Evaluating the effect of PFAS on liver cells

New experimental data could significantly enhance knowledge of several types of PFAS and their potential health effects, according to researchers from the Division of Translational Toxicology.

PFAS are an important class of chemicals with a broad range of industrial applications, molecular structures, and toxicological properties. Because there are hundreds of PFAS in commercial use, traditional toxicity testing is untenable to obtain data for all of them in a timely manner. Currently, only limited toxicity data are available for human health evaluation.

To address the lack of data, researchers used targeted liquid chromatography–mass spectrometry to investigate how human liver cells clear 54 PFAS. The results showed that there was no significant clearance for 35 PFAS. However, structural evaluations showed appreciable clearance for fluorotelomer carboxylic acids, and per- and polyfluorosulfonamides were also more readily metabolized. Additional results suggested that PFAS sulfonamides are broken down to more stable sulfonic acids, which is an important consideration for exposure modeling.

According to the authors, this research greatly expands the PFAS toxicokinetic dataset in cells beyond the legacy carboxylic and sulfonic acids. The study could enable refined modeling and human health evaluations across this important set of emerging contaminants. (JW)

Citation: Crizer DM, Rice JR, Smeltz MG, Lavrich KS, Ravindra K, Wambaugh JF, DeVito M, Wetmore BA. 2024. In vitro hepatic clearance evaluations of per- and polyfluoroalkyl substances (PFAS) across multiple structural categories. Toxics 12(9):672.

Prenatal organophosphate ester exposure may influence blood pressure in pregnancy

Exposure to organophosphate esters (OPEs) during pregnancy may influence blood pressure in pregnancy, according to NIEHS researchers and their collaborators.

OPEs are chemicals that are commonly used as plasticizers and flame retardants in a variety of consumer products, such as children’s toys, food packaging, and personal care products. OPE metabolites are often detected in urine in the general U.S. population, including pregnant women. Various studies have reported that adverse pregnancy outcomes, including preeclampsia, a disorder in which pregnant women develop high blood pressure, and gestational high blood pressure may be influenced by exposure to environmental pollutants, including OPEs. However, potential links between prenatal OPE exposure and high blood pressure during pregnancy remain understudied.

To address this knowledge gap, the researchers examined the link between maternal urinary OPE metabolites and preeclampsia and blood pressure during pregnancy. Their analysis involved 900 participants from the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort study for babies born at the small and large ends of the growth spectrum. The authors evaluated the urinary concentrations of OPE biomarkers, repeated blood pressure measurements in pregnancy, and diagnosis of preeclampsia.

The researchers did not find significant associations between OPE metabolites and preeclampsia; however, certain OPE metabolites were associated with blood pressure. A strong positive association was observed between bis(1-chloro-2-propyl) phosphate and blood pressure, whereas an inverse association was found between bis(2-chloroethyl) phosphate and blood pressure during pregnancy.

Together, the results indicate that OPE exposure during pregnancy may influence blood pressure in pregnancy. According to the authors, future research is warranted to specifically address the potential effects of OPE exposure during pregnancy with a larger number of preeclampsia cases. (SS)

Citation: Lueth AJ, Bommarito PA, Stevens DR, Welch BM, Cantonwine DE, Ospina M, Calafat AM, Meeker JD, McElrath TF, Ferguson KK. 2024. Exposure to organophosphate ester flame retardants and plasticizers and associations with preeclampsia and blood pressure in pregnancy. Environ Res. 262(Pt 2):119910.

Mineralocorticoid receptors shape brain development and adult behavior

Prenatal inhibition of mineralocorticoid receptors, a particular stress hormone receptor, is sufficient to alter neuronal circuitry and adult behavior, according to NIEHS researchers.

Mineralocorticoid receptors are highly enriched in area CA2, which is part of a brain region called the hippocampus, and function in learning, memory, and behavioral adaptation to stress in adults. They are also expressed during embryonic development, when brain connections are being made, but it is not fully known how the receptors contribute to brain development. Importantly, variations of the gene encoding mineralocorticoid receptors are seen in individuals with a syndromic form of autism spectrum disorder.

The researchers found that prenatal exposure to spironolactone, which blocks mineralocorticoid receptors, disrupted CA2 connectivity and altered behavior in adult mice. Specifically, the animals became more reactive to novel objects, which may be attributable to the observed loss of specific neuronal inputs to CA2 and lack of appropriate outputs from CA2.

Taken together, the results indicate that mineralocorticoid receptor activity during development is required for normal connections to form in the brain and normal behavior in adult animals, suggesting one mechanism by which genetic impairment of the receptor may contribute to neuropsychiatric disorders. In addition, exposure to stress increases the release of stress hormones, and increased stress hormones can affect expression and activity of mineralocorticoid receptors. According to the authors, these findings suggest that exposure to prenatal stress may affect formation of proper neuronal connections, which can have lasting effects into adulthood. (JW)

Citation: Jones SM, Sleiman SJ, McCann KE, Jarmusch AK, Alexander GM, Dudek SM. 2024. Prenatal exposure to the mineralocorticoid receptor antagonist spironolactone disrupts hippocampal area CA2 connectivity and alters behavior in mice. Neuropsychopharmacology; doi: 10.1038/s41386-024-01971-7 [online 5 Sept 2024]

Gut microbes are linked to HIV-1 infection among men who have sex with men

Sexual behavior is linked to changes in gut microbes and inflammation, leading to HIV-1 infection among men who have sex with men, according to NIEHS researchers and their collaborators.

Sexual contact among men who have sex with men has been the primary route of HIV-1 transmission in the U.S. Changes in gut microbial composition have been found to precede the onset of HIV-1 infection in men who have sex with men (MSM). However, it has not been clear how sexual behavior, inflammatory biomarkers such as cytokines, and the gut microbiome may interact to influence subsequent HIV-1 infection.

The researchers hypothesized that changes in gut microbial composition are associated with local and systemic immune activation and inflammation, leading to increased susceptibility to HIV-1 infection. In the current study, they discovered that the effects of sexual behavior on HIV-1 infection are mediated by the inflammatory cytokines sCD14 and sCD163, as well as changes in the abundance of several gut microbes. Specifically, among MSM, the researchers linked the effects of receptive anal intercourse with large number of partners to a reduction of many commensal bacteria, such as several species of Bacteroides that play a prominent role in gut health, before HIV-1 infection. The imbalance in gut microbes was strongest for those with the highest number of sexual partners.

According to the authors, these results reveal an intricate interplay among sexual behavior, immune response, and the gut microbiota composition, which greatly affect one’s susceptibility to HIV-1 infection. (Watch related YouTube video.) (JW)

Citation: Lin H, Chen Y, Abror-Lacks G, Price M, Morris A, Sun J, Palella F, Chew KW, Brown TT, Rinaldo CR, Peddada SD. 2024. Sexual behavior is linked to changes in gut microbiome and systemic inflammation that lead to HIV-1 infection in men who have sex with men. Commun Biol 7(1):1145.

How glucocorticoid receptors support corneal health

Glucocorticoid receptor signaling in the cornea plays a critical role in ocular development and in maintaining proper eye function, according to NIEHS researchers and their collaborators.

The cornea protects the interior of the eye from external agents such as bacteria, viruses, and debris. Synthetic glucocorticoids are widely prescribed for the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor, but the functions of glucocorticoid signaling in the cornea are poorly understood.

The researchers found that treatment with glucocorticoid eye drops led to significant changes in the activity of corneal genes associated with multiple biological functions, including the immune response. Specifically, glucocorticoid receptor signaling in the cornea regulated the expression of genes implicated in cell growth, proliferation, and movement, as well as in repair mechanisms. In addition, mice lacking corneal glucocorticoid receptors exhibited loss of pupils, as well as a deformed and opaque lens. Glucocorticoid receptor signaling in the cornea also played a critical role in regulating the growth of new blood vessels and the infiltration of immune cells into the cornea.

According to the authors, the study could aid future research in developing improved strategies for treating corneal inflammation.

Citation: Kadmiel M, Diaz-Jimenez D, Oakley RH, Petrillo MG, He B, Xu X, Cidlowski JA. 2024. Glucocorticoid receptor signaling is critical for mouse corneal development, inhibition of inflammatory response, and neovascularization of the cornea. Am J Pathol 194(10):1938-50.