Deleterious functional consequences of perfluoroalkyl substances accumulation into the myelin sheath.

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.

Towards a humanized PPARγ reporter system for in vivo screening of obesogens.

Overeating and lack of exercise are major contributors to the current obesity epidemic, but environmental contaminants, or obesogens, are also considered to be potential actors. A common obesogen target is the Peroxisome Proliferator Activated Receptor Gamma (PPARγ). Screening for exogenous obesogens requires in vivo systems as many xenobiotics exert their effects through metabolites. We thus developed a humanized in vivo PPARγ reporter model, using Xenopus laevis larvae, a species possessing metabolic capacities comparable to mammals. A somatic transgenesis approach was used to co-express an expression vector for the human PPARγ protein simultaneously with one of a series of reporter vectors, each containing a PPARγ Response Element (PPRE)-eGFP sequence. Treatment of tadpoles with PPARγ agonists, antagonists or candidate obesogens, significantly modulated eGFP expression. Thus, the system provides a promising proof of principle for a sensitive and reliable humanized in vivo tool to screen both novel PPARγ drug ligands and potential endocrine disruptors or obesogens targeting this receptor.

Is thyroid hormone signaling relevant for vertebrate embryogenesis?

Classically, thyroid hormones (THs) have been primarily associated with postembryonic development (Tata, 1968), notably metamorphosis in anuran amphibians and flat fish. This period is parallel to the perinatal period in man and many marked developmental transitions in other species. As amply described in other chapters, metamorphosis is characterized by a peak of thyroxine (T(4)) and triiodothyronine (T(3)) that is synchronous with the metamorphic climax. In contrast, the developmental period that characterizes embryonic development prior to the significant production of TH by the endogenous thyroid gland has received little attention. Furthermore, the prevailing concepts of TH physiology during this period have been framed by two observations in amphibians and mammals: first, TRs are expressed, while circulating TH levels are much lower than those during metamorphosis and, second, extrapolating from the knowledge largely obtained from in vitro models, in the absence of TH, the aporeceptor represses target gene transcription during premetamorphic development. We propose to revisit both concepts in the light of accumulating data, first, on TH availability both in eggs and in embryos and, second, on the increasing knowledge of the complexity of TR and TH control of transcription.

Thyroid hormone signaling in the Xenopus laevis embryo is functional and susceptible to endocrine disruption.

Thyroid hormone (TH) is essential for vertebrate brain development. Most research on TH and neuronal development focuses on late development, mainly the perinatal period in mammals. However, in human infants neuromotor development correlates best with maternal TH levels in the first trimester of pregnancy, suggesting that TH signaling could affect early brain development. Studying TH signaling in early embryogenesis in mammals is experimentally challenging. In contrast, free-living embryos, such as Xenopus laevis, permit physiological experimentation independent of maternal factors. We detailed key elements of TH signaling: ligands, receptors (TR), and deiodinases during early X. laevis development, before embryonic thyroid gland formation. Dynamic profiles for all components were found. Between developmental stages 37 and 41 (~48 h after hatching, coincident with a phase of continuing neurogenesis) significant increases in T(3) levels as well as in mRNA encoding deiodinases and TR occurred. Exposure of embryos at this developmental stage for 24 h to either a TH antagonist, NH-3, or to tetrabromobisphenol A, a flame retardant and known TH disruptor, differentially modulated the expression of a number of TH target genes implicated in neural stem cell function or neural differentiation. Moreover, 24-h exposure to either NH-3 or tetrabromobisphenol A diminished cell proliferation in the brain. Thus, these data show first, that TH signaling exerts regulatory roles in early X. laevis neurogenesis and second, that this period represents a potential window for endocrine disruption.