Biology subjects

Pattarawat, P.

Publications and source records attributed to Pattarawat, P..

4 recordsLinked to original sources

bioRxiv2026

Proprotein convertase activity regulates cumulus-oocyte-complex matrix integrity and cumulus cell migration during ovulation via a GDF9-dependent mechanism

Cumulus cells have well-established roles early in ovulation but the key molecules that drive their behavior in later stages, leading to follicle rupture, remain underexplored. Here, we observed that inhibition of proprotein convertases (PCSKs) via a pan-inhibitor (PCI) impaired follicular rupture and disrupted the cumulus matrix integrity within intact follicles. Reduced cumulus cell adherence to the cumulus-oocyte-complex (COC) matrix was also observed in isolated COCs and notably occurred late during the maturation window without affecting oocyte maturation. Visualization of PCSK transcript and protein expression, as well as selective inhibition of specific PCSKs, determined that the observed phenotype in COCs is likely attributed to PCSK5A inhibition. We conducted bulk RNA-sequencing and proteomics of PCI-treated COCs which revealed that PCSK inhibition caused dysregulation of extracellular matrix organization, cell migration/adhesion, and TGF-{beta} signaling pathways. Subsequent validation showed that this inhibition translated to disrupted matrix organization and altered migratory and adhesive behaviors in cumulus cells. The TGF-{beta} ligand GDF9 has a predicted PCSK cleavage site, and supplementation with GDF9 rescued matrix integrity suggesting its role as a downstream substrate of PCSKs to regulate matrix organization. Altogether, this study identified PCSK5A and GDF9 as key regulators of COC matrix integrity and cumulus cell migration during late ovulation. These findings highlight novel factors required for follicle rupture which can be leveraged for the development of fertility therapeutics and contraceptives.

cell biology↗

bioRxiv2026

Wildfire emitted particulate matter induces ovarian hyperandrogenism through aryl hydrocarbon receptor activation

Wildfires have become more frequent and intense worldwide. Wildfire emitted particulate matter (WFPM) can be more toxic than urban background PM due to its greater content of nanoscale size (WFPM0.1) and presence of more polar organic compounds, including polycyclic aromatic hydrocarbons (PAHs). While exposure to WFPM has been linked to cardiovascular and respiratory diseases, its impact on female reproduction remains elusive. Here, we used an in vivo mouse intratracheal exposure model and a 3D ovarian follicle culture system, together with molecular, transcriptomic, and computational approaches, to examine the female reproductive effects of lab-synthesized (LS-WFPM0.1) and real-world Canadian WFPM0.1 (C-WFPM0.1), collected from the New York City and New Jersey metropolitan area during the June 2023 wildfire events. Intratracheal exposure to environmentally relevant dose of LS-WFPM0.1 disrupted mouse estrous cycles and elevated serum concentrations of estradiol and testosterone. RT-qPCR and single-follicle RNA-sequencing (RNA-seq) analysis revealed altered steroidogenic genes, transcriptomic changes, and activation of aryl hydrocarbon receptor (AhR) in antral follicles from mice treated with LS-WFPM0.1. LS-WFPM0.1 consistently increased testosterone secretion and stimulated genes related to androgen synthesis and AhR in vitro. Single-follicle and single-oocyte RNA-seq analysis identified differentially expressed genes related to inflammation in somatic cells and mitochondrial respiratory chain in oocytes. Both C-WFPM0.1 and benzo[a]pyrene, a high-molecular-weight PAH, reproduced these ovarian defects. Mechanistically, AhR inhibition reversed hyperandrogenism induced by WFPM0.1. Together, our findings suggest that WFPM0.1, an increasingly pervasive environmental exposure, adversely impacts female reproductive functions by disrupting ovarian steroidogenesis and inducing hyperandrogenism through AhR activation, highlighting an urgent unmet need for further mechanistic studies and epidemiological investigations to define the reproductive risks of wildfire smoke exposure in human populations.

pharmacology and toxicology↗

bioRxiv2024

Ovarian disrupting effects and mechanisms of long- and short-chain per- and polyfluoroalkyl substances in mice

BackgroundThe extensive use of per- and polyfluoroalkyl substances (PFAS) has led to environmental contamination and bioaccumulation. Previous research linked PFAS exposure to female reproductive disorders, but the mechanism remains elusive. Further, most studies focused on legacy long-chain PFOA and PFOS, yet the reproductive impacts of other long-chain PFAS and short-chain alternatives are rarely explored. ObjectivesWe investigated the effects and mechanisms of long- and short-chain PFAS on the ovary and associated ovarian functions. MethodsA 3D in vitro ovarian follicle culture system and an in vivo mouse model, together with approaches of reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, RNA-sequencing, pharmacological treatment, in situ zymography, histology, in situ hybridization, analytical chemistry, and benchmark dose modeling (BMD), were used to test environmentally relevant exposure levels of six long- and short-chain PFAS on follicle maturation, hormone secretion, and ovulation. ResultsIn vitro exposure revealed that long-but not short-chain PFAS interfered with gonadotropin-dependent follicle maturation, ovulation, and hormone secretion. Mechanistically, long-chain perfluorononanoic acid (PFNA) acted as a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist in granulosa cells to disrupt follicle-stimulating hormone (FSH)-dependent follicle maturation, luteinizing hormone (LH)-stimulated ovulation, and associated gene regulatory pathways. In vivo mouse exposure confirmed the ovarian accumulation of PFNA and the mechanism of PPAR{gamma}-mediated ovarian toxicities of PFNA observed in vitro. The BMD analysis of in vitro and in vivo results suggested human relevant exposure levels of long-chain PFAS in our study pose an extra risk of ovarian defects, with follicular rupture as the most sensitive endpoint. DiscussionUsing in vitro follicle culture and in vivo mouse models, we discovered that long-chain PFAS interfere with gonadotropin-dependent follicle maturation, hormone secretion, and ovulation, posing a non-negligible risk to womens reproductive health including anovulation, irregular menstrual cycles, and sub- or infertility.

pharmacology and toxicology↗

bioRxiv2022

Structure-based discovery of selective histone deacetylase (HDAC) 3 and 4 inhibitors

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. Here, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the NCOR protein. These pockets were then targeted using an ensemble docking approach combined with consensus scoring to identify compounds with a different mechanism of binding than the currently known HDAC modulators. Using this approach, 18 compounds predicted in silico to bind to HDAC4s novel pockets were tested in vivo testing on two cancer cell lines. Of these, 5 compounds decreased cell viability to less than 60%. One inhibited the catalytic activity of HDAC4 but not HDAC3, which belongs to a different family of HDACs (Class I). The most potent compound has an IC50 comparable to the FDA-approved compound SAHA (Vorinostat). While there are currently no known inhibitors reported to bind highly selectively to HDAC4, the present result suggests potential mechanistic and chemical approaches for the development of selective HDAC4 modulators.

cancer biology↗