Thyrotoxic Effects of Mixed Exposure to Perfluorinated Compounds: Integrating Population-Based, Toxicogenomic, Animal, and Cellular Evidence to Elucidate Molecular Mechanisms and Identify Potential Effector Targets.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are emerging environmental endocrine disruptors that may adversely affect the human endocrine system, particularly the thyroid gland, the largest endocrine gland in the human body. An epidemiologic survey was conducted involving 318 community residents in Shanghai, China, to assess PFAS exposure levels. The relationship between PFAS exposure and five thyroid function indicators was analyzed using Bayesian Kernel Regression (BKMR) and Weighted Quantile Sum Regression (WQS). Ten effector genes related to PFAS and thyroid diseases were identified through the Comparative Toxicogenomics Database (CTD) for bioinformatics analysis and pathways involved were explored through mediation analysis. In vivo validation of these effector genes was conducted using PCR, complemented by in vitro cellular experiments involving transcriptome sequencing and the construction of animal models to simulate mixed PFAS exposure in the general population. Mixed PFAS exposure was found to impact thyroid health primarily through pathways related to lipid metabolism in toxicogenomic studies and resulted in the upregulation of key genes associated with lipid metabolism in animal models. Our results demonstrate that PFAS exposure could affect the expression of lipid metabolism pathways through the modulation of transcription factors, contributing to the development of thyroid disease.

Exploring the molecular mechanisms by which per- and polyfluoroalkyl substances induce polycystic ovary syndrome through in silico toxicogenomic data mining.

The pathogeny of polycystic ovary syndrome (PCOS) is intricate, with endocrine disruptors (EDCs) being acknowledged as significant environmental factors. Research has shown a link between exposure to per- and polyfluoroalkyl substances (PFAS) and the development and progression of PCOS, although the precise mechanism is not fully understood. This study utilized toxicogenomics and comparative toxicogenomics databases to analyze data and investigate how PFAS mixtures may contribute to the development of PCOS. The results indicated that 74 genes are associated with both PFAS exposure and PCOS progression. Enrichment analysis suggested that cell cycle regulation and steroid hormone synthesis may be crucial pathways through which PFAS mixtures participate in the development of PCOS, involving important genes such as CCNB1 and SRD5A1. Furthermore, the study identified transcription factors (TFs) and miRNAs that may be involved in the onset and progression of PCOS, constructing regulatory networks encompassing TFs-mRNA interactions and miRNA-mRNA relationships to elucidate their regulatory roles in gene expression. By utilizing data mining techniques based on toxicogenomic databases, this study provides relatively comprehensive insights into the association between exposure factors and diseases compared to traditional toxicology studies. These findings offer new perspectives for further in vivo or in vitro investigations and contribute to understanding the pathogenesis of PCOS, thereby providing valuable references for identifying clinical treatment targets.

Prenatal cadmium exposure has inter-generational adverse effects on Sertoli cells through the follicle-stimulating hormone receptor pathway.

In brief: Exposure to cadmium (Cd) during pregnancy can potentially harm the reproductive system of male offspring. This article shows that pregnant woman should be protected from cadmium exposure. Abstract: Exposure to cadmium (Cd) during pregnancy can potentially harm the reproductive system of male offspring, although the full extent of its heritable effects remains partially unresolved. In this study, we examined the inter-generational impacts of Cd using a distinct male-lineage generational model. Pregnant Sprague-Dawley female rats (F0) were administered control or cadmium chloride (0.5, 1 and 2 mg/day) via intra-gastric administration from gestation day 1 to 20. Subsequently, the first filial generation (F1) male rats were mated with untreated females (not exposed to Cd) to produce the second filial generation (F2). Histopathological analysis of the F1 and F2 generations revealed abnormal testicular development, while ultrastructural examination indicated damage to Sertoli cells. Cd exposure also led to alterations in serum hormone levels (gonadotropin-releasing hormone, follicle-stimulating hormone) and reduced follicle-stimulating hormone receptor (FSHR) protein expression in Sertoli cells in the F1 generation. Furthermore, Cd affected the mRNA and protein expression of FSHR pathway factors and DNA methyltransferase, albeit with distinct patterns and inconsistencies observed between the F1 and F2 generations. Overall, our findings indicate that prenatal Cd exposure, using a male-lineage transmission model, can induce inter-generational effects on male reproduction, particularly by causing toxicity in Sertoli cells. This effect appears to be primarily mediated through disruptions in the FSHR pathway and changes in DNA methyltransferase activity in the male testes.

Marital status and survival in laryngeal squamous cell carcinoma patients: a multinomial propensity scores matched study.

OBJECTIVE: To explore the correlation between the marital status and prognosis of patients with laryngeal squamous cell carcinoma (LSCC). STUDY DESIGN: MPSM was adopted to minimize the maximum standardized average difference of the covariates among the four groups with different marital status. SETTING: Multinomial propensity scores matching (MPSM) based on data from the surveillance, epidemiology, and end results (SEER) database. METHODS: The Kaplan-Meier method and log-rank test were used to compare the survival outcomes of these groups with different marital status. RESULTS: Totally, 16,981 LSCC patients (median [IQR] age 62 [55-69] years; 829 [76.41%] males) from 2004 to 2016 were included in this study. Among them, 9112 (53.66%) were married, 2708 (15.95%) divorced or separated, 1709 (10.06%) widowed, and 3452 (20.33%) single. After MPSM, the weights make the characteristics of four groups with different marital status sufficient balance. The Kaplan-Meier method and log-rank test showed widowed patients may lead to the highest mortality rate while married patients have a higher survival rate than the other three groups. Single and divorced or separated patients had no significant difference in the survival rate. In addition, multivariate analysis by controlling for confounding factors showed that in male, well-differentiated, and early stage patients, compared with married, unmarried was an independent risk factor for CSS (P < 0.05). CONCLUSION: Marital status showed a significant association with the survival status of LSCC patients. Importantly, the outcome of married patients was better, while widowed patients tended to have worse prognosis.

Effects of cadmium exposure during pregnancy on genome-wide DNA methylation and the CREB/CREM pathway in the testes of male offspring rats.

This experimental study explored the multigenerational and transgenerational effects of cadmium (Cd) exposure during pregnancy on the testicular tissue and spermatogenesis of male offspring rats. CdCl2 at different doses (0, 0.5, 1, 2 mg/kg/day) were dispensed to pregnant SD rats, thus producing generation F1. Adult females in F1 (PND 56) were mated with untreated fertile males so as to produce generation F2. Likewise, adult females in F2 were mated to produce generation F3. Damages to testicular tissue were observed in all the three generations, with serum testosterone (T) increased in F2 and F3. Notably, the genome-wide DNA methylation level in the testicular tissue of F1 was altered, as was the expression of F1-F3 methyltransferases. In addition, the expression of Creb/Crem pathway, a pathway critical for the metamorphosis from postmeiotic round spermatocytes to spermatozoa, was also remarkably altered in the three generations. In concludion, prenatal Cd exposure might bring multigenerational and transgenerational toxic effects to testes via genome-wide DNA methylation and the regulation of CREB/CREM pathway.

Organophosphate esters in human serum: a relatively simple and efficient liquid chromatography-mass spectrometry method.

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers, which are of growing concern due to their endocrine-disrupting effects, developmental toxicity, and potential carcinogenicity. However, data on human exposure to OPEs is still scarce. In this study, a relatively simple and efficient method with less serum consumption for the detection of OPEs in human serum was developed and validated. Nine OPEs in 200 µL of human serum were extracted by an acetonitrile-formic acid system and analyzed using ultra-high-performance liquid chromatography-quadrupole tandem time-of-flight high-resolution mass spectrometry. Several experiments were conducted to optimize the chromatographic and mass spectrometric conditions as well as sample preparation to obtain a more sensitive and efficient analytical protocol. The proposed method was examined in terms of its linearity, accuracy, precision, detection limit, and matrix effect. The matrix-spiked recoveries of the target OPEs ranged from 83.3% to 111.1%, with relative standard deviations between 2.7% and 16.6%. The detection limits were within (0.002 to 0.029) ng mL-1, while the quantification limits were within (0.007 to 0.098) ng mL-1. The internal standard-corrected matrix effects varied from 82.7% to 113.9%. Finally, the method was applied to detect OPEs in actual human serum samples. All nine OPEs were detected in 269 serum samples to varying degrees, with the average concentrations ranging from (0.08 to 1.77) ng mL-1. After validation, the method was found to be simple in pretreatment, high in sensitivity, good in practicality, and suitable for exposure evaluation of OPEs in populations.

Association between PFAS exposure and thyroid health: A systematic review and meta-analysis for adolescents, pregnant women, adults and toxicological evidence.

A burgeoning body of epidemiological and toxicological evidence suggests that thyroid health may be significantly impacted by exposure to both long- and short-chain perfluoroalkyl substances (PFAS) compounds. We conducted a meta-analysis to examine the association between 16 PFAS compounds and five thyroid hormones (TSH, TT3, TT4, FT3, and FT4) in the serum of a pregnant women, adolescents, and adults. The dose-response relationship between some PFAS and thyroid hormones in different population subpopulation was found and the model was fitted. We also amalgamated data from 18 animal experiments with previously published in vitro studies to elucidate the toxicological mechanisms underlying the impact of PFAS on the thyroid gland. The results of the study showed that (a) both conventional and emerging PFAS compounds were identified in human samples and exhibited associations with thyroid health outcomes; (b) in animal studies, PFAS have been found to impact thyroid gland health through two primary mechanisms: by influencing the hypothalamic-pituitary-thyroid axis and by binding to thyroid receptors. This study provides a systematic description of the health effects and risk assessment associated with PFAS exposure on the thyroid gland. Furthermore, dose-response relationships were established through the Hill model in python.