Adverse PFAS effects on mouse oocyte in vitro maturation are associated with carbon‐chain length and inclusion of a sulfonate group

Abstract

Objectives: Per-and polyfluoroalkyl substances (PFAS) are man-made chemicals that are widely used in various products. PFAS are characterized by their fluorinated carbon chains that make them hard to degrade and bioaccumulate in human and animals. Toxicological studies have shown PFAS toxic effects: cytotoxicity, immunotoxicity, neurotoxicity, and reproductive toxicity. However, it is still unclear how the structures of PFAS, such as carbon-chain length and functional groups, determine their reproductive toxicity.Methods and Results: By using a mouse-oocyte-in-vitro-maturation (IVM) system, we found the toxicity of two major categories of PFAS, perfluoroalkyl carboxylic acid (PFCA) and perfluoroalkyl sulfonic acid (PFSA), is elevated with increasing carbonchain length and the inclusion of the sulfonate group. Specifically, at 600 μM, perfluorohexanesulfonic acid (PFHxS) and perfluorooctanesulfonic acid (PFOS) reduced the rates of both germinal-vesicle breakdown (GVBD) and polar-body extrusion (PBE) as well as enlarged polar bodies. However, the shorter PFSA, perfluorobutanesulfonic acid (PFBS), and all PFCA did not show similar adverse cytotoxicity. Further, we found that 600 μM PFHxS and PFOS exposure induced excess reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP). Cytoskeleton analysis revealed that PFHxS and PFOS exposure induced chromosome misalignment, abnormal F-actin organization, elongated spindle formation, and symmetric division in the treated oocytes. These meiotic defects compromised oocyte developmental competence after parthenogenetic activation. Conclusions:Our study provides new information on the structure-toxicity relationship of PFAS.

Mixture Effects of Per- and Polyfluoroalkyl Substances on Embryonic and Larval Sheepshead Minnows (Cyprinodon variegatus)

“…These results indicate that the length of the carbon chain may correlate with the level of observed toxicity, as all three compounds had the same carboxylic acid functional group and only differed by the number of carbons in their backbone. A trend of increased PFAS toxicity has been observed with increased carbon chain length and the presence of a sulfonate group [ 30 , 35 , 57 ], but to our knowledge, this is the first study which provides evidence of increased antagonistic effects of carboxylic acids with increasing carbon chain lengths co-treated with PFOS. In a similar study using zebrafish ( Danio rerio ) embryos, Ding et al [ 32 ] observed a complex interactive effect of a PFOS-PFOA mixture, observing antagonistic, additive, and synergistic effects depending on the concentration of each compound.…”

“…It is unknown if this is due to differences in life stages, if the mechanisms are species-specific, or a different reason. While PFOS and other sulfonic acid-containing PFAS have been attributed as major contributors to PFAS-induced oxidative stress [ 29 , 30 , 78 ], both PFOS and PFOA have been shown to up- or downregulate several oxidative stress genes in myriad fish species (summarized in Lee et al [ 7 ]). An ROS-generating mechanism of PFOS has been explored in zebrafish (Shi and Zhou [ 28 ]), but there are few comparisons between other individual PFAS and mixtures, warranting further study.…”

“…In contrast, PFAS with sulfonic acids are typically less potent PPAR agonists but induce greater acute toxicity [ 25 ]. A potential mechanism of toxicity for sulfonic acids (e.g., PFOS) is the induction of reactive oxygen species (ROS) which results in oxidative stress [ 28 , 29 , 30 ]. While PPARα activation and ROS generation are potential modes of action for some PFAS species, further work is required to validate these mechanisms.…”

Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models

“…Specifically, longer-chain compounds with 7–10 carbons were found to be more likely to induce changes in gene expression . Prior studies, utilizing a mouse-oocyte-in vitro-maturation system to detect the toxicity of PFOA, PFHxA, PFBA, PFOS, PFHxS, and PFBS, found that the toxicity of the two major categories of PFAS, perfluoroalkyl carboxylic acid (PFCA) and perfluoroalkyl sulfonic acid (PFSA), increases with increasing carbon chain length and the inclusion of the sulfonate group . Our cytotoxicity result of evaluated PFAS aligns with this trend, with PFOS exhibiting the strongest cytotoxicity, followed by PFOA, PFHxS, PFHxA, and then PFBS and PFBA.…”

How Per- and Poly-Fluoroalkyl Substances Affect Gamete Viability and Fertilization Capability: Insights from the Literature

“…Environmental exposure has led to high concentrations found in the blood and lungs due to their amphiphilic properties and high affinity for proteins such as albumin [ 1 , 2 , 19 ]. PFAS can pass through the blood ovarian follicle barrier and have been detected in follicular fluid, impacting female reproduction [ 14 , 20 , 21 , 22 , 23 ]. Other notable concentrations have been found in serum, seminal fluid, thyroid, reproductive organs, brain, and many fetal-dependent structures, such as the umbilical cord and breast milk [ 3 , 17 ].…”