Characterizing cleft palate toxicants using ToxCast data, chemical structure, and the biomedical literature.

Cleft palate has been linked to both genetic and environmental factors that perturb key events during palatal morphogenesis. As a developmental outcome, it presents a challenging, mechanistically complex endpoint for predictive modeling. A data set of 500 chemicals evaluated for their ability to induce cleft palate in animal prenatal developmental studies was compiled from Toxicity Reference Database and the biomedical literature, which included 63 cleft palate active and 437 inactive chemicals.

Embryonic Midfacial Palatal Organ Culture Methods in Developmental Toxicology.

The morphogenesis of the secondary palate provides an interesting model for many of the processes involved in embryonic development. A number of in vitro models have been used to study craniofacial development, including whole embryo culture, palatal mesenchymal and micromass cell cultures, and Trowell-like palatal cultures in which dissected palates are cultured individually or as pairs in contact on a support above medium. This chapter presents a detailed protocol for the culture of maxillary midfacial tissues, including the palatal shelves, in suspension culture.

A Three-Dimensional Organoid Culture Model to Assess the Influence of Chemicals on Morphogenetic Fusion.

Embryologic development involves cell differentiation and organization events that are unique to each tissue and organ and are susceptible to developmental toxicants. Animal models are the gold standard for identifying putative teratogens, but the limited throughput of developmental toxicological studies in animals coupled with the limited concordance between animal and human teratogenicity motivates a different approach. In vitro organoid models can mimic the three-dimensional (3D) morphogenesis of developing tissues and can thus be useful tools for studying developmental toxicology.

Development of an organotypic stem cell model for the study of human embryonic palatal fusion.

Background: Cleft palate (CP) is a common birth defect, occurring in an estimated 1 in 1,000 births worldwide. The secondary palate is formed by paired palatal shelves, consisting of a mesenchymal core with an outer layer of epithelial cells that grow toward each other, attach, and fuse. One of the mechanisms that can cause CP is failure of fusion, that is, failure to remove the epithelial seam between the palatal shelves to allow the mesenchyme confluence.

Engineering human cell spheroids to model embryonic tissue fusion in vitro.

Epithelial-mesenchymal interactions drive embryonic fusion events during development, and perturbations of these interactions can result in birth defects. Cleft palate and neural tube defects can result from genetic defects or environmental exposures during development, yet very little is known about the effect of chemical exposures on fusion events during human development because of a lack of relevant and robust human in vitro assays of developmental fusion behavior. Given the etiology and prevalence of cleft palate and the relatively simple architecture and composition of the embryonic palate, we sought to develop a three-dimensional culture system that mimics the embryonic palate and could be used to study fusion behavior in vitro using human cells.

Engineering epithelial-stromal interactions in vitro for toxicology assessment.

Crosstalk between epithelial and stromal cells drives the morphogenesis of ectodermal organs during development and promotes normal mature adult epithelial tissue homeostasis. Epithelial-stromal interactions (ESIs) have historically been examined using mammalian models and ex vivo tissue recombination. Although these approaches have elucidated signaling mechanisms underlying embryonic morphogenesis processes and adult mammalian epithelial tissue function, they are limited by the availability of tissue, low throughput, and human developmental or physiological relevance.

Perfluoroalkyl acids-induced liver steatosis: Effects on genes controlling lipid homeostasis.

Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to their extensive use in industrial and consumer products, and their slow decay. Biochemical tests in rodent demonstrated that these chemicals are potent modifiers of lipid metabolism and cause hepatocellular steatosis. However, the molecular mechanism of PFAAs interference with lipid metabolism remains to be elucidated.

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted.

The effects of perfluorinated chemicals on adipocyte differentiation in vitro.

The 3T3-L1 preadipocyte culture system has been used to examine numerous compounds that influence adipocyte differentiation or function. The perfluoroalkyl acids (PFAAs), used as surfactants in a variety of industrial applications, are of concern as environmental contaminants that are detected worldwide in human serum and animal tissues. This study was designed to evaluate the potential for PFAAs to affect adipocyte differentiation and lipid accumulation using mouse 3T3-L1 cells.

Evaluating the additivity of perfluoroalkyl acids in binary combinations on peroxisome proliferator-activated receptor-α activation.

Perfluoroalkyl acids (PFAAs) are found globally in the environment, detected in humans and wildlife, and are typically present as mixtures of PFAA congeners. Mechanistic studies have found that responses to PFAAs are mediated in part by PPARα. Our previous studies showed that individual PFAAs activate PPARα transfected into COS-1 cells.

Evaluation of perfluoroalkyl acid activity using primary mouse and human hepatocytes.

While perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been studied at length, less is known about the biological activity of other perfluoroalkyl acids (PFAAs) detected in the environment. Using a transient transfection assay developed in COS-1 cells, our group has previously evaluated a variety of PFAAs for activity associated with activation of peroxisome proliferator-activated receptor alpha (PPARα). Here we use primary heptatocytes to further assess the biological activity of a similar group of PFAAs using custom designed Taqman Low Density Arrays.

Testing for departures from additivity in mixtures of perfluoroalkyl acids (PFAAs).

This study is a follow-up to a paper by Carr et al. that determined a design structure to optimally test for departures from additivity in a fixed ratio mixture of four perfluoroalkyl acids (PFAAs) using an in vitro transiently-transfected COS-1 PPARα reporter model with a mixing ratio that is based on average serum levels in NHANES subjects. Availability of information regarding potential for additivity of PFAAs in mixtures is critically important for risk assessors who are concerned with the ability of the compounds to affect human health and impact ecological systems.

Effects of perfluorooctanoic acid (PFOA) on expression of peroxisome proliferator-activated receptors (PPAR) and nuclear receptor-regulated genes in fetal and postnatal CD-1 mouse tissues.

PPARs regulate metabolism and can be activated by environmental contaminants such as perfluorooctanoic acid (PFOA). PFOA induces neonatal mortality, developmental delay, and growth deficits in mice. Studies in genetically altered mice showed that PPARα is required for PFOA-induced developmental toxicity.

Activation of mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) by perfluoroalkyl acids (PFAAs): further investigation of C4-C12 compounds.

Perfluorinated alkyl acids (PFAAs) are manufactured surfactants found globally in the environment and in tissues of humans and wildlife. Several PFAAs adversely affect rodents and activation of PPARα is thought to be their mode of action. Our previous study demonstrated that some PFAAs activate mouse and human PPARα in transiently transfected COS-1 cells.

Gene Expression Profiling in Wild-Type and PPARα-Null Mice Exposed to Perfluorooctane Sulfonate Reveals PPARα-Independent Effects.

Perfluorooctane sulfonate (PFOS) is a perfluoroalkyl acid (PFAA) and a persistent environmental contaminant found in the tissues of humans and wildlife. Although blood levels of PFOS have begun to decline, health concerns remain because of the long half-life of PFOS in humans. Like other PFAAs, such as, perfluorooctanoic acid (PFOA), PFOS is an activator of peroxisome proliferator-activated receptor-alpha (PPARα) and exhibits hepatocarcinogenic potential in rodents.

Developmental effects of perfluorononanoic Acid in the mouse are dependent on peroxisome proliferator-activated receptor-alpha.

Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα). In the current study, we used PPARα knockout (KO) and 129S1/SvlmJ wild-type (WT) mice to investigate the role of PPARα in mediating PFNA-induced in vivo effects.

Peroxisome proliferator-activated receptors alpha, Beta, and gamma mRNA and protein expression in human fetal tissues.

Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study examines expression of PPARalpha, beta, and gamma mRNA and protein in human fetal tissues.

The etiology of cleft palate: a 50-year search for mechanistic and molecular understanding.

Dates of special, historical significance, such as the 50th anniversary of the founding of the Teratology Society, prompt a desire to pause and look back and contemplate where we began, how far we have come, and consider the future for our scientific endeavors. The study of the etiology of cleft palate extends many years into the past and was a subject of interest to many of the founding members of the Teratology Society. This research area was intensively pursued and spawned a vast portfolio of published research.

Effects of perfluorooctanoic acid on mouse mammary gland development and differentiation resulting from cross-foster and restricted gestational exposures.

The adverse consequences of developmental exposures to perfluorooctanoic acid (PFOA) are established in mice, and include impaired development of the mammary gland (MG). However, the relationships between timing or route of exposure, and consequences in the MG have not been characterized. To address the effects of these variables on the onset and persistence of MG effects in female offspring, timed pregnant CD-1 dams received PFOA by oral gavage over various gestational durations.

Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development.

The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily and there are three primary subtypes, PPARalpha, beta, and gamma. These receptors regulate important physiological processes that impact lipid homeostasis, inflammation, adipogenesis, reproduction, wound healing, and carcinogenesis. These nuclear receptors have important roles in reproduction and development and their expression may influence the responses of an embryo exposed to PPAR agonists.

Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths.

Perfluoroalkyl acids (PFAAs) are surfactants used in consumer products and persist in the environment. Some PFAAs elicit adverse effects on rodent development and survival. PFAAs can activate peroxisome proliferator-activated receptor alpha (PPARalpha) and may act via PPARalpha to produce some of their effects.

Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR alpha) in the mouse.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of perfluorinated compounds. Both are environmentally persistent and found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in laboratory rodents.

Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPAR-alpha knockout and wild-type mice.

Perfluorooctanoic acid (PFOA) is a chemical used in the production of fluoropolymers. Its persistence in the environment and presence in humans and wildlife has raised health concerns. Liver tumor induction by PFOA is thought to be mediated in rodents by PPAR-alpha.

Gene profiling in the livers of wild-type and PPARalpha-null mice exposed to perfluorooctanoic acid.

Health concerns have been raised because perfluorooctanoic acid (PFOA) is commonly found in the environment and can be detected in humans. In rodents, PFOA is a carcinogen and a developmental toxicant. PFOA is a peroxisome proliferator-activated receptor alpha (PPARalpha) activator; however, PFOA is capable of inducing heptomegaly in the PPARalpha-null mouse.