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Environ Int
2023 Oct 01;180:108211. doi: 10.1016/j.envint.2023.108211.
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Deleterious functional consequences of perfluoroalkyl substances accumulation into the myelin sheath.
Butruille L
,
Jubin P
,
Martin E
,
Aigrot MS
,
Lhomme M
,
Fini JB
,
Demeneix B
,
Stankoff B
,
Lubetzki C
,
Zalc B
,
Remaud S
.
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Exposure to persistent organic pollutants during the perinatal period is of particular concern because of the potential increased risk of neurological disorders in adulthood. Here we questioned whether exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) could alter myelin formation and regeneration. First, we show that PFOS, and to a lesser extent PFOA, accumulated into the myelin sheath of postnatal day 21 (p21) mice, whose mothers were exposed to either PFOA or PFOS (20 mg/L) via drinking water during late gestation and lactation, suggesting that accumulation of PFOS into the myelin could interfere with myelin formation and function. In fact, PFOS, but not PFOA, disrupted the generation of oligodendrocytes, the myelin-forming cells of the central nervous system, derived from neural stem cells localised in the subventricular zone of p21 exposed animals. Then, cerebellar slices were transiently demyelinated using lysophosphatidylcholine and remyelination was quantified in the presence of either PFOA or PFOS. Only PFOS impaired remyelination, a deleterious effect rescued by adding thyroid hormone (TH). Similarly to our observation in the mouse, we also showed that PFOS altered remyelination in Xenopus laevis using the Tg(Mbp:GFP-ntr) model of conditional demyelination and measuring, then, the number of oligodendrocytes. The functional consequences of PFOS-impaired remyelination were shown by its effects using a battery of behavioural tests. In sum, our data demonstrate that perinatal PFOS exposure disrupts oligodendrogenesis and myelin function through modulation of TH action. PFOS exposure may exacerbate genetic and environmental susceptibilities underlying myelin disorders, the most frequent being multiple sclerosis.
Fig. 1. . Accumulation of PFAS into pups myelin fraction. A) Flow chart of PFAS exposure (20 mg/L) of adult female mice via the drinking water from E15 of gestation and during the lactation period. At 3 weeks (p21), dams and pups were euthanized, brains dissected out and myelin bulk fraction purified on a Percoll gradient. B-E) At p21, PFAS were assayed by LC-MS/MS in the serum of dams and pups (B, D) and corresponding myelin fractions (C, E). Although similar levels of either PFOS or PFOA passed from the drinking water into the mother serum and from the mother milk into the pups serum, 133 time more PFOS was detected into the pups myelin fraction compared to PFOA. Note that low level of both PFOS and PFOA were detected into the myelin of control animals (E), which is explained by the presence of these PFAS into the normal drinking water given to control dams (see Supplementary Table 1).
Fig. 2. . Perinatal exposure to PFOS, but not PFOA, increased the generation of SVZ-derived oligodendrocyte precursor cells (OPCs), which were not able to maturate into myelin-forming oligodendrocytes. A, F) Schematic drawing showing on coronal sections of p21 pups level illustrated in B-D for subventricular zone and in G-I and K-M for corpus callosum exposed to either PFOS, PFOA or control (CTL). B-E) section at the level of the SVZ immunostained for OLIG2 (green in B-D), at the level of the corpus callosum doubly stained for OLIG2 (green) and CC1 (red in G-I), and with anti-PLP to stain myelinated fibers (K-M) above the lateral ventricles. Note for PFOS exposed animals the increased density of OPC-OLIG2+ cells (C, E) contrasting with the lower ratio of mature oligodendrocytes OLIG2+/CC1+ (H, I) and the lower myelin staining (PLP+ ) in (L, N). In contrast, in brain sections of PFOA exposed animals, no significative differences compared to controls were observed. Nuclei are counterstained with DAPI; CC = corpus callosum, SVZ = subventricular zone, LV = lateral ventricles. Scale bar: B, C, D, F, G, H = 50 m; K, L, M = 25 m. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3. . Ex vivo PFOS exposure inhibited remyelination. A) Flow chart showing the sequence of lysophosphatidylcholine-induced transient demyelination (from DIV6 to DIV7) of cerebellar slices followed by exposure to PFAS during the endogenous remyelination period, from DIV7 to DIV12. B-D) Cerebellar slices from p9 mice at 12 DIV doubly immunostained for calbindin (Purkinje cell bodies and axons in red in B, D, E, G) and PLP, (myelinated axons in green in C, D, F, G); note the decreased PLP + myelin staining in slices exposed to PFOS, while Purkinje cells and axons appeared unaffected (E) compared to controls (B); arrow head in E and G point to axons not ensheathed by myelin. (H, I) Dose response curve of either PFOS (H) or PFOA (I) exposure on the myelin index measured as a ratio between the calbindin (axon)and PLP (myelin) stainings. Note the non-monotonic dose response of PFOS and the reversal of PFOS inhibitory effect on remyelination by addition of T3 into the culture medium (hachured column in H). In contrast, PFOA (I) did not affect remyelination. Scale bar: B-G = 50 m. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4. In vivo PFOS inhibited remyelination. (A) Flow chart showing the sequence of events tested. (B) Whole mount of Tg(Mbp:GFP-ntr) Xenopus laevis (stage 50 tadpoles) showing GFP expression in the brain, optic nerve (white arrows) and spinal cord. At this magnification GFP+ oligodendrocyte cell bodies are not visible. (C-F) Higher magnification of Tg(Mbp:GFP-ntr) Xenopus laevis optic nerve before (D0)(C), at the end of metronidazole-induced demyelination (D10)(D) and after 3 days (R3) of spontaneous recovery in control (E) or PFOS exposed tadpoles (F); scale bar in B = 500 m in C-F = 50 m. (G, H) Dose response of remyelination after addition for 3 days of either PFOS (G) or PFOA (H). Remyelination was evaluated by counting the number of GFP + oligodendrocytes per optic nerve. Note the non-monotonic inhibition of remyelination following PFOS exposure, while PFOA had no effect. (I-K) PFOS inhibition of remyelination affected tadpoles behavior as assayed by distance traveled (I), speed of swimming (J) and visual avoidance of a virtual collision (K) contrasting with the absence of effect of PFOA.
Supplemental Figure 1.
Remyelination is dependent on thyroid hormone signaling. Spontaneous remyelination of mouse cerebellar slices demyelinated by LPC is increased by addition of T3 (10nM) into the culture medium and inhibited by NH3 (5M) a thyroid hormone receptor antagonist. Purkinje cells and axons were immunostained with anti-calbindin (A, C, D, F) and myelin sheath with anti-PLP (B, E). G) Myelination index was evaluated in all 4 conditions
