2024: Prenatal PFAS exposure, gut microbiota dysbiosis, and neurobehavioral development in childhood

[pfpcnews]

NOTE:

1) Both inorganic and organic fluoride compounds may affect gut dysbiosis. SEE: viewtopic.php?p=1857#p1857
2) Oxidative phosphorylation is regulated by thyroid hormone (see i.e. Davies et al.2021; Sinha et al., 2015)
3) Gq/11 pathways play a crucial role

Zhou Y, Zhang L, Li Q, Wang P, Wang H, Shi H, Lu W, Zhang Y - "Prenatal PFAS exposure, gut microbiota dysbiosis, and neurobehavioral development in childhood" Journal of Hazardous Materials 133920 (2024) doi.org/10.1016/j.jhazmat.2024.133920
https://www.sciencedirect.com/science/a ... 9424004990

Abstract

Studies on the role of the gut microbiota in the associations between per- and polyfluoroalkyl substance (PFAS) exposure and adverse neurodevelopment are limited. Umbilical cord serum and faeces samples were collected from children, and the Strengths and Difficulties Questionnaire (SDQ) was conducted. Generalized linear models, linear mixed-effects models, multivariate analysis by linear models and microbiome regression-based kernel association tests were used to evaluate the associations among PFAS exposure, the gut microbiota, and neurobehavioural development. Perfluorohexane sulfonic acid (PFHxS) exposure was associated with increased scores for conduct problems and externalizing problems, as well as altered gut microbiota alpha and beta diversity. PFHxS concentrations were associated with higher relative abundances of Enterococcus spp. but lower relative abundances of several short-chain fatty acid-producing genera (e.g., Ruminococcus gauvreauii group spp.). PFHxS exposure was also associated with increased oxidative phosphorylation. Alpha and beta diversity were found significantly associated with conduct problems and externalizing problems. Ruminococcus gauvreauii group spp. abundance was positively correlated with prosocial behavior scores. Increased alpha diversity played a mediating role in the associations of PFHxS exposure with conduct problems. Our results suggest that the gut microbiota might play an important role in PFAS neurotoxicity, which may have implications for PFAS control.


OXPHOS and Thyroid Hormone

Davies KL, Smith DJ, El-Bacha T, Stewart ME, Easwaran A, Wooding PFP, Forhead AJ, Murray AJ, Fowden AL, Camm EJ - "Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner" FASEB J 35(5):e21591 (2021) doi: 10.1096/fj.202100075R
https://faseb.onlinelibrary.wiley.com/d ... 202100075R

Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128 and 142 days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105 dGA (term ~145 dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128 dGA and 142 dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128 dGA and 142 dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128 dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128 dGA and 142 dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.


Sagliocchi S, Cicatiello AG, Di Cicco E, Ambrosio R, Miro C, Di Girolamo D, Nappi A, Mancino G, De Stefano MA, Luongo C, Raia M, Ogawa-Wong AN, Zavacki AM, Paladino S, Salvatore D, Dentice M - "The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress" Redox Biol 24:101228 (2019) doi: 10.1016/j.redox.2019.101228
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543119/

Silvestri E, Lombardi A, Cioffi F, Goglia F - "BN-PAGE-Based Approach to Study Thyroid Hormones and Mitochondrial Function" Methods Mol Biol. 2310:33-45 (2021). doi: 10.1007/978-1-0716-1433-4_3
https://link.springer.com/protocol/10.1 ... 6-1433-4_3

Sinha RA, Singh BK, Zhou J, Wu Y, Farah BL, Ohba K, Lesmana R, Gooding J, Bay BH, Yen PM - "Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling" Autophagy 11(8):1341-57 (2015). doi: 10.1080/15548627.2015.1061849
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590606/

Venediktova NI, Mashchenko OV, Talanov EY, Belosludtseva NV, Mironova GD - "Energy metabolism and oxidative status of rat liver mitochondria in conditions of experimentally induced hyperthyroidism" Mitochondrion 52:190-196 (2020). doi: 10.1016/j.mito.2020.04.005
https://pubmed.ncbi.nlm.nih.gov/32278087/