showed that exposure to BPF (10 and 100 µg/L) and BPS (100 µg/L) significantly elevated the levels of TTR protein in the plasma, liver, and brain tissues. Moreover, immunofluorescence showed that 100 µg/L BPF and BPS induced the production of TTR protein in liver and brain tissues. In addition, BPF and BPS increased THs levels and damaged thyroid tissue structure in adult female zebrafish. Especially, 100 µg/L BPF significantly increased T4 and T3 levels by 2.05 and 1.14 times, and induced pathological changes of thyroid follicles. The changes in the expression levels of genes involved in the hypothalamus-pituitary-thyroid (HPT) axis further illustrated that BPF and BPS had significant adverse effects on THs homeostasis and thyroid function in zebrafish. Therefore, TTR immunoassays could be used for the evaluation of thyroid-disrupting effects in fish and BPF exhibited greater disruption than BPS.

Thyroid disrupting effects and the developmental toxicity of hexafluoropropylene oxide oligomer acids in zebrafish during early development.

As perfluorooctanoic acid (PFOA) alternatives, hexafluoropropylene oxide dimeric acid (HFPO-DA) and hexafluoropropylene oxide trimeric acid (HFPO-TA) have been increasingly used and caused considerable water pollution. However, their toxicities to aquatic organisms are still not well known. Therefore, in this study, zebrafish embryos were exposed to PFOA (0, 1.5, 3 and 6 mg/L), HFPO-DA (0, 3, 6 and 12 mg/L) and HFPO-TA (0, 1, 2 and 4 mg/L) to comparatively investigate their thyroid disrupting effects and the developmental toxicity. Results demonstrated that waterborne exposure to PFOA and its two alternatives decreased T4 contents, the heart rate and swirl-escape rate of zebrafish embryos/larvae. The transcription levels of genes related to thyroid hormone regulation (crh), biosynthesis (tpo and tg), function (trα and trß), transport (transthyretin, ttr), and metabolism (dio1, dio2 and ugt1ab), were differently altered after the exposures, which induced the thyroid disrupting effects and decreased the heart rate. In addition, the transcription levels of some genes related to the nervous system development were also significantly affected, which was associated with the thyroid disrupting effects and consequently affected the locomotor activity of zebrafish. Therefore, HFPO-DA and HFPO-TA could not be safe alternatives to PFOA. Further studies to uncover the underlying mechanisms of these adverse effects are warranted.

Thyroid-disrupting effects caused by exposure to alternative flame retardants from groundwater contamination in rural central China.

Accumulating evidence reveals that exposure to alternative flame retardants (AFRs) results in defective thyroid functions. AFRs are detectable in various environmental media in developed cities in China. However, few studies have reported the contamination levels of AFR in groundwater in rural areas, indicating an urgent need to investigate exposure of AFRs and perform health risk assessment for populations that use groundwater as the main source of drinking water. This study investigated the concentrations of AFRs in groundwater in rural areas of central China. Moreover, Nthy-ori-3-1 cells were used to determine the thyroid cytotoxicities and thyroid-interfering effects of a single AFR as well as the mixtures of AFRs based on the AFR contamination levels in real-world. The results revealed that all classes of AFRs were detectable in rural areas in central China. Dechlorane plus, hexabromocyclododecane, bromophenols (BPs), novel brominated flame retardants (NBFRs) and organophosphate flame retardants (OPFRs) exhibited spatial contamination patterns, with an average concentrations (median) of 157.89 ± 88.61 (185.47) pg/L, 0.09 ± 0.29 (not detectable) ng/L, 5.20 ± 5.92 (3.43) ng/L, 3338.11 ± 3758.78 (2836.72) pg/L, and 79.35 ± 97.19 (53.62) ng/L, respectively. The half maximal effective concentrations (EC50) of BPs, OPFRs, and NBFRs ranged 98.4-4012 µM, 42.0-2506 µM, and 10.1-203.7 µM, respectively. Several AFRs exhibited more cytotoxic effects than did traditional brominated flame retardants. It is intriguing that several single AFRs and mixtures at environmentally-relevant exposure levels promoted the viability of Nthy-ori-3-1 cells. Taken together, our study demonstrates that AFRs are present in the groundwater in rural areas in central China and AFRs exhibit thyroid disrupting effects.

[Effect of Dissolved Humic Acid on Thyroid Receptor Antagonistic Activity of Zinc in Aquatic Environment].

A rapid recombinant human thyroid (hTR) gene yeast bioassay was used to evaluate the effect of dissolved humic acid on thyroid receptor antagonistic activity of ZnCl2.The concentration of bio-available zinc after its reaction with dissolved humic acids was measured by anodic stripping voltammetry (ASV).Furthermore,the reaction mechanism of humic acid and zinc was investigated by three-dimensional excitation-emission matrix fluorescence spectroscopy (3DEEM).The results revealed that ZnCl2 demonstrated strong thyroid receptor antagonistic activity,and the concentration inhibiting 20% of the maximum effect of ZnCl2 was 1.70×10-5 mol·L-1.The thyroid receptor antagonistic activity of ZnCl2 was reduced by 30%-50% after the reaction of dissolved humic acids.The results of ASV showed that the concentration of bio-available zinc was decreased after the reaction of dissolved humic acids,the result was similar to that of bioassay test.The thyroid receptor antagonistic activity of the mixed solution of humic acid and ZnCl2 was increased after UV radiation treatment,however it was still lower than the antagonistic activity induced by ZnCl2.The results of 3DEEM showed that ZnCl2 could reduce the fluorescence peak intensity of humic acid,which could intuitively characterize the interaction between humic acid and ZnCl2.The above results can provide basic data and theoretical support for zinc toxicity study in aquatic environment and the establishment of water quality criteria for znic.