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TBT

Page 1γ ofEnvironmental 25 Science & Technology PPAR

ACS Paragon Plus Environment TBT agonist affinity towards PPARg : gain; loss.

Environmental Science & Technology

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The evolutionary exploitation of vertebrate peroxisome proliferator-activated receptor γ by

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organotins

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Ana M. F. Capitão1,2●, Mónica S. Lopes-Marques1●, Yoichiro Ishii3, Raquel Ruivo1, Elza S. S.

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Fonseca1,2, Inês Páscoa1, Rodolfo P. Jorge1, Mélanie A. G. Barbosa1,2, Youhei Hiromori3,4,

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Takayuki Miyagi3, Tsuyoshi Nakanishi3, Miguel M. Santos1,2* and L. Filipe C. Castro1,2*

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1Interdisciplinary

Centre of Marine and Environmental Research (CIIMAR/CIMAR), University

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of Porto (U.Porto), 4450-208 Matosinhos, Portugal

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2Faculty

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Porto, Portugal

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3Laboratory

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1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan

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4Faculty

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Minamitamagaki, Suzuka, Mie 513-8670, Japan.

of Sciences (FCUP), Department of Biology, University of Porto (U.Porto), 4169-007

of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University,

of Pharmaceutical Sciences, Suzuka University of Medical Science 3500-3,

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●Equal

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*Address

contribution correspondence to:

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Luís Filipe Costa Castro and Miguel Santos

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Interdisciplinary Centre for Marine and Environmental Research (CIIMAR)

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Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal

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Tel.: +351223401800

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Fax: +351223390608

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E-mail: [email protected]; [email protected]

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Keywords: PPAR; chordates; evolutionary toxicology; obesogens

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ACS Paragon Plus Environment

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Abstract

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Globally persistent man-made chemicals display ever-growing ecosystemic consequences, a

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hallmark of the Anthropocene. In this context, the assessment of how lineage-specific gene

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repertoires influence organism sensitivity towards endocrine disruptors is a central question in

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toxicology. A striking example highlights the role of a group of compounds known as obesogens.

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In mammals, most examples involve the modulation of the nuclear receptor, peroxisome

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proliferator-activated receptor  (PPAR). To address the structural and biological determinants

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of PPARγ exploitation by a model obesogen, tributyltin (TBT), in chordates, we employed

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comparative genomics, transactivation and ligand binding assays, homology modeling and site-

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directed-mutagenesis. We show that the emergence of multiple PPARs (,  and ) in vertebrate

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ancestry coincides with the acquisition of TBT agonist affinity, as can be deduced from the

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conserved transactivation and binding affinity of the chondrichthyan and mammalian PPAR. The

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amphioxus single copy PPAR is irresponsive to TBT; as well as the investigated teleosts, a

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probable consequence of a specific mutational remodeling of the ligand binding pocket. Our

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findings endorse the modulatory ability of man-made chemicals and suggest an evolutionary

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diverse setting, with impacts for environmental risk assessment.


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Introduction

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Over the past decades, various examples from disparate phylogenetic lineages have clearly

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established the central role of nuclear receptor (NR) exploitation by xenobiotics in the generation

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of endocrine imbalances. A critical question is to decipher how variations in NR gene function

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and repertoire underscore variable endocrine responses to xenobiotic exposure1. One of these

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examples has hypothesized that the exposure to an ample group of chemicals (termed obesogens)

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parallels the ongoing obesity epidemic

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extensive and includes a wide variety of compounds including phthalates, bisphenol A and

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organotins 5. Importantly, a string of studies using mice has documented that the obesity

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phenotype induced by obesogens such as tributyltin (TBT), results from the activation of a master

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gene regulator of adipogenesis: the peroxisome proliferator–activated receptor γ (PPARγ)

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In addition to mammals, this class of endocrine disruptors has also been shown to induce lipid

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alterations in other animal phyla 7-13, with several lipid metabolic modifications described upon

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obesogen exposure in teleosts and amphibians 7, 9, 10, 14-16. Yet, while the toxico-metabolic impact

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has been described in various taxa, is it mostly unknown whether these effects underpin conserved

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(or divergent) mechanisms of action, exploited by compounds such as TBT and acting via PPARs

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8, 17, 18.

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partial)

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revealed that TBT is a potent repressor of PPARα and β but inactive on PPARγ 22. In effect,

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animals exhibit conserved and divergent sensitivities to external stimuli yet, the role of PPARγ as

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a direct target of obesogens has been addressed in a minute number of species 3, 7, 23, 24. Thus, the

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extent to which genetic variation underlies such dissimilar responses is far from fully assessed.

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Therefore, we have carried out an extensive examination of PPAR gene diversity in the main

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chordate lineages, including cephalochordates (amphioxus), chondrichthyans (sharks, skates and

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chimaeras), ray-finned fish and amphibians. We surveyed a phylogenetic blueprint to address the

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impact of a model obesogen, TBT, acting via PPARγ, a critical regulator of adipogenesis. By

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investigating representative species of the chordate phylum (Figure S1), we provide a detailed

2-4.

The list of confirmed and suspected obesogens is

3, 6, 7.

For instance, while in mammals TBT was shown to act as a PPARγ agonist 7, 19 (although 20, 21,

in the teleost fish Pleuronectes platessa (European plaice) a reporter gene assay


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map of TBT activation/repression of PPARγ, as a proxy for potential obesogenic disorder. Our

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study illustrates the central importance of comparative approaches to unravel the full ecosystem

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impact of endocrine disruptors and contributes for the informed selection of model animal systems

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in human health risk assessments.


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Materials and Methods

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Sequence investigation

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Tblastn and blastp searches using human PPARα (Q07869), PPARβ (Q03181) and

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PPARγ (P37231) as query were performed in the available databases NCBI Ensembl and JGI.

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Ppar sequences were retrieved for the major vertebrate lineages: mammals (Homo sapiens, Mus

83

musculus); birds (Gallus gallus) and reptiles (Anolis carolinesis); amphibians (Xenopus

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tropicalis); coelacanths (Latimeria chalumnae); Lepisosteiformes (Lepisosteus oculatus),

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Osteoglossomorpha (Pantodon buchholzi) and Cypriniforme (Danio rerio), Chondrichthyes

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(Callorhinchus milii and Leucoraja erinacea) and for the following invertebrates, tunicates

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(Ciona intestinalis) cephalochordate (Branchiostoma floridae, Branchiostoma lanceolatum,

88

Branchiostoma belcheri) (Figure S1 and Table S1 for accession numbers).

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Phylogenetic analysis

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Phylogenetic analysis was performed using the set of sequences through database search

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as well as the isolated sequences. A total of 36 sequences were aligned in MAFFT 25, 26 with L-

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INS-I method. The resulting sequence alignment was stripped of all columns containing 90% gaps

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leaving a total of 515 positions for phylogenetic analysis. Maximum likelihood phylogenetic

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analysis was performed in PhyML V3.0 27 and the evolutionary model was determined using the

95

smart model selection (SMS) option resulting in a JTT +G. The branch support was calculated

96

using aBayes. The resulting tree was analyzed in Fig Tree V1.3.1 available at

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http://tree.bio.ed.ac.uk/software/figtree/ and rooted with the invertebrate sequences.

98

Synteny maps

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Comparative synteny maps were constructed using NCBI Gene database, using as

100

reference the latest available genome assemblies for the following species: H. sapiens

101

(GCF_000001405.33), L. oculatus (GCF_000242695.1), C. milii (GCF_000165045.1), B.

102

floridae (GG666565.1) and B. belcheri (AYSS01004225.)1. For each species, with the exception


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of the cephalochordates that present a sole PPAR, we analysed the genomic location of PPARα,

104

PPARβ and PPARγ gene. The genomic locus of each PPAR gene was retrieved, as well as, the

105

five contiguous flanking genes to each side, when possible. Following the assembly of the synteny

106

maps, we proceeded to identify and localize the corresponding human orthologues of non-

107

conserved neighboring genes in the B. floridae and B belcheri. Orthology was determined through

108

the Ensembl orthologue-paralogue pipeline and our own phylogenetic analysis (not shown).

109

Finally, synteny maps and annotated orthologues were then used to infer the localization of the

110

ancestral PPAR gene in the reconstructed genome of the vertebrate ancestor using as reference

111

the reconstruction presented by Nakatani and colleagues

112

Putnam and colleagues 29.

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Gene isolation and cloning

28

and the reconstruction presented by

114

Hinge and ligand binding domain (LBD) of PPARγ genes from Homo sapiens, X.

115

tropicalis, P. buchholzi, D. rerio, L. oculatus, L. erinacea and PPAR from B. lanceolatum (Table

116

S1) were predicted using NCBI's conserved domain database30 and isolated using a polymerase

117

chain reaction (PCR) approach (Table S2 for primer sequence). The hinge and LBD were then

118

cloned into the pBIND vector to produce a nuclear receptor (NR) LBD-Gal4 hybrid protein. This

119

hybrid protein, contain the DNA binding domain (DBD) of Gal4 and acts on an upstream

120

activation sequence (UAS) response element. The hinge and LBD of PPARγ from L. erinacea

121

was then cloned into the pCold-TF vector (Takara bio) to produce a PPARγ LBD-His6-tagged

122

trigger factor hybrid protein (HisTF-LePPARγ). Plasmid sequences were confirmed using Sanger

123

sequencing (GATC).

124

Homology modeling

125

Homology models were calculated in SWISS-MODEL homology modelling workspace

126

in alignment mode

127

submitted to SWISS-MODEL for homology modelling. Homology models were calculated using

128

ProMod3 and human PPARγ crystal structure 3WJ4 was selected as template. All models were

31, 32.

For each species PPARγ sequence corresponding to the LBD was


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evaluated for the following parameters: sequence identity, GQME (Global model Quality

130

estimation), QMEAN 33, 34 and rendered as reliable (Table S3). Finally, models were visualized,

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inspected and aligned to human crystal structure 3WJ4 in PyMOL v1.74 35.

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Chemicals and solutions

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All chemicals and reagents were obtained from Sigma-Aldrich unless stated otherwise in

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the text. Three TBT-Cl (tributyltin chloride) and three TPT-Cl (triphenyltin chloride) (250μM,

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100μM and 10μM), three ARA (Arachidonic acid), three EPA (cis-5,8,11,14,17-

136

Eicosapentaenoic acid) and three erucic acid (200mM, 100mM and 50mM), one Rosiglitazone

137

(Cayman) (1mM) and one T0070907 (Cayman) (1mM) solutions were prepared in DMSO

138

(dimethyl sulfoxide).

139

Cell culture and in vitro assays

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Cell culture and transactivation assays were performed as described in André et al. 36.

141

Briefly, Cos-1 cells were seeded in 24-well culture plates. After 24 hours cells

142

were transfected using lipofectamine 2000 reagent (Invitrogen), in Opti-MEM reduced

143

serum medium (Gibco, Thermo Fisher), according manufacturer’s indications and 0.5 μg

144

of pBIND PPAR LBD-Gal4 or RXR LBD-Gal4 and 1μg of pGL4.31 luciferase reporter

145

vector, containing five UAS elements upstream the firefly luciferase reporter gene. For

146

heterodimer transfection assays 0.5 μg of pBind PPAR LBD-Gal4, 0.5 μg of pACT and

147

1μg of pGL4.31, were used. After 5 hours of incubation the medium was replaced with medium

148

containing the test compounds (TBT – 10nM, 100nM and 250nM; TPT– 10nM, 100nM and

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250nM; ARA - 50µM, 100µM and 200µM; EPA - 50µM, 100µM and 200µM; Erucic acid -

150

50µM, 100µM and 200µM; Rosiglitazone (Rosi) - 1µM and T0070907 - 1µM) dissolved in

151

DMSO (0.1%). DMSO (0.1%) was used as solvent control. 24 hours later cells were lysed and

152

the luminescent activities of Firefly luciferase (pGL4.31) and Renilla luciferase (pBIND) were

153

determined. All assays were performed, independently, five times and each time two technical


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replicates per condition were performed to validate the results. Two different batches of Cos-1

155

cells were used; three replicates per batch were included per assay.

156

Ligand Binding Assay

157

The L. erinacea PPARγ LBD-His6-tagged trigger factor hybrid protein were expressed

158

in Escherichia coli BL21 (DE3) cells and purified by using His-select nickel affinity gel (Sigma

159

Aldrich). Ligand binding assay was assessed as previously described (39-41). In brief, the purified

160

protein (100, 200, 400 or 800 µg/ml) were incubated with 200 nM of tri[U-14C]phenyltin

161

hydroxide ([14C]TPT; radiochemical purity > 96.6 %, 2.04 GBq/mmol; Amersham Biosciences)

162

or 50 nM of [3H]rosiglitazone ([3H]rosiglitazone; radiochemical purity > 97 %, 2.168 TBq/mmol;

163

PerkinElmer). After incubation at 4 ◦C for 1 h, hydroxyapatite was added to precipitate the

164

receptor protein and bound radioactive compounds. The hydroxyapatite pellets was washed and

165

then radioactivity in the pellet was determined by liquid scintillation. Binding in the presence of

166

a 100-fold molar excess of unlabeled compound was defined as nonspecific binding; specific

167

binding was defined as total binding minus nonspecific binding. For competition binding assay,

168

the purified protein (800 µg/ml) were incubated with 200 nM of [14C]TPT and increasing

169

concentrations of test compounds.

170

Statistical analysis

171

Transactivation data was normalized dividing by the solvent control (DMSO) and the

172

mean of the technical replicates was used in the statistical analysis. One-way ANOVA followed

173

by Tukey post hoc test was used to analyze differences when parametric criteria was achieved,

174

otherwise a non-parametric Kruskal-wallis ANOVA followed by a Games-Howel test was used.

175

All analyses were performed using IBM SPSS Statistics 24. P Thr and Phe363>Met. Additionally, Cys285 is replaced by a tyrosine in

323

butterfly fish, though conserved in the spotted gar (Figure 5A). The butterfly fish homology model

324

reveals that the aromatic ring of tyrosine projects into the LBP, altering the pocket organization

325

as observed in human PPARγ (Figures 5A, D and E). Also, the replacement of Ile281 by a Phe in

326

Helix 3 in both spotted gar and butterfly fish results in a second aromatic ring protruding into the


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LBP (Figures 5A, 5D and 5E). We next constructed an homology model of the LBP of zebrafish

328

PPARγ, a popular comparative model in lipid endocrine disruption studies

329

interacting residues of the PPARγ-LBP in zebrafish are conserved with those of the butterfly fish,

330

in line with the incapacity of TBT to bind and transactivate PPARγ (Figures 5A and 5E). Finally,

331

B. lanceolatum presents the lowest number of conserved TBT-interacting residues; aside from the

332

replacement of the Cys285 by a leucine, we find six additional substitutions, including amino

333

acids that were found to be totally conserved in vertebrates such as Phe282>Leu and Phe360>Leu

334

(Figure 5G). Overall, our analysis strongly suggests that, Cys285 is essential for PPARγ

335

transactivation in the presence of TBT.

9, 10.

The TBT-

336 337

Conserved and derived molecular features in PPARγ exploitation by organotins

338

Animal endocrine systems encompass an intricate network of signaling cascades, that

339

when perturbated lead to episodes of disruption with developmental and physiological

340

impairment 48. In this context, a critical and complex issue is that of how man-made chemicals

341

differently exploit the genetic and physiological make-up of animal species and influence

342

homeostasis. This question assumes a key importance, since animal model-derived studies are

343

essential to evaluate the risk of man-made chemicals in human populations. In recent years, the

344

concept of obesogens has gathered increased attention as the obesity epidemic gained pace in

345

western societies. The overall feature of these compounds is their capacity to activate the

346

mammalian adipogenesis master control gene PPAR; yet, PPAR is largely uncharacterized in

347

most vertebrate lineages and in some species seems irresponsive to a model obesogen, TBT 22, 23,

348

47.

349

heterodimer emerged in the ancestor of vertebrates concomitant with the appearance of PPAR

350

(Fig.7). This might result in potential obesogenic impacts at environmental conditions which

351

require further investigations. The conversion of activation to a neutral/negative profile observed

352

in the tested teleost represents a secondary event dictated by changes in the ligand pocket of

353

PPAR. These observations raise a paradoxical scenario. While both mammals and teleosts

Considering this set-up, we show that the TBT agonist capacity towards PPARγ/RXR


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354

experience obesogenic outcomes upon organotin exposure

355

mechanisms of such disruption are possibly different, since the tested teleost PPAR does not

356

activate transcription in the presence of TBT

357

apparent absence of obesogenic impacts in fish. Yet, TBT was suggested to inhibit teleost

358

PPAR/

359

accumulation 9. Other hypothesis to consider includes the activation of the heterodimer

360

PPARγ/RXR by TBT through the RXR monomer 10, although our in vitro results are contradictory

361

with this scenario. Overall, our results pave the way for future functional and in vivo studies to

362

investigate the diversity of physiological landscapes resulting from the exposure to obesogens.

22,

22

7, 9, 10, 49

(Fig. 7), the molecular

(this work) (Fig. 7). This would involve an

eventually suppressing lipid oxidation in vivo, which could potentially cause fat

363

364 365 366

Fig. 7 – The chordate taxonomic scope of PPARγ exploitation by TBT. PPARs transactivation results in the presence of TBT.

367 368

Acknowledgments

369

This work was supported by Norte2020 and FEDER (Coral - Sustainable Ocean Exploitation -

370

Norte-01-0145-FEDER-000036), Project No. 031342 co-financed by COMPETE 2020, Portugal

371

2020 and the European Union through the ERDF, and by FCT through national funds. We

372

acknowledge the Branchiostoma lanceolatum genome consortium for providing access to the

373

genome sequence and Fundação para a Ciência e a Tecnologia for the support to AC

374

(SFRH/BD/90664/2012), RR (SFRH/BPD/72519/2010) and to EF (SFRH/BD/100262/2014). We

375

acknowledge Ana André and Ricardo Capela for their help in the sampling process.

376

The authors declare no competing financial interest.


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377 378 379

Supporting Information.

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Additional results and experimental details regarding gene isolation, homology modeling,

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transactivation assays and synteny maps.

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The evolutionary exploitation of vertebrate peroxisome proliferator

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