Sensitivity and Accumulation of Perfluorooctanesulfonate and Perfluorohexanesulfonic Acid in Fathead Minnows (Pimephales promelas) Exposed over Critical Life Stages of Reproduction and Development.

Per- and polyfluoroalkyl substances (PFAS) have emerged as contaminants of environmental concern following release from industrial practices and use of aqueous film-forming foam (AFFF). Of the identified PFAS in surface water samples from known AFFF release sites, perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonic acid (PFHxS) are frequently detected. The focus of the present study was to determine the effects of PFOS and PFHxS to the native (and common) fathead minnow, Pimephales promelas, over critical life stages of reproduction and development. Two separate, 42-d experiments were carried out using sexually mature fish, exposed to either PFOS or PFHxS. Measured exposure concentrations for PFOS and PFHxS were 0, 44, 88, 140, and 231 µg/L and 0, 150, 300, 600, and 1200 µg/L, respectively. At day 21 of the adult exposure, eggs were collected and reared for 21 d to determine the effects of PFOS or PFHxS on development, growth, and survival of larvae. The no-observable-effect concentration (NOEC) for PFOS was 44 µg/L, and the lowest-observable-effect concentration was 88 µg/L based on reduced growth in juvenile (F1) fish. Effects from PFOS exposures that did not follow a standard dose-response curve were reduced gonadosomatic index in adult males (at 44 µg/L) and reduced fecundity in females (at 140 µg/L). There was no toxicity on apical endpoints to report on adult or juvenile fish exposed to PFHxS up to 1200 µg/L. Importantly, we note that both PFOS and PFHxS accumulated in gonads and liver of adult fish following the respective exposures. The present study supports previous literature on PFOS toxicity and accumulation in fathead minnows but resulted in a lower NOEC than previously established for this species. Environ Toxicol Chem 2021;40:811-819. © 2020 SETAC.

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process.

Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-α) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.

PGC-1ß mediates adaptive chemoresistance associated with mitochondrial DNA mutations.

Primary mitochondrial dysfunction commonly leads to failure in cellular adaptation to stress. Paradoxically, however, nonsynonymous mutations of mitochondrial DNA (mtDNA) are frequently found in cancer cells and may have a causal role in the development of resistance to genotoxic stress induced by common chemotherapeutic agents, such as cis-diammine-dichloroplatinum(II) (cisplatin, CDDP). Little is known about how these mutations arise and the associated mechanisms leading to chemoresistance. Here, we show that the development of adaptive chemoresistance in the A549 non-small-cell lung cancer cell line to CDDP is associated with the hetero- to homoplasmic shift of a nonsynonymous mutation in MT-ND2, encoding the mitochondrial Complex-I subunit ND2. The mutation resulted in a 50% reduction of the NADH:ubiquinone oxidoreductase activity of the complex, which was compensated by increased biogenesis of respiratory chain complexes. The compensatory mitochondrial biogenesis was most likely mediated by the nuclear co-activators peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) and PGC-1ß, both of which were significantly upregulated in the CDDP-resistant cells. Importantly, both transient and stable silencing of PGC-1ß re-established the sensitivity of these cells to CDDP-induced apoptosis. Remarkably, the PGC-1ß-mediated CDDP resistance was independent of the mitochondrial effects of the co-activator. Altogether, our results suggest that partial respiratory chain defects because of mtDNA mutations can lead to compensatory upregulation of nuclear transcriptional co-regulators, in turn mediating resistance to genotoxic stress.

Relationship of prefrontal connections to inhibitory systems in superior temporal areas in the rhesus monkey.

The prefrontal cortex selects relevant signals and suppresses irrelevant signals in behavior, as exemplified by its functional interaction with superior temporal cortices. We addressed the structural basis of this process by investigating quantitatively the relationship of prefrontal pathways to inhibitory interneurons in superior temporal cortices. Pathways were labeled with neural tracers, and two neurochemical classes of inhibitory interneurons were labeled with parvalbumin (PV) and calbindin (CB), which differ in mode of inhibitory control. Both markers varied significantly and systematically across superior temporal areas. Calbindin neurons were more prevalent than PV neurons, with the highest densities found in posterior high-order auditory association cortices. Axons from anterior lateral, medial prefrontal and orbitofrontal areas terminated in the anterior half of the superior temporal gyrus, targeting mostly the superficial layers (I to upper III), where CB neurons predominated. Reciprocal projection neurons were intermingled with PV neurons, and emanated mostly from the deep part of layer III and to a lesser extent from layers V-VI, in proportions matching the laminar density of inhibitory interneurons. In marked contrast, prefrontal connections in temporal polar cortex were found mostly in the deep layers, showing mismatch with the predominant upper laminar distribution of interneurons. Differences in the relationship of connections to inhibitory neurons probably affect the dynamics in distinct superior temporal cortices. These findings may help explain the reduced efficacy of inhibitory control in superior temporal areas after prefrontal cortical damage.