Perinatal exposure to environmental chemicals that disrupt thyroid function can perturb testis development.

Thyroid hormones (THs) are essential for normal growth and development. Their role in skeletal and brain development is well established, with congenital hypothyroidism causing stunted growth and severe intellectual disability. THs are also important for the development of other tissues and organs, including the testis.

Distinct transcriptional profiles in rat thyroid glands after developmental exposure to three in vitro thyroperoxidase inhibiting chemicals.

Thyroperoxidase (TPO) is central in thyroid hormone (TH) synthesis and inhibition can lead to TH deficiency. Many chemicals can inhibit TPO activity in vitro, but how this may manifest in the developing thyroid gland at the molecular level is unclear. Here, we characterized the thyroid gland transcriptome of male rats developmentally exposed to the in vitro TPO-inhibitors amitrole, 2-mercaptobenzimidazole (MBI), or cyanamide by use of Bulk-RNA-Barcoding (BRB) and sequencing.

AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor-Responsive Genes in Target Tissues.

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers.

Enhanced identification of endocrine disruptors through integration of science-based regulatory practices and innovative methodologies: The MERLON Project.

The prevalence of hormone-related health issues caused by exposure to endocrine disrupting chemicals (EDCs) is a significant, and increasing, societal challenge. Declining fertility rates together with rising incidence rates of reproductive disorders and other endocrine-related diseases underscores the urgency in taking more action. Addressing the growing threat of EDCs in our environment demands robust and reliable test methods to assess a broad variety of endpoints relevant for endocrine disruption.

Perfluorooctanesulfonic acid (PFOS) disrupts cadherin-16 in the developing rat thyroid gland.

Perfluorooctanesulfonic acid (PFOS) can disrupt the thyroid hormone (TH) system in rodents, potentially affecting perinatal growth and neurodevelopment. Some studies also suggest that gestational exposure to PFOS can lead to lower TH levels throughout life, indicating that PFOS may compromise thyroid gland development. To address this question, we utilized a rat thyroid gland culture system to study direct effects of PFOS on the developing thyroid.

In vitro assessment of potential endocrine disrupting activities of chlorinated paraffins of various chain lengths.

The production of chlorinated paraffins (CPs) has risen in the past two decades due to their versatile industrial applications. Consequently, CPs are now widely detected in human food sources, the environment, and in human matrices such as serum, the placenta and breast milk. This raises concern about prenatal and postnatal exposure.

PFOS disrupts key developmental pathways during hiPSC-derived cardiomyocyte differentiation in vitro.

Exposure to perfluorooctanesulfonic acid (PFOS) has been associated with congenital heart disease (CHD) and decreased birth weight. PFOS exposure can disrupt signaling pathways relevant for cardiac development in stem cell-derived cardiomyocyte assays, such as the PluriBeat assay, where spheroids of human induced pluripotent stem cells (hiPSCs) differentiate into contracting cardiomyocytes. Notably, cell line origin can also affect how the assay responds to chemical exposure.

PFOS-induced thyroid hormone system disrupted rats display organ-specific changes in their transcriptomes.

Perfluorooctanesulfonic acid (PFOS) is a persistent anthropogenic chemical that can affect the thyroid hormone system in humans and animals. In adults, thyroid hormones (THs) are regulated by the hypothalamic-pituitary-thyroid (HPT) axis, but also by organs such as the liver and potentially the gut microbiota. PFOS and other xenobiotics can therefore disrupt the TH system at various locations and through different mechanisms.

Using alternative test methods to predict endocrine disruption and reproductive adverse outcomes: do we have enough knowledge?

Endocrine disrupting chemicals (EDCs) are a matter of great concern. They are ubiquitous in the environment, are considered harmful to humans and wildlife, yet remain challenging to identify based on current international test guidelines and regulatory frameworks. For a compound to be identified as an EDC within the EU regulatory system, a plausible link between an endocrine mode-of-action and an adverse effect outcome in an intact organism must be established.

Developmental effects of PFOS, PFOA and GenX in a 3D human induced pluripotent stem cell differentiation model.

Polyfluoroalkyl substances (PFASs), including perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), are persistent pollutants routinely found in human blood. PFASs have been associated with health issues such as decreased birth weight and impaired vaccination response in children. Substitutes to these PFASs, such as ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate (GenX) have been introduced, although hazard information is limited.

Human-relevant concentrations of the antifungal drug clotrimazole disrupt maternal and fetal steroid hormone profiles in rats.

Clotrimazole is a non-prescription and broad-spectrum antifungal drug sold under brand names such as Canesten® and Lotrimin®. It is used to treat different types of fungal infections, from oral thrush to athlete's foot and vaginal mycosis. The level of exposure to clotrimazole is uncertain, as the exact usage amongst self-medicating patients is unclear.

Assessment of chemical mixtures using biomarkers of combined biological activity: A screening study in human placentas.

Humans are simultaneously exposed to complex mixtures of chemicals with limited knowledge on potential health effects, therefore improved tools for assessing these mixtures are needed. As part of the Human Biomonitoring for Europe (HBM4EU) Project, we aimed to examine the combined biological activity of chemical mixtures extracted from human placentas using one in vivo and four in vitro bioassays, also known as biomarkers of combined effect. Relevant endocrine activities (proliferative and/or reporter gene assays) and four endpoints were tested: the estrogen receptor (ER), androgen receptor (AR), and aryl hydrocarbon receptor (AhR) activities, as well as thyroid hormone (TH) signaling.

Assessment of source and treated water quality in seven drinking water treatment plants by in vitro bioassays - Oxidative stress and antiandrogenic effects after artificial infiltration.

Drinking water quality and treatment efficacy was investigated in seven drinking water treatment plants (DWTPs), using water from the river Göta Älv, which also is a recipient of treated sewage water. A panel of cell-based bioassays was used, including measurements of receptor activity of aryl hydrocarbon (AhR), estrogen (ER), androgen (AR), peroxisome proliferator-activated receptor alpha (PPARα) as well as induction of oxidative stress (Nrf2) and micronuclei formation. Grab water samples were concentrated by solid phase extraction (SPE) and water samples were analyzed at a relative enrichment factor of 50.

Receptor-based in vitro activities to assess human exposure to chemical mixtures and related health impacts.

Humans are exposed to a large number of chemicals from sources such as the environment, food, and consumer products. There is growing concern that human exposure to chemical mixtures, especially during critical periods of development, increases the risk of adverse health effects in newborns or later in life. Historically, the one-chemical-at-a-time approach has been applied both for exposure assessment and hazard characterisation, leading to insufficient knowledge about human health effects caused by exposure to mixtures of chemicals that have the same target.

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

Organophosphate ester flame retardants (OPFRs) are used to prevent ignition and spreading of fire. They are present in various human matrices suggesting adult, fetal, and neonate exposure. Endocrine related effects have been observed in vivo, but information at the molecular level is lacking for some OPFRs.

A novel human pluripotent stem cell-based assay to predict developmental toxicity.

There is a great need for novel in vitro methods to predict human developmental toxicity to comply with the 3R principles and to improve human safety. Human-induced pluripotent stem cells (hiPSC) are ideal for the development of such methods, because they are easy to retrieve by conversion of adult somatic cells and can differentiate into most cell types of the body. Advanced three-dimensional (3D) cultures of these cells, so-called embryoid bodies (EBs), moreover mimic the early developing embryo.

The toxicity of the methylimidazolium ionic liquids, with a focus on M8OI and hepatic effects.

Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) - an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site.

Migration studies and toxicity evaluation of cyclic polyesters oligomers from food packaging adhesives.

Multilayer materials used in food packaging are commonly manufactured with a polyurethane adhesive layer in its structure that may contain cyclic esters oligomers as potential migrants. However, little is known about their toxicity. In this work, two cyclic esters of polyurethane are evaluated in migration from 20 multilayer packaging samples.

Bisphenols B, E, F, and S and 4-cumylphenol induce lipid accumulation in mouse adipocytes similarly to bisphenol A.

Bisphenol A (BPA) has been widely reported to exert endocrine disrupting effects, including the induction of adipogenesis in cultured preadipocytes and intact animals. Because of the potential harm to human health, BPA is being substituted by structurally related bisphenols. Whether or not such BPA analogues are safe substitutes, however, remains largely unknown.

Effect-based assessment of recipient waters impacted by on-site, small scale, and large scale waste water treatment facilities - combining passive sampling with in vitro bioassays and chemical analysis.

Waste water treatment facilities are a major sources of organic micropollutants (MPs) in surface water. In this study, surface water samples were collected from seven sites along a river system in Uppsala, Sweden, during four seasons and evaluated based on the occurrence of MPs in the samples and bioactivity using in vitro bioassays. The sampling sites were differentially impacted by on-site sewage treatment facilities (OSSFs), small scale, and large scale waste water treatment plants (WWTPs).

Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis.

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC.

Methods: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens.

In vitro bioanalysis of drinking water from source to tap.

The presence of chemical pollutants in sources of drinking water is a key environmental problem threatening public health. Efficient removal of pollutants in drinking water treatment plants (DWTPs) is needed as well as methods for assessment of the total impact of all present chemicals on water quality. In the present study we have analyzed the bioactivity of water samples from source to tap, including effects of various water treatments in a DWTP, using a battery of cell-based bioassays, covering health-relevant endpoints.

Toxicity bioassays with concentrated cell culture media-a methodology to overcome the chemical loss by conventional preparation of water samples.

The use of in vitro bioassays for studies of toxic activity in environmental water samples is a rapidly expanding field of research. Cell-based bioassays can assess the total toxicity exerted by a water sample, regardless whether the toxicity is caused by a known or unknown agent or by a complex mixture of different agents. When using bioassays for environmental water samples, it is often necessary to concentrate the water samples before applying the sample.