Fatty Acid Metabolism in Fish Species As A Biomarker For Environmental Biomarker

Environmental Pollution xxx (2016) 1e16
Contents lists available at ScienceDirect
Environmental Pollution
journal homepage: www.elsevier.com/locate/envpol
Review
Fatty acid metabolism in fish species as a biomarker for environmental

monitoring*
Hugo F. Olivares-Rubio*, Armando Vega-Lo
pez*
gicas, Instituto Polit
Laboratorio de Toxicología Ambiental, Escuela Nacional de Ciencias Biolo ecnico Nacional, Av. Wilfrido Massieu s/n, Unidad Profesional
Zacatenco, Ciudad de M exico, C. P. 07738, Mexico
a r t i c l e i n f o a b s t r a c t
Article history: Pollution by Organic Contaminants (OC) in aquatic environments is a relevant issue at the global scale.
Received 25 March 2016 Lipids comprised of Fatty Acids (FA) play many important roles in the physiology and life history of fishes.
Received in revised form Toxic effects of OC are partly dependent on its bioaccumulation in the lipids of aquatic organisms due its
2 July 2016
physicochemical properties. Therefore, there is an increasing interest to investigate the gene expression
Accepted 3 July 2016
Available online xxx
as well as the presence and activity of proteins involved in FA metabolism. The attention on Peroxisome
Proliferation Activate Receptors (PPARs) also prevails in fish species exposed to OC and in the transport,
biosynthesis and b-oxidation of FA. Several studies have been conducted under controlled conditions to
Keywords:
Biomarkers
evaluate these biological aspects of fish species exposed to OC, as fibrates, endocrine disrupting com-
Fatty acid metabolism pounds, perfluoroalkyl acids, flame retardants, metals and mixtures of organic compounds associated
Fish with a polluted area. However, only fibrates, which are agonists of PPARs, induce biological responses
PPARs suitable to be considered as biomarkers of exposure to these pollutants. According to the documented
findings on this topic, it is unlikely that these physiological aspects are suitable to be employed as
biomarkers with some noticeable exceptions, which depend on experimental design. This emphasises
the need to investigate the responses in fish treated with mixtures of OC and in wild fish species from
polluted areas to validate or refute the suitability of these biomarkers for environmental or fish health
monitoring.
© 2016 Elsevier Ltd. All rights reserved.
1. Introduction Contaminants (OC), as in the cases of polyaromatic hydrocarbons

(PAH), polychlorinated hydrocarbons, pesticides, perfluoroalkyl
Lipids comprised of Fatty Acids (FA) are a class of biomolecules acids and pharmaceutical products, among others, are the most
that possess a wide diversity of functions in structure and biological investigated. These pollutants are hydrophobic, and due to their
process through interactions with proteins (Dowhan et al., 2008; physicochemical properties are able to accumulate in the lipids of
Sul and Smith, 2008). In fish species, lipids and proteins are the aquatic organism in a dose-dependent manner (Kainz and Fisk,
main organic constituents, and play many important roles in the 2009). There is an increase in the number of studies exploring
fish’s life history and physiology, which includes growth, move- the responses of proteins involved in Fatty Acid Metabolism (FAM).
ment, reproduction and migration (Tocher, 2003). The main role of
lipids in these organisms is the storage and provision of energy in 2. Proteins involved in FA metabolism
the form of Adenosine Triphosphate (ATP) through the b-oxidation
of fatty acids (Froyland et al., 2000). A lot of studies had docu- The digestion, transport, synthesis and oxidation of FA are
mented the toxic responses of fish species from polluted aquatic relevant processes in the metabolism of these biomolecules in fish
environments at a global scale. In this regard, Organic species. Although there are large numbers of proteins whose
presence and activity are responsible for FAM, only a few of them
have been employed to evaluate their responses in fish exposed to
*
OC. To provide good background knowledge of this topic, we
This paper has been recommended for acceptance by Maria Cristina Fossi.
* Corresponding authors.
describe the most studied proteins in this regard.
E-mail addresses: hugolivares@yahoo.com.mx (H.F. Olivares-Rubio), avegadv@ Triacylglycerol is the main lipid component in the diet of marine
yahoo.com.mx (A. Vega-Lo pez). and freshwater fish (Tocher, 2003). Lipoprotein lipase (LPL; EC
http://dx.doi.org/10.1016/j.envpol.2016.07.005
0269-7491/© 2016 Elsevier Ltd. All rights reserved.
pez, A., Fatty acid metabolism in fish species as a biomarker for environmental
Please cite this article in press as: Olivares-Rubio, H.F., Vega-Lo
monitoring, Environmental Pollution (2016), http://dx.doi.org/10.1016/j.envpol.2016.07.005
2 pez / Environmental Pollution xxx (2016) 1e16
H.F. Olivares-Rubio, A. Vega-Lo
3.1.1.34) is an enzyme responsible for the hydrolysis of tri- H2O2, FA, amino acids and uric acid (Cooper, 2000). Specific
acylglycerol and it plays a central role in the overall lipid meta- endogenous substrates for peroxisomal b-oxidation are very long
bolism and transport (Mead et al., 2002). The product of this chain FA, methyl-branched carboxylic acids, prostaglandins, dicar-
hydrolysis provides non-esterified FA and 2-monoacylglycerol for boxylic acids, leukotrienes, isoprenoid-derived fat soluble vitamins,
their use in the tissues, which could be useful for the re- pristanic acid and xenobiotic compounds (Hashimoto, 1999; Poirier
esterification involved in the storage of energy as triacylglycerol et al., 2006). The substrates for b-oxidation enter to the peroxi-
(Cryer, 1981). somes via ATP-binding cassette transporters of subfamily D and are
Generally, the intracellular transport of FA is performed by Fatty activated by specific acyl CoA synthetases (ACS; EC 6.2.1.1) for their
Acid Binding Proteins (FABP) which are highly conserved cyto- metabolism (Baker et al., 2015). In addition, the proteins of
plasmic proteins possessing low molecular weight between 14 and peroxisome membrane of 70 and 69 KDa are also involved (Schulz,
15 kDa (Tocher, 2003; Schulz, 2008). FABP are involved in some 2008). Although the transport of FA in the matrix of peroxisomes is
physiological processes, such as sequestering FA and other lipo- independent of carnitine, the presence of carnitine octanoyl
philic compounds, transporting FA to the mitochondria, storage, transferase (CROT; EC 2.3.1.137) has been documented (Miyazawa
modulating the cell proliferation and the FAM by Nuclear Receptors et al., 1983). CROT is responsible for the catalysis of the shortened
(NRs) (Meunier-Durmort et al., 1996; Bernlohr et al., 1997; Poirier FA to acyl carnitine favouring in this way its output of the peroxi-
et al., 2001; Leaver et al., 2005; Schulz, 2008). some (Le Borgne et al., 2011). Peroxisomal b-oxidation is comprised
FA oxidation is the major source of energy for many fish species. of CoA oxidase, enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydro-
This physiological process occurs in cellular organelles as mito- genase bifunctional protein (these two enzymes conform to the L-
chondria and peroxisomes by a different set of enzymes (Tocher, bifunctional protein), and 3-ketoacyl-CoA thiolase (Hashimoto,
2003). FA oxidation is also known as b-oxidation, since this 1999; Poirier et al., 2006). However, the metabolism of palmitoyl-
degradation begins in the third carbon atom (b-carbon) on the FA CoA oxidase, which is a specific enzyme of the type acyl-CoA oxi-
chain; the resulting b-keto acid is cleaved between the a-carbon dase (AOX; EC 1.3.3.6), oxidizes the CoA esters of straight chain FA
and b-carbon to yield FA, shortened by two carbon atoms that (Van Veldhoven et al., 1992; Reddy and Mannaerts, 1994). This
generate acetyl-CoA, which supports gluconeogenesis, ketogenesis enzyme was more studied in fish species exposed to OC while being
and the production of ATP through the Krebs cycle (Kompare and employed as a biomarker.
Rizzo, 2008; Schulz, 2008). The b-oxidation is a biochemical pro- The main pathway of lipogenesis is catalysed in the cytosol of
cess catalysed in the mitochondria and peroxisomes (Schulz, 2008) the cell by the Fatty Acid Synthase (FAS; EC 2.3.1.85), a multienzyme
with some peculiar differences. complex characterized in fish species (Tocher, 2003). Mainly, the
Mitochondria are cellular organelles that provide useful energy products of de novo FAS are saturated FA of 16 and 18 atoms of
by utilizing part of the free energy released during the consumption carbon (palmitic and stearic acids, respectively), including the
of hydrogen in the form of ATP, NADPH, DpH, and DJ derived from nicotinamide adenine dinucleotide phosphate in almost all or-
different food, such as carbohydrates, FA and proteins (Panov et al., ganisms, including fish species (Stoops and Wakil, 1981; Tocher,
2014). Mitochondrial b-oxidation is a specific process for long, 2003; Sul and Smith, 2008).
medium and short chain of FA, which are taken from the liver and The malonyl-CoA is a molecule that plays important roles in
the muscle where they are activated to their coenzyme A (CoA) FAM, and it is able to inhibit the activity of CPT I; therefore, it fa-
esters through the metabolism of long-chain acyl-CoA synthetase vours the decrease on the transference of FA residues from CoA to
(ACSL; EC 6.2.1.3) (Hashimoto, 1999; Kompare and Rizzo, 2008). carnitine and their translocation to mitochondria. In this way, it
Long FA esters, which typically contain between 16 and 18 atoms of causes the depression of b-oxidation (Schulz, 2008). However, the
carbon, are transported to mitochondria in a system dependent on malonyl-CoA is also a co-substrate for the condensation reaction of
carnitine/acyl-carnitine balance named as “carnitine shuttle” the cytosolic FAS complex and is a co-substrate for the FA elonga-
(Kerner and Hoppel, 2000; Kompare and Rizzo, 2008). In this re- tion system, which occurs in the membrane of the endoplasmic
gard, the carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) is the reticulum (Saggerson, 2008). The malonyl-CoA is synthesized by
enzyme responsible for the conversion of acyl-CoA compounds to the carboxylation of acetyl-CoA through the metabolism of acetyl-
their acylcarnitine metabolites at the outer membrane of the CoA carboxylases (ACC; EC 6.4.1.2), and both enzymes are depen-
mitochondria and it plays a pivotal role in the regulation of b- dent on the biotin (Kim, 1997; Harwood, 2005). In mammals and
oxidation by the rate-limiting step of carnitine transport (Kerner fish species, two isoforms of ACC exist: i) ACC1, located in the
and Hoppel, 2000; Kompare and Rizzo, 2008). In contrast, me- cytosol produces malonyl-CoA utilized for FA biosynthesis, and ii)
dium chains FA are independent of carnitine (Hashimoto, 1999). ACC2 is found in the mitochondria generating malonyl-CoA
Each cycle of mitochondrial b-oxidation requires the sequential involved in the inhibition of b-oxidation (Cheng et al., 2011; Zu
metabolism of the following enzymes: acyl-CoA dehydrogenase, 2- et al., 2013).
enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-
ketoacyl-CoA thiolase. The last three comprised the mitochon- 3. Peroxisome proliferator-activated receptors (PPARs)
drial trifunctional protein (Kompare and Rizzo, 2008). The short-
ened acyl-CoA is subject to another b-oxidation process to generate The PPARs are a cluster of NRs, which participate in some bio-
shorter FA, whereas their final products are involved in the gluco- logical processes as in the cases of development, growth, repro-
neogenesis, ketogenesis and ATP generation (Kompare and Rizzo, duction, metabolism, immune response, apoptosis and cancer,
2008). among others (Berger and Moller, 2002; Poulsen et al., 2012). The
The peroxisomes are single membrane-delimited organelles name “PPARs” was derived from the ability of one of these receptors
found in almost all eukaryotic cells that undergo diverse metabolic to induce the Peroxisome Proliferation (PP) in the hepatocytes of
processes, and they differ between organisms according to their rodents (Christodoulides and Vidal-Puig, 2010). The PPARs are
developmental stages or as a response to environmental conditions sensitive to dietary lipids ingest or to essential FA metabolites and
(Wanders and Waterham, 2006; Baker et al., 2015). Peroxisomes participates on the FA signals as key regulators of lipid metabolism
contain almost 50 enzymes that are involved in the metabolism of (Varga et al., 2011). In vertebrates, three subtypes of PPAR have
pez / Environmental Pollution xxx (2016) 1e16
H.F. Olivares-Rubio, A. Vega-Lo 3
been identified, namely, a, b/d and g (Kota et al., 2005). These 4. FA metabolism in fish exposed to pollutants
subtypes of PPAR are highly expressed in tissues and are involved in
energy homeostasis because dietary FA and its metabolite de- 4.1. Fibrates
rivatives are able to activate PPARs (Varga et al., 2011).
The main endogenous ligands of PPARs are FA, metabolized FA In recent years, the presence of many pharmaceutical and per-
and eicosanoids (Kota et al., 2005; Berger and Moller, 2002; sonal care products in water have been reported, thereby increasing
Christodoulides and Vidal-Puig, 2010). However, many exogenous the global concern about these pollutants in aquatic life (Rivera-
compounds as in the case of plasticizers of phthalate esters, her- Utrilla et al., 2013; Zhang et al., 2014). In this regard, fibric acid
bicides, pharmaceutical products as derivatives of fibric acid and derivatives, also known as fibrates, for example, gemfibrozil,
thiazolidinedione, PAHs and polychlorinated biphenyls (PCBs) are fenofibrate and bezafibrate, are types of pharmaceutical products
agonists of these receptors (Berger and Moller, 2002; Bocher et al., commonly employed for the treatment of hypertriglyceridemia
2002; Cajaraville et al., 2003). PPARs perform their functions in a (Kennedy et al., 2013). These compounds stimulate the cellular
similar way to other NRs. The ligands are bound to PPARs by the capture of FA and induce the catabolism of FA through the b-
Ligand Binding Domain (LBD), the subsequent binding to DNA re- oxidation (Staels et al., 1998). In addition, these pharmaceutical
quires the dimerization with other NRs, such as of Retinoid X re- products act as peroxisomal proliferators (Gervois et al., 2000;
ceptor (RXR), which is a ligand independent of PPARs Suga, 2004). In rodents, the fibrates cause a massive proliferation
(Christodoulides and Vidal-Puig, 2010; Poulsen et al., 2012). The of peroxisomes (Hess et al., 1965), which provoke an increase in the
PPAR-RXR transcription factor is bound to Peroxisome Proliferator gene expression of liver lipoprotein lipase, an enzyme responsible
Response Element (PPRE), which promotes the activations of the for the hydrolysis of triglycerides (Staels and Auwerx, 1992). In
corresponding target genes (Berger and Moller, 2002; Kota et al., addition, it has been reported that fibrates induce other gene ex-
2005; Christodoulides and Vidal-Puig, 2010). One group of these pressions related to b-oxidation, FA transport and uptake of
transcription factors is involved in FAM; therefore, its presence is cholesterol (Cornwell et al., 2004). In the environment, these
higher on the active tissues involved in the anabolism and catab- pharmaceutical products and their metabolites have been detected
olism of FA (Poulsen et al., 2012). In mammals and fish species, the in surface water, wastewater, treated and drinking water. High
gene expression of PPARs is different among the cell types concentrations of bezafibrate were detected at 4.6 and 3.1 mg/L in
(Braissant et al., 1996; Ibabe et al., 2004). In rodents, the PPARa is wastewater and surface water, respectively (Stumpf et al., 1996). In
the main inductor of FA oxidation in the mitochondria and perox- streams, the maximum level of gemfibrozil was found at 0.79 mg/L
isome and is highly expressed in several tissues, such as the cases of (Kolpin et al., 2002). Concentrations of fibric acid are in the range of
the brown adipose tissue, the liver, the kidney and the heart (Escher 0.46e1.56 mg/L in sewage effluent for Germany; those of bezafibrate
et al., 2001; Varga et al., 2011; Poulsen et al., 2012). In addition, range from 0.25 to 4.56 mg/L, and for gemfibrozil, a maximum
peroxisome AOX is a transcription factor regulated by PPARa concentration of 1.5 mg/L was quantified (Zweiner and Frimmel,
(Cajaraville et al., 2003). The PPARb/d is widely expressed in several 2004). Common concentrations in the aquatic environment of
tissues, as in the case of brown adipose tissue, white adipose tissue, bezafibrate and clofibric acid are up to 3.1 and 1.6 mg/L, respectively
liver, pancreatic cells, heart and muscle. The main functions of this (Weston et al., 2009). The maximum detected concentration of
type of PPAR are oxidation and glucose storage, lipoproteins cap- gemfibrozil in a source of drinking water in the United States was
ture, diminution of inflammation and FA oxidation (Varga et al., 24 ng/L (Benotti et al., 2009). The water content of gemfibrozil
2011; Poulsen et al., 2012). Since its discovery in the 1990s of the collected from localities in Texas, of wastewater influent, effluent,
last century, PPARɣ has been perceived as being responsible for and groundwater were between 3.47 and 63.8 mg/L, 0.08 and
adipocyte differentiation (Christodoulides and Vidal-Puig, 2010). 19.4 mg/L, and from undetectable to 6.86 mg/L, respectively (Fang
The PPARɣ is mainly detected in brown adipose tissues, immune et al., 2012b). In the Tiger River in Italy, a mean concentration of
cells, the intestines, the kidney and the liver (Vidal-Puig et al., 1997; gemfibrozil within the value of 65.0 ng/L was estimated (Grenni
Fajas et al., 1997; Varga et al., 2011). Increases in the size, number et al., 2013). Therefore, several studies under laboratory condi-
and volume of peroxisomes in aquatic organisms exposed to OC tions have been conducted for the monitoring of the toxicological
were documented in molluscs and fish species since the last decade response elicited by fibrates in fish species. It has been documented
of the 20th century with some promising results. Therefore, PP has that the rainbow trout (Oncorhynchus mykiss), treated with cipro-
been proposed as a biomarker for environmental pollution fibrate at 15, 25, or 35 mg/kg for three weeks, presented an increase
assessment (Cajaraville et al., 2003). in the hepatic AOX and catalase (CAT; EC 1.11.1.6), a characteristic
The PPARs gene expression is one of the aspects mostly studied enzyme of peroxisomes responsible for the reduction of H2O2 in O2
in FAM and in fish species exposed to OC. First reports about the and H2O. Both enzymatic activities were induced in a dose-related
PPARs in fish species included the gene sequence of PPAR in the way (Yang et al., 1990). In the rainbow trout hepatocytes, a dose-
plaice (Pleuronectes platessa) (Leaver et al., 1998) and in the Atlantic related AOX metabolism was found by exposure for 48 h to acid
salmon (Salmo salar) (Ruyter et al., 1997; Andersen et al., 2000). In clofibric and ciprofibrate (2.25e3.00 mM and 0.25e1.00 mM,
addition, the tissue distribution of PPARs in zebrafish (Danio rerio) respectively), and a peroxisomal b-oxidation enzyme induction was
was performed through the use of commercial antibodies (Ibabe detected; however, the gemfibrozil (0.25e1.25 mM by 48 h) did not
et al., 2002). Actually, for bony fish, 149 gene sequences have elicit the same response (Donohue et al., 1993). The gemfibrozil,
been reported for PPARs, of which 35 correspond to Cypri- dosified at 46e152 mg/kg/day for two weeks, provokes significant
nodontiformes, 25 to Cichliformes, 23 to Salmoniformes, 8 to Tet- increases in the activity of AOX at all treatments in the rainbow
raodontiformes and Esociformes, 7 to Cypriniformes, trout. Meanwhile, in the Japanese medaka (Oryzias latipes) exposed
Characiformes and Perciformes, 6 to Clupeiformes and Pleuro- for 2 weeks to concentrations of 0, 1.25, 2.5, or 5 ppm of gemfibrozil,
nectiformes, 5 to Sciaenidae and 4 to Beloniformes, Semi- a significant increase in peroxisomal bifunctional enzyme in the
onotiformes and Pomacentridae (NCBI, 2016). Despite this vast greater treatment was documented (Scarano et al., 1994). In the
number of sequences reported for PPARs in fishes, only a few hepatocytes of the Atlantic salmon treated for three days to 0.5 and
studies reported the expression of these genes as biomarkers for 1.0 mM of clofibric acid and bezafibrate in an independent expo-
exposure to pollutants. sure, an induction of the transcription of PPARg and increases in the
activity of AOX were observed (Ruyter et al., 1997). In contrast to
these findings, in the liver, gill, and kidney of the European seabass response on AOX activity and 20 mg/L provokes greater expres-
(Dicentrarchus labrax) exposed for two weeks to doses of 35 or sion of PPARa in a time-independent manner (Corcoran et al.,
70 mg/kg of clofibrate, an induction of palmitoyl-CoA oxidase and 2015). In the grass carp (Ctenopharyngodon idella), increases of
CPT I (enzyme involved in mitochondrial b-oxidation) was not hepatic AOX mRNA were detected, but not in CPT elicited by food
found (Pretti et al., 1999). Acute exposure to clofibrate (18.4, 37.9, (rich in carbohydrates and fats) uptake polluted with 1.25 mg/kg of
73.8, 147.5 and 295 mg/L) and clofibric acid (1.01, 2.02, 4.03, 8.06 and clofibrate for 4 weeks (Guo et al., 2015). However, using a diet of
16.12 mg/L) for 28 days elicited a decrease in liver CAT activity in an carbohydrates, the up-regulation of AOX mRNA was diminished
Eastern mosquitofish (Gambusia holbrooki) (Nunes et al., 2004). In a through the activation of FAS and ACC involved in the de novo FA
primary hepatocyte culture of a zebrafish treated with 0.5, 1.0 and synthesis (Guo et al., 2015). In a general way, the gemfibrozil, clo-
2.0 mM of clofibrate for 24 h, the PPARa was induced in a dose- fibrate, bezafibrate and acid fibric are able to increase the gene
dependent response; however, the PPARg was slightly increased expression of PPARs as well as the proliferation of peroxisome
using the immunolabeling technique (Ibabe et al., 2005). In the indirectly measured by the metabolism of AOX, despite their lower
goldfish (Carassius auratus) exposed to 1500 mg/L of gemfibrozil, the concentration (mg/L) and diverse developmental stages in the fish
hepatic mRNA expression of PPARb was noticeably reduced after 14 species of the tests (Table 1). Mainly, these studies were focused on
and 28 days. However, an increase of AOX activity was not found, in the liver; although this organ is relevant to the metabolism of
contrast with CAT activity, which was significantly induced toxicants, in other tissues with high demands of energy, the b-
(Mimeault et al., 2006). The bezafibrate had no effects either on oxidation is an important aspect that needs to be evaluated. These
PPARa gene expression or on AOX activity in the liver of fathead outcomes suggest that PPARs gene expression and the proliferation
minnows (Pimephales promelas) treated with 0.1e106.7 mg/L of of peroxisomes are suitable biomarkers for the environmental
bezafibrate for 14 days. Nevertheless, the clofibric acid provoked an monitoring of the effects elicited by fibrates. Nevertheless, there is a
induction on AOX activity only in male fish exposed to the greater lack of information about the FAM in wild fish potentially exposed
concentration for 21 days, whereas in specimens exposed to lower to these compounds. Studies in the field are necessary to support
concentrations (1.07e108.91 mg/L), a response was not found this hypothesis, mainly in countries with severe problems of hu-
(Weston et al., 2009). The hepatic response of the rainbow trout man obesity, which consumes large amounts of these pharma-
dosed with gemfibrozil at 100 mg/kg every third day for 15 days ceutical products.
showed no significant increase in the expression of PPARa and
PPARg and no change in PPARb regarding controls. In contrast, the 4.2. Perfluoroalkyl Acids
mRNA of LPL was increased, which was accompanied by a notice-
able decrease in several types of lipids (Prindiville et al., 2011). In a Perfluoroalkyl Acids (PFAAs) such as perfluorooctanoic Acid
line cell of the plaice that expresses recombinant fusion proteins (PFOA) and perfluorooctane sulfonate (PFOS) are compounds
Gal4- PPARs, an induction of Gal4-PPARa elicited by gemfibrozil routinely used due to their numerous properties such as repellency
and ciprofibrate at concentrations of 100 mM for 24 h was found; to water and oil, resistance to high temperatures and acid media,
however, the bezafibrate had no effects on the Gal4-PPARa. On the hydrolysis, biodegradation by microorganism and vertebrates due
other hand, the Gal4-PPARb was induced by the bezafibrate at to the high energy in the carbon-fluorine bonds. In addition, these
10 mM and 100 mM; nevertheless, none of the tested fibrates chemical are released into the environment and their bio-
(gemfibrozil, bezafibrate, ciprofibrate, fenofibrate and clofibric accumulation could be monitored through the food web in aquatic
acid) induced the Gal4-PPARg (Colliar et al., 2011). In the liver of ecosystems (Wang et al., 2015). Therefore, there is a global concern
fathead minnows exposed to gemfibrozil at 0, 15 and 600 mg/L, an about the concentrations of these chemical compounds in aquatic
induction of PPARa and decreases in FABP were found in a dose- environments. For example, the PFAAs have been measured in
dependent manner after 8 days of treatment. In contrast, after 2 these abiotic compartments in the United States of America, Can-
days of exposure, an increase in PPARa and FABP by 15 mg/L was ada, Germany, Japan and Korea (Lau et al., 2007). Recently, the
documented, but not by 600 mg/L (Skolness et al., 2012). In this monitoring of PFAAs has been increased with reports about
study, PLP and FAS were not stimulated by gemfibrozil after 8 days Australian drinking water (Thompson et al., 2011), water from the
of exposure, but these biomolecules were induced by 600 mg/L after Czech Republic (Dufkova et al., 2012; Hlouskova et al., 2014), the
2 days of treatment. After 21 days of exposure to 1.5, 15, 600 and National Park and Llobregat River ecosystem in Spain (Pico et al.,
1500 mg/L of gemfibrozil, a dose-related decrease of mRNA, PPARa, 2012; Campo et al., 2015), and raw and treated tap water in
FABP, LPL and FAS was found (Skolness et al., 2012). In the zebrafish France (Boiteux et al., 2012). In addition, the presence of PFAAs was
fed with clofibrate (0.25, 0.5, 0.75 and 1% w/w) for four weeks, a found in water from Spain and Germany (Llorca et al., 2012), the
dose-related hepatic PP was documented; in addition, the gene Faroe Islands (Eriksson et al., 2013) and Ontario, Canada (Gewurtz
expression of AOX in the liver, intestine, muscle and heart was et al., 2014). A similar occurrence was detected in the river Tama
clearly induced (Venkatachalam et al., 2012). Under the same of Japan (Ye et al., 2014), in the wastewater treatment plants of
experimental model in the zebrafish, an up-regulation in the mRNA Kenya (Chirikona et al., 2015), in the urban rivers of Vietnam
expression of FABP in a dose-dependent response in the liver, in- (Duong et al., 2015), as well as in seawater from German Bight,
testine, muscle, brain and heart was reported (Venkatachalam North Sea (Zhao et al., 2015). In addition to the fact that in China the
et al., 2013). In the liver of a European eel (Anguilla anguilla) measurement of these compounds was performed since 2003 due
treated with gemfibrozil (0.1e200 mg/g fish) at 24 and 96 h after to its industrial relevance, the quantification of these compounds
exposure, a weak induction of the activities of AOX and CAT was has been done in several aquatic environments as well as in large
found (Lyssimachou et al., 2014). In the liver of a common carp mammals, human tissues, aquatic organisms and in a the food web
(Cyprinus carpio) treated for 4 and 10 days with environmentally (Wang et al., 2015). The PFAAs are present in surface, ground, ma-
relevant concentration of clofibric acid (4 mg/L), a time-related rine, and drinking water at concentrations from pg/L to mg/L;
response on the activity of AOX was documented; in addition, at meanwhile, in the wastewaters containing these compounds, the
20 mg/L a similar response was found (Corcoran et al., 2015). interval ranged from mg/L to below 1.0 g/L (Rayne and Forest,
Moreover, the mRNA of PPARa was up-regulated after 4 days of 2009). In rodent liver, the toxicity and hepatocarcinogenesis
exposure, and then a reduction was detected at day 10 regarding induced by PFAAs have been documented; they involve the acti-
AOX activity. The concentration of 4 mg/L induces a time-related vation of PPARa and are a key event in the development of these
Table 1
Reported effects of fibrates in FAM of fish species under controlled conditions.
Fish species Fibrate Treatment Time Response Reference
Rainbow trout Ciprofibrate 15, 25 or 35 mg/kg 3 weeks d-r [ AOX and CAT in liver Yang et al., 1990
Rainbow trout Clofibric acid 2.25e3.00 mM 48 h t-r [ AOX in hepatocytes Donohue et al., 1993
Ciprofibrate 0.25e1.00 mM t-r [ AOX in hepatocytes
Gemfibrozil 0.25e1.25 mM Not response in hepatocytes
Rainbow trout Gemfibrozil 0, 46, 87, or 152 mg/kg/day 2 weeks [ AOX in all treatments Scarano et al., 1994
Japanese medaka Gemfibrozil 0, 1.25, 2.5, or 5 ppm [ peroxisomal bifunctional enzyme at 5 ppm
Atlantic salmon Clofibric acid 0.5 and 1.0 mM in 3 days [ AOX and [ PPARg in hepatocytes Ruyter et al., 1997
and bezafibrate independent experiments
European seabass Clofibrate 35 or 70 mg/kg 2 weeks No induction of AOX and CPT-I in liver, gill, Pretti et al., 1999
and kidney
Eastern mosquitofish Clofibrate 18.4, 37.9, 73.8, 147.5 and 295 mg/L 28 days Y CAT in liver Nunes et al., 2004
Clofibric acid 1.01, 2.02, 4.03, 8.06 and 16.12 mg/L Y CAT in liver
Zebrafish Clofibrate 0.5, 1.0 and 2.0 mM 24 h d-r [ PPARa and PPARg slightly [ in hepatocytes Ibabe et al., 2005
Goldfish Gemfibrozil 1500 mg/L 14 and 28 days Y PPARb, [ CAT and AOX no changes in liver Mimeault et al., 2006
Fathead minnows Bezafibrate 0.1, 1.27, 10.18, 101.56, 14 days No effects on PPARa and AOX in liver Weston et al., 2009
and 106.7 mg/L
Clofibric acid 1.07, 10.75, and 108.91 mg/L 21 days [ AOX at 108.91 mg/L in liver of males
Rainbow trout Gemfibrozil 100 mg/kg Each third No significant [ PPARa and PPARg; no Prindiville et al., 2011
day by changes for PPARb and [ LPL with Y lipids
15 days in plasma
Plaice Gemfibrozil, 10 and 100 mM 24 h [ Gal4-PPARa by gemfibrozil and Colliar et al., 2011
bezafibrate, ciprofibrate at 100 mM; [ Gal4-PPARb by
ciprofibrate, bezafibrate at 10 mM and 100 mM and none
fenofibrate and of the tested fibrates induces Gal4-PPARg
clofibric acid
Fathead minnows Gemfibrozil 0, 15 and 600 mg/L by 2 and 2, 8 and 21 days [ d-r PPARa and Y FABP at 8 days; [ PPARa Skolness et al., 2012
8 days; 0, 1.5, 15, 600 and and FABP at 15 mg/L at day 2. Y d-r PPARa,
1500 mg/L by 21 days FABP, LPL and FAS in liver after 21 days
Zebrafish Clofibrate 0.25, 0.5, 0.75 and 1.0% w/w fed. 4 weeks d-r [ PP in hepatocytes; [ AOX hearth, liver, Venkatachalam
intestine, muscle and heart et al., 2012
d-r [ FABP in liver, intestine, muscle and brain Venkatachalam
and increases in the heart et al., 2013
European eel Gemfibrozil 0.1e200 mg/g 24 and 96 h Weak [ of AOX and CAT in liver Lyssimachou
et al., 2014
Common carp Clofibric acid 4 mg/L and 20 mg/L 4 and 10 days [ tm-related of AOX and PPARa activity at Corcoran et al., 2015
4 mg/L; [ tm-related of PPARa at 20 mg/L
Grass carp Clofibrate 4% in rich diet of carbohydrates 4 weeks [ AOX and LPL; no changes in CPT-I and Guo et al., 2015
and lipids PPARa in liver
AOX, acyl CoA-oxidase; CAT, catalase; PPAR, peroxisome proliferator-activated receptor; CPT-I, cartnitine palmitoyl trasnferase I; FABP, fatty acid binding proteins; PP,
peroxime proliferation: LPL, lipoprotein lipase; FAS, fatty acid synthase; d-r, dose-related; t-r, treatment-related; tm-r, time-related; [, induction respect to controls, and Y,
inhibition respect to controls.
pathologies (Klaunig et al., 2003; Wolf et al., 2008, 2012; 2014). In up-regulation of PPARa gene at 100 mg/L of PFOA for 7 days (Yang,
this regard, PFOA and PFOS are capable of inducing PP in rodents, 2010). In the liver of the grey mullet (Chelon labrosus) treated with
despite the fact that these chemical species have shown a little 2 ppm of PFOS by 2 and 16 days, an increase in the gene expression
affinity for PPARa compared to fibrates (Lau et al., 2007). In fish of PPARa and AOX was found, including AOX metabolism and RXR
species, some studies have been conducted to explore the toxico- mRNA, only at day 2; in contrast, the PPARg (2 and 16 days) and CAT
logical response of PFAAs evaluating biomarkers as PPARs expres- activity only at day 2 were reduced with regard to the control fish
sion, FAM and PP. Due to the physicochemical properties of these (Bilbao et al., 2010). In addition, the expression of RXR was
pollutants in the environment, their presence and bioaccumulation increased at day 2 and reduced at day 16 (Bilbao et al., 2010). The
have been documented in the tissues of several fish species from juvenile Atlantic salmon treated with pellets spiked with PFOA or
polluted localities with PFAAs (Baduel et al., 2014; Fujii et al., 2015; PFOS (each at 0.2 mg/kg), monitored at 2, 5 and 8 days, showed a
Svihlikova et al., 2015; Koponen et al., 2015; Hong et al., 2015; Giari time-related response of PPARa and PPARg by PFOA and in PPARa
et al., 2015). In the liver of the female zebrafish dosed with a single and PPARb by PFOS (Arukwe and Mortensen, 2011). The hepatic
intraperitoneal injection of perfluorododecanoic acid (0, 20, 40, or response of zebrafish chronically exposed to perfluorononanoic
80 mg/g body weight) by 48 and 96 h, or at seven days, the gene acid (PFNA) at 0, 0.1, 0.5, and 1.0 mg/L by 180 days showed that the
expression of FABP, PPARa and CPT-I in the liver was reduced expression of PPARs did not explain the hepatotoxicity mechanism
regarding controls. In addition, on these specimens three enzymes elicited by the PFAAs in this fish species (Zhang et al., 2012a).
involved in peroxisomal b-oxidation (acyl-CoA oxidase, very long- Moreover, in other PFNA treatments (0, 0.01, 0.1, and 1.0 mg/L), an
chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydro- increase in cholesterol was found in zebrafish of both sexes and a
genase) did not show changes in relation to unexposed fish (Liu sex-linked response on triglycerides levels was observed. In male
et al., 2008). The gene expression of PPARa was induced in the fish an increase was found, and in female fish the opposite was
liver of the rare minnow (Gobiocypris rarus) exposed to 0, 3, 10, or noted. A similar pattern of response was observed in the expression
30 mg/L of PFOA for 14 days; meanwhile, PPARg was induced only of FABP; this gene was up-regulated in males, whereas in females it
at 30 mg/L (Fang et al., 2010). In the liver of the male Japanese was down-regulated (Zhang et al., 2012b). In a primary culture of
medaka acclimated to sea water (to mimic the marine environ- hepatocytes of the Atlantic salmon treated with perfluorooctane
ment), an increase of AOX activity was found and was parallel to the sulfonamide (PFOSA) at 2, 20, and 50 mM by 12 and 24 h, alterations
in the fatty acid composition were found and they provoked an days, it was found that at 7 days after exposure the gene expression
apparent concentration-dependent increase of mRNA for PPARa of carnitine O-octanoyltransferase (CROT) was inversely related to
and PPARg (Wågbø et al., 2012). However, the expression of PPARb the concentration of the treatments, whereas the mRNA expression
and AOX did not show changes; in contrast, the CAT activity was of FABP3 showed an irregular pattern of treatments and time
increased in a dose-dependent manner at 24 h (Wågbø et al., 2012). (Carlson and Van Beneden, 2014). In hepatocytes from grass carp
In embryos of small marine medaka (Oryzias melastigma) at 4 days exposed to 0, 10 and 100 mM of Cu by 24, 48 and 96 h, the activity of
post-fertilization exposed to 1, 4 and 16 mg of PFOS/L, a dose- 6PGD, G6PD and CPT-I showed an increase related to time and Cu.
related down-regulation of PPARa mRNA, which was accompa- In the other hand, the triglycerides content was inversely correlated
nied by an irregular expression of PPARɣ regarding the control with time and treatments. The mRNA expression of SREBP-1, ACC
group was observed. Nevertheless, at 10 days post-fertilization, a and FAS was reduced regarding controls; however, it was only in
dose-dependent up-regulation of mRNA of PPARa and PPARb was the fish treated with 100 mM for 96 and 48 h that noticeable in-
documented, in contrast, the PPARɣ mRNA showed an irregular creases of PPARa and CPT-I were found (Zhu et al., 2014). Although
expression in comparison to the basal expression (Fang et al., metals are not ligands of PPARs, it has been proposed that As are
2012a). In hepatocytes of the Atlantic salmon treated with 25 and able to modify the activation of PKB/AKT1 signaling pathway,
50 mM of PFOSA by 24 and 48 h, the gene expression of AOX was not which is responsible for the phosphorylation of PPARg that follows
stimulated. However, at 25 mM of PFOSA in co-exposure with the reduction in the expression of CROT and 3-Hydroxy-3-
125 mM of CoCl2 or with deferroxamine alone (100 mM) and with Methylglutaryl-CoA Synthase 1 Soluble involved in sterol synthe-
25 mM of PFOSA for 48 h a significant up-regulation of AOX mRNA sis (Carlson and Van Beneden, 2014). These findings could also be
was detected (Olufsen et al., 2014). In contrast, a significant increase reviewed in Table 3. In addition, it is possible that transcription
in the expression of PPARa was noted using 50 mM of PFOSA alone, factors of PPARs, which participate in the FAM, could modify the
but the PFOSA (25 and 50 mM) in co-exposure with 125 mM of CoCl2 DNA binding domains, as in the case of zinc finger motifs. Other
favors the mRNA of PPARg at 48 h. Using deferroxamine (100 mM) metals with similar properties to Zn could enhance or reduce these
alone and with PFOSA, the expression of PPARs in the hepatocytes responses as it has been documented for the estrogenic response
of the Atlantic salmon presented a noticeable increase (Olufsen (Martin et al., 2003; Darbre, 2006). Due to the relevance of metals
et al., 2014). It stands out that the PFAAs induce contradictory re- in pollution at the global scale and the increasing concern about the
sponses in PPARs (mainly in PPPARa and PPARg) gene expression as toxic effects of classical PPARs agonists, such as the case of fibrates,
in the AOX mRNA in some fish species, or when this response oc- it is advisable to probe the implications of these chemicals in FAM
curs, a lack of changes regarding the control fish prevails (Table 2). in fish under controlled conditions, including mixtures as occurs in
This is probably because these pollutants have a low affinity to the environment.
PPARa with regard to fibrates (Lau et al., 2007) and depend on of
particularities in the experimental design, including higher doses 4.4. Endocrine Disrupting Compounds
or concentrations, and variation on the fish developmental stages.
These findings support the hypothesis stating that it is not possible Endocrine Disrupting Compounds (EDCs) are exogenous
to ensure that the PFAAs are xenobiotics able to increase the lipo- chemical species which are able to impact the synthesis, signaling
genesis and/or b-oxidation in fish species. However, it is possible to and metabolism of hormones (Diamanti-Kandarakis et al., 2009). In
focus on the effects of PFAAs on the endocrine sexual axis, as it has fish species, the alteration of the sexual endocrine control impacted
been reported in the Atlantic salmon and the zebrafish (Spachmo by EDCs has been widely studied. Some EDCs as pharmaceutical
and Arukwe, 2012; Jo et al., 2014). products, phytoestrogens, pesticides and industrial chemicals could
change the estrogenic signaling by activation of estrogen receptor,
4.3. Metals probably by its high promiscuity of this receptor (Shanle and Xu,
2011). In this regard, some studies have been carried out on the
Metals have been present in the Earth since its formation; impact of some EDCs in response to the transcription factors of
however, when their concentrations in the environment cause PPARs, particularly those involved in FAM.
damages to life, they must be paid attention. In many cases, this Methoxychlor was synthesized as an alternative to 1,1,1-
phenomenon could be elicited by industrial activities as in the cases trichloro-2,2-bis(p-chlorophenyl) ethane (DDT); however, its use
of mining and smelting or it could be caused by natural processes was banned by the US EPA in 2003 since it is well documented that
such as volcanic activities (Walker et al., 2012). Despite the envi- it possesses endocrine disrupting properties (Shanle and Xu, 2011)
ronmental relevance of metals, only a few studies have been con- among its other toxic effects. In the liver of an adult male zebrafish
ducted with regard to their effects on PPARs expression and exposed to 100 mg methoxychlor/L, significant increases in the
transcription factors related to FAM in fish. In the liver of the yellow metabolism of CAT after 15 days of exposure and in the activity of
catfish (Pelteobagrus fulvidraco) exposed for 6 weeks to Cu at 2, 24, AOX after 7 and 15 days was detected (Ortiz-Zarragoitia and
71 and 198 mg/L, the activity and expression of 6- Cajaraville, 2000). In the zebrafish treated on independent experi-
phophoglugluconate dehydrogenase (6PGD), glucose 6-phosphate ments for 15 days with 17b-estradiol at 10 mg/L, dibutylphthalate at
dehydrogenase (G6PD), malic enzyme (ME) and isocitrate dehy- 500 mg/L (plasticizer), methoxychlor at 100 mg/L (pesticide), 4-tert-
drogenase (ICDH), which are involved in energy metabolism and octylphenol at 500 mg/L (t-OP; estrogenic alkylphenol) and 17a-
FAS, decreased with the increases in Cu content in water. A similar ethynylestradiol at 10 mg/L (a widely used synthetic estrogen), a
response was noted on the expression of sterol-regulator element- significant proliferation of peroxisome and greater activities of AOX
binding protein (SREBP-1). In visceral adipose tissue, these metals were found (Ortiz-Zarragoitia and Cajaraville, 2005). In addition, by
also induce depletion on the expression of the protein lipase, FAS the effects of 17b-estradiol, dibutylphthalate and methoxychlor, an
and PPARg in the liver (Chen et al., 2013). In the javelin goby association between peroxisomal density parameters and AOX
(Synechogobius hasta) treated within 30 dayse77 mg Cu/L, 79 mg Cd/ metabolism were found (Ortiz-Zarragoitia and Cajaraville, 2005).
L and in co-exposure of both metals, an increase in the lipid content Nonylphenol (NP) is an EDC generated by microbial degradation of
and in hepatic activities of 6PGD, G6PD, ME, ICDH and FAS was alkylphenol polyethoxylates within an elevated persistence in the
found (Song et al., 2014). On the other hand, in the liver of adult aquatic ecosystem (Soverchia et al., 2005; Lacorte et al., 2006;
specimens of male zebrafish exposed to sodium arsenite for 21 Shanle and Xu, 2011). The concentration of NP in surface waters
Table 2
Reported effects of PFAAs, PFOA, PFOS, PFNA and PFOSA in FAM of fish species under controlled conditions.
Fish species Compound Treatment Time Response Reference
Zebrafish PFDoA 0, 20, 40, or 80 mg/g 48 h, 96 h or Y PPARa, FABP and CPT-I; peroxisomal b-oxidation Liu et al., 2008
body weight. seven days. were not change in liver
Rare minnow PFOA 0, 3, 10, or 30 mg/L 14 days [ PPARa and [ PPARb only at 30 mg/L in liver Fang et al., 2010
Japanese medaka PFOA 100 mg/L 7 days [ PPARa and AOX in liver Yang, 2010
Grey mullet PFOS 2 ppm 2 and 16 days [ PPARa, AOX, RXR at day 2, and CAT at day 16; Y PPARg Bilbao et al., 2010
and CAT at day 2 and XRX at day 16 in the liver
Atlantic salmon PFOA and 0.2 mg/kg fish 2, 5 and 8 days tm-r [ of PPARa and PPARg by PFOA and PPARa Arukwe and
PFOS and PPARb by PFOS Mortensen, 2011
Zebrafish PFNA 0, 0.1, 0.5, and 1.0 mg/L 180 days Expression of PPARs did not explain hepatotoxicity Zhang et al., 2012a
mechanism of PFAAs
Zebrafish PFNA 0, 0.01, 0.1, and 1.0 mg/L 180 days [ cholesterol in both sexes and a differentiated response Zhang et al., 2012b
of triglycerides and FABP ([ males and Y females)
Atlantic salmon PFOSA 2, 20, and 50 mM 12 and 24 h t-r [ of PPARa and PPARg, and not changes for PPARb Wågbø et al., 2012
and AOX; t-r [ CAT at 24
Small marine medaka PFOS 1, 4 and 16 mg/L 4 and 10 dpf t-r Y PPARa and Y PPARɣ at 16 mg/L in 4 dpf; t-r [ PPARa Fang et al., 2012a
and PPARb at 10 dpf
Atlantic salmon PFOSA 25 and 50 mM 24 and 48 h AOX was not stimulated; only [ PPARa at 50 mM Olufsen et al., 2014
by 48 h in hepatocytes
CoCl2 at 150 mM alone and 24 and 48 h [ AOX only 25 mM of PFOSAþCoCl2 by 48 h; [ PPARa
with 25 mM, and with 50 mM for CoCl2 at 150 mM with 25 and 50 mM of PFOSA; [ PPARg
of PFOSA for 25 mM of PFOSAþCoCl2 by 48 h in hepatocytes
Deferroxamine at 100 mM 24 and 48 h In general way, [ AOX and PPARs at 48 h for all
alone and with 25 mM, and treatments in hepatocytes
with 50 mM of PFOSA
PFAAs, perfluoroalkyl acids; PFDoA, perfluorododecanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane Sulfonate; PFNA, perfluorononanoic acid; PFOSA, per-
fluorooctane sulfonamide; PPAR, peroxisome proliferator-activated receptor; FABP, fatty acid binding proteins; CPT-I, cartnitine palmitoyl trasnferase I; AOX, acyl CoA-
oxidase; RXR, retinoid X receptor; CAT, catalase; tm-r, time-related; t-r, treatment-related; [, induction respect to controls and Y, inhibition respect to controls.
Table 3
Reported effects of metals in FAM of fish species under controlled conditions.
Fish species Metal Treatment Time Response Reference
Yellow catfish Cu 2, 24, 71 and 198 mg/L 6 weeks t-r Y 6PGD, G6PD, ME, ICDH, FAS and SREBP-1 in the liver; Chen et al., 2013
similar responses for LPL, FAS and PPARg in visceral adipose tissue
Javelin goby Cu and Cd 77 mg Cu/L, 79 mg Cd/L 30 days [ lipid content and in hepatic activities of 6PGD, G6PD, ME, ICDH and FAS Song et al., 2014
and in co-exposure
Zebrafish Sodium 0, 10, 50, or 500 ppb 21 days t-r Y CROT; FABP3 showed an irregular pattern among treatments Carlson and Van Beneden, 2014
arsenite and time in the liver
Grass carp Cu 0, 10 and 100 mM 24, 48 tm-r and t-r [ 6PGD, G6PD and CPT-I and tm-r and t-r Y of Zhu et al., 2014
and 96 h triglycerides; Y SREBP-1, ACC and FAS; [ PPARa and CPT-I at 96
and 48 h at 100 mM in hepatocytes
6PGD, 6-phophoglugluconate dehydrogenase; G6PD, glucose 6-phosphate dehydrogenase; ME, malic enzyme; ICDH, isocitrate dehydrogenase; FAS, fatty acid synthase;
SREBP-1, sterol-regulator element-binding protein; LPL, lipoprotein lipase; PPAR, peroxisome proliferator-activated receptor; CPT-I, cartnitine palmitoyl trasnferase I; FABP,
fatty acid binding proteins; ACC, acetyl-CoA carboxylase; d-r, dose-related; t-r, treatment-related; tm-r, time-related; [, induction respect to controls; Y, inhibition respect to
controls.
is from 0.64 to 180.0 mg/L (Naylor et al., 1992; Blackburn and of NP and t-OP and for both treatments of BPA (Maradonna et al.,
Waldock, 1995). In the liver of juvenile sole (Solea solea), the gene 2015). Up-regulation in the expression of RXR was estimated by
expression of RXRa and PPARa were higher than controls even at cause of NP (50 mg/kg). In the case of FAS (5 and 50 mg/kg), the BPA
106 M within 3 days of exposure; meanwhile, the PPARb was increased the RXR mRNA at 5 mg/kg and for expression FAS, this
slightly higher than controls (Cocci et al., 2013). Bisphenol A (BPA) response was noticeable at 50 mg/kg; nevertheless, t-OP does not
is a key material used in the synthesis of polycarbonate plastics and induce changes in the expression of both genes. In addition, the
epoxy resins in several products, such as food and beverage pack- mRNA of LPL was induced for all treatments (Maradonna et al.,
ing, flame retardants, adhesives, building materials, electronic 2015). In a general way, increases of the activity of CCA, FAS and
components and paper coatings, with well-documented endocrine CPT-I in the liver of rare minnow exposed to 15 mg BPA/L for 28 days
disruption effects in fish species (Crain et al., 2007; Flint et al., were noted, but its gene expression was reduced regarding control;
2012). In the liver of juvenile gilthead seabream (Sparus aurata), besides, it was only in male fish that the content of triglyceride in
the activity of CAT was stimulated in specimens fed daily with the liver and serum was greater than controls, suggesting a gender-
commercial food enriched with 5 mg BPA/kg (21 days). However, no related response (Guan et al., 2016).
changes were noted at 50 mg/kg regarding controls (Maradonna Phytoestrogens are naturally-occurring compounds present in
et al., 2014). By the effect of NP, t-OP and BPA (dosed in commer- plants and are analogous to mammalian estrogens (Whitten et al.,
cial food at 5 and 50 mg/kg), an increased expression of PPARg was 1997). The genistein and daidzein are two phytoestrogens
found in the liver of gilthead seabream by 21 days (Maradonna commonly present in soybean meal, which are used in fish food
et al., 2015). However, it was only at the greater dose (50 mg/kg) that causes abnormalities in the growth of the fish (Refstie et al.,
of these toxins that an up-regulation of PPARa was detected; in 2010). In the rainbow trout the genistein at 5 and 50 mg/g body
contrast, the PPARb expression was increased by effects of 5 mg/kg weight (intraperitoneal dosed) provokes a reduced gene expression
of PPARb, PPARg and RXR after 24 h of treatment; in contrast, the glucose 6-phosphate dehydrogenase involved in energy meta-
mRNA of FABP3, LPL, SREBP-1, ACC, FAS were increased (Cleveland bolism was also noted (Arnold et al., 1995). The linuron, a urea-
and Manor, 2015). Six genes involved in mitochondrial FA transport based herbicide (Lambright et al., 2000), is able to induce the PP
showed an irregular response regarding control; meanwhile, genes in hepatic and renal cells of the rainbow trout exposed for 5 weeks
related to mitochondrial and peroxisomal b-oxidation possessed a to 30, 120 and 240 mg/L (Oulmi et al., 1995a). The atrazine is a
similar response to their basal expression (Cleveland and Manor, herbicide found in aquatic environments due to its persistence and
2015). It is well documented that tributyltin (TBT) and triphe- mobility (Fan et al., 2007). In the segment I of the proximal tubules
nyltin (TPT) are EDC in mammals and fish species (Saitoh et al., of the rainbow trout exposed to 0, 10, 20, 40, 80, and 160 mg atra-
2001; Thibaut and Porte, 2004; Ohno et al., 2005). These chem- zine/L for 4 weeks, a PP as well as a formation of peroxisomes
icals were reported as agonists of PPARg and XRX in the range of clusters were found above 80 mg atrazine/L (Oulmi et al., 1995b). In
nanomolar concentrations (Nakanishi, 2008). In the juvenile addition, the presence of paclobutrazol (PBZ), a fungicide that
Atlantic salmon exposed for 72 h to TBT (0.1, 1 and 10 mg/kg), the contains triazole widely used in agriculture, could be a global
gene expression of PPARb in interrenal tissues were similar to concern because its presence in the aquatic environment, as well as
controls, and the PPARa showed an irregular response. However, its toxic effects in aquatic organisms (Kolpin et al., 2002; Li et al.,
the PPARg was greater at 0.1 mg/kg, rather than at other treatments 2010). In the liver of male specimens of false kelpfish (Sebastiscus
and PPARs; in contrast, a noticeable reduction on PPARg, even marmoratus) exposed to 10, 100 and 1000 ng/L of PBZ for 50 days, it
lower than controls, was detected at 1 and 10 mg/kg (Pavlikova was found that the liver content of total lipids, triglycerides, FA and
et al., 2010). In the same specimens, the activity of AOX was total cholesterol, as well as the gene expression of PPARa, PPARb,
significantly greater at 0.1 mg/kg regarding controls and the rest of PPARg, acetyl-CoA carboxylase, FAS and FABP4, were linked to
the treatments (Pavlikova et al., 2010). The tributyl tin oxide was an treatments (Sun et al., 2013). Triclosan (TCS) is a common antimi-
antagonist of the recombinant fusion proteins, Gal4-PPARa and crobial agent widely used in personal care products, and it has been
Gal4-PPARb, of the plaice exposed to real environmental concen- detected in sewage treatment plant effluents as well as surface,
trations of this toxicants (1e50 nM) (Colliar et al., 2011). In the liver ground and drinking water (Dhillon et al., 2015). In 5 days post
and brain from pre-hatch zebrafish to 9 months-old exposed to 10 fertilization zebrafish larva exposed for 5 days to TCS at 250, 500
and 50 ng TBT/L, it was found that this obesogenic compound is and 750 mg/L, a treatment-related reduction in the expression of
able to modify the transcription of key factors involved in lipid ACC and CPT-I was found; however, change in FAS was not found
regulation in a sex-related way (Lyssimachou et al., 2015). As re- (Ho et al., 2016). On the other hand, the TCS reduces the beta-
ported in the case of PFAAs, EDCs also exert controversial responses oxidation process (PPARa, L-peroxisomal bifunctional enzyme and
regarding FAM (Table 4). Probably, these compounds are not suit- AOX) and lipogenic factors such as SREBP-1 and carbohydrate
ably monitored in the environment using these physiological as- response element-binding protein (CHREBP). A similar response
pects as biomarkers in fish species. occurred with the polypeptide 10 of the cytochrome P450, family 4,
subfamily A (Ho et al., 2016). Despite the fact that only a few reports
4.5. Pesticides about the effects of pesticides on FAM in fish species exist (Table 5),
Pesticides have been widely used to ensure the supply of human the PP in fish species has been induced by endosulfan and disul-
food in agricultural crops since the 1940s, and since then their use foton, linuron and atrazine. Recently, more detailed studies have
has increased (Grung et al., 2015). Their presence in aquatic envi- been performed about the effects of PBZ and TCS on FAM of fish
ronments has been detected in several studies at the global scale for species at pre-transcriptional levels (Sun et al., 2013; Ho et al.,
several years. Some pesticides exert their biological effects by 2016). Nevertheless, more studies are required to clarify if these
agonistic and antagonistic activities on certain NRs that regulate compounds have effects on the FAM of fish species in a sensible way
key physiological functions as in the case of PPARs (Kojima et al., to be considered as suitable biomarkers to these pollutants.
2010). Despite this information, only a few studies have been per-
formed about the toxic effects of pesticides on FAM in fish species. 4.6. Flame retardants, plasticizers and others compounds
The dinitro-o-cresol (DNOC) is used in the formulation of non-
phosphate ester pesticide. In the hepatocytes of the European eel Although studies on the effects of fibrates and perfluoroalkyl
exposed for four weeks to 5, 50, and 250 mg DNOC/L, a stimulation acids have been conducted, more studies regarding alteration in
of the peroxisomes was demonstrated through the increases of FAM in fish are required. The organophosphate esters (OP esters)
three enzymes of this organelle, such as the cases of catalase, are synthetic compounds used as flame-retardants and plasticizers
allantoinase and uricase (Braunbeck and Vo € lkl, 1991). Dieldrin and are produced in large amounts at global levels; however, these
(DLN) was widely used as an insecticide and has been banned for chemicals possess environmental relevance. For example, the tris
several years; nevertheless, due to its chemical characteristics, the (1,3-dichloro-2-propyl) phosphate (TDCPP), triphenyl phosphate
presence of this compound in the environment has been docu- (TPP) and tri-m-cresyl phosphate (TMCP) are chemical species
mented in a recent study (Stern, 2014). In the liver of juvenile belonging to OP esters and have been detected in aquatic envi-
gilthead seabrams injected with DLN at 0.15 mg/kg for 2 and 7 days, ronments with high occurrence (van der Veen and de Boer, 2012).
increases at day 7 in the activity of AOX on CAT activity measured The phthalate dibutylphthalate (DBP), another plasticizer widely
indirectly by PP and of the protein content of the peroxisomal used, is able to alter the FAM in fish species. In hepatic tissue of
fraction were found (Pedrajas et al., 1996). The endosulfan and zebrafish exposed to 500 mg DBP/L for 7 and 15 days, a statistically
disulfoton are insecticides that act as cholinesterase inhibitors used significant increase in the metabolism of AOX was documented
in the control of pests in vegetables, fruits, cereal grains and cotton, (Ortiz-Zarragoitia and Cajaraville, 2000). In the zebrafish embryos/
ornamental shrubs, trees, vines and ornamental plants (Chen and larvae exposed to 0.02, 0.2 and 2 mg/L of TDCPP for 4e120 h post-
Huang, 2006; Mrema et al., 2013). In hepatocytes and in the liver fertilization, an increased dose-related response in the gene
of the male rainbow trout treated with a combination of endosulfan expression of peroxisome proliferator-activated receptor gamma
and disulfoton (50 mg/L of endosulfan and 0, 1, 5 or 10 mg/L of coactivator 1 alpha (PPARgc1), LPL and PPARa were observed.
disulfoton) for 18 and 34 days, notable increases in the total volume Meanwhile, when this specimen was exposed to TPP at the same
of peroxisome and in the metabolism of uricase (a peroxisomal concentrations, the PPARa, PPARgc1 and LPL showed a similar
enzyme) were detected. However, a reduction in the activity of pattern of response regarding outcomes observed by the effects of
Table 4
Reported effects of EDCs in FAM of fish species under controlled conditions.
Zebrafish MXC 100 mg/L 15 and 7 days [ CAT after 15 days of exposure and AOX after Ortiz-Zarragoitia
7 and 15 days in the liver and Cajaraville, 2000
Zebrafish E2, EE2, MXC, E2 and EE2 at 10 mg/L; MXC at 15 days [ PP and AOX for all compounds; effects of E2, Ortiz-Zarragoitia
t-OP and DBP in 100 mg/L and t-OP and DBP DBP and MXC cause related responses among and Cajaraville, 2005
independent for 500 mg/L peroxisome parameters and AOX in liver.
experiments
Sole 4-NP 108 and 106 M 3 days [ RXRa and PPARa at 106 M; slight induction Cocci et al., 2013
PPARb in liver
Gilthead Bisphenol A Fed daily with commercial food 21 days [ CAT at 5 mg BPA/Kg and not changes at Maradonna et al., 2014
seabream enriched with 5 and 50 mg BPA/Kg 50 mg/kg in liver
Gilthead NP, t-OP and Commercial food enriched 21 days [ PPARg for all treatments, [ PPARa at 50 mg/kg Maradonna et al., 2015
seabream Bisphenol A with 5 and 50 mg/kg for all compounds, [ PPARb by 5 mg/kg of NP and
t-OP and for both treatments of BPA; [ RXR by
NP (50 mg/kg) and [ FAS (5 and 50 mg/kg),
[ RXR by BPA (5 mg/kg) and [ FAS (50 mg/kg);
t-OP no induce changes in RXR and FAS; LPL was
induced for all treatments in the liver
Rare minnow Bisphenol A 15 mg/L 28 days [ ACC, FAS and CPT-I activities, but its gene Guan et al., 2016
expression was Y in liver; only in males
[ triglycerides in liver and serum
Rainbow trout Genistein 5 and 50 mg/g 24 h Y PPARb, PPARg and RXR; [ FABP3, LPL, SREBP-1, Cleveland and
ACC and FAS and six genes involved in FA transport Manor, 2015
into mitochondria showed an irregular response
regarding to control; genes related with b-oxidation
were similar to control in the liver
Atlantic salmon Tributyltin 0.1, 1 and 10 mg/kg 72 h PPARa irregular response, PPARb similar to controls, Pavlikova et al., 2010
[ PPARg at 0.1 mg/kg and above was Y;
[ AOX at 0.1 mg/kg in interrenal tissues.
Plaice Tributyl tin oxide 1-50 nM 24 h Y Gal4-PPARa and Gal4-PPARb Colliar et al., 2011
Zebrafish Tributyltin 10 and 50 ng/L From pre-hatch Alterations the transcription of key factors involved Lyssimachou
to 9 months of age in lipid regulation in a sex-related way. et al., 2015
E2, 17b-estradiol; EE2, 17a-ethinyl estradiol; MXC, Methoxychlor; NP, nonylpnenol; t-OP, 4-tert-octylphenol; DBP, dibutylphthalate; CAT, catalase; AOX, acyl CoA-oxidase; PP,
peroxime proliferation; RXR; retinoid X receptor; PPAR, peroxisome proliferator-activated receptor; LPL, lipoprotein lipase; ACC, acetyl-CoA carboxylase; FAS, fatty acid
synthase; CPT-I, cartnitine palmitoyl trasnferase I; SREBP-1, sterol-regulator element-binding protein.
TDCPP, but with lesser clarity (Liu et al., 2013). In hepatocytes of the (recombinant fusion proteins) (Colliar et al., 2011). In contrast, the
gilthead seabream treated during 48 h with 0.1, 1.0 or 10 mM of mono-1-methyl-hexyl-phthalate and 1-mono-benzylphthlate
TMCP, an up-expression of PPARa, PPARb, PPARg, RXRa, liver reti- induce the transcriptional activities of Gal4-PPARa and Gal4-PPARb
noid receptor isoform a (LXRa), CPT1A, LPL, fatty acid desaturase 2 at 100 mM in a cell line of the plaice (Colliar et al., 2011). The dii-
(FADS2), SREBP-1c, stearoyl-CoA desaturase 1A and 1B (SCD1A, sodecyl phthalate (DiDP) is a common contaminant of aquatic en-
SCD1B, respectively) and apolipoprotein (APO-A1) were found vironments with obesogenic effects posing a potential risk to the
(Palermo et al., 2016). The plasticizers of phthalate, dimethylph- health of fish (Cocci et al., 2015). In the gilthead seabream hepa-
thalate and benzylbutylphthalate, along with their mono-ester tocytes, it was found that DiDP activates the signaling of PPAR:RXR,
equivalents, mono-1-methyl-hexyl-phthalate and 1-mono- inducing in this way changes in lipid homeostasis (CPT-I, FADS2,
benzyl-phthalate, were not able to activate any of the Gal4-PPARs SCD1A, SCD1B, LPL, FABP, APO-1A, SREBP) (Cocci et al., 2015).
Table 5
Reported effects of pesticides in FAM of fish species under controlled conditions.
Fish species Pesticide Treatment Time Response Reference
European eel DNOC 5, 50, and 250 mg/L 4 weeks [ CAT, allantoinase and uricase as stimulation of peroxisome Braunbeck and Vo €lkl, 1991
Gilthead DLN 0.15 mg/kg 2 and 7 days AOX at day 7; [ protein content of the Pedrajas et al., 1996
seabrams peroxisomal fraction and CAT activity as
an indirect way of measuring PP
Rainbow trout EDS and 50 mg EDS/L and 18 and 34 days [ uricase and peroxisome volume and Arnold et al., 1995
DSF 0, 1, 5 or 10 mg DSF/L Y G6PD activity in hepatocytes and liver of male fishes
Rainbow trout Linuron 30, 120 and 240 mg/L 5 weeks [ PP in hepatic and renal cells Oulmi et al., 1995a
Rainbow trout Atrazine 0, 10, 20, 40, 80, and 4 weeks [ PP in the proximal segment in the renal Oulmi et al., 1995b
160 mg atrazine/L tubules above of 80 mg/L
False kelpfish PBZ 10, 100 and 1000 ng/L 50 days t-r [ lipids and cholesterol, as well as PPARa, PPARb, Sun et al., 2013
PPARg, ACC, FAS and FABP4 in the liver
Zebrafish TCS 250, 500 and 750 mg/L 5 days t-r Y ACC and CPT-I; no changes in FAS; Y SREBP-1, Ho et al., 2016
CHREBP, AOX, PPARa, CYP4A10 and LPBE
DNOC, dinitro-o-cresol; DLN, dieldrin; EDS, endosulfan; DSF, disulfoton; PBZ, Paclobutrazol; TCS, Triclosan; CAT, catalase; AOX, acyl CoA-oxidase; PP, peroxime proliferation;
G6PD, glucose 6-phosphate dehydrogenase; PPAR, peroxisome proliferator-activated receptor; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; FABP, fatty acid binding
proteins; CPT-I, cartnitine palmitoyl trasnferase I; SREBP-1, sterol regulatory element binding protein-1; CHREBP, carbohydrate-response element-binding protein; CYP4A10,
cytochrome P450, family 4, subfamily a, polypeptide 10; LPBE, L-peroxisomal bifunctional enzyme; t-r, treatment-related; [, induction respect to controls; Y, inhibition
respect to controls.
Halogenated derivatives of bisphenol A (HBPA) are commonly them. In this section, it was shown that only some of these have
used as flame retardants and are able to activate the PPARg which is been investigated out of a typical cluster of chemical species that
involved in adipogenesis; in addition, its presence in the environ- induce changes in FAM. Den Broeder et al. (2015) have suggested
ment has been reported (Fukazawa et al., 2001; Riu et al., 2014; that the proteins involved in this physiological process are
Delfosse et al., 2014). In the juvenile of zebrafish previously conserved between mammals and fish; therefore, it is suitable to
exposed as larvae to tetrabromobisphenol-A (TBBPA) and test such compounds with the capacity of inducing changes in this
tetrachlorobisphenol-A (TCBPA) for 48 h at 1 mM, a weight gain was biological aspect in mammals and also in fish species. On the other
observed. This effect could be explained because these compounds hand, more studies are required to increase knowledge about the
are agonists of PPARg. Although BPA is a well-documented EDC in affinity of emergent OC to PPARs; their tendency to disrupt the FAM
fish species, its derivatives such as HBPA contribute to support the has been recently studied (Palermo et al., 2016).
hypothesis that this compound possesses obesogenic properties in
these organisms (Riu et al., 2014). 4.7. Mixtures of compounds under controlled conditions and
Forskolin is a diterpene that is produced by the plant Coleus environmental studies
forskohlii; it is used to raise levels of cyclic AMP, which is an
important second messenger necessary for the proper biological In aquatic environments, the exposure of fish species to a sole
response of cells to hormones and other extracellular signals pollutant is improbable. Therefore, studies with mixtures of OC-
(Seamon et al., 1981). In addition, Pavlikova et al. (2010) reported associated, for example, with an industrial source or impacted
that forskolin (200 mg/L) alone, and in a mixture with TBT (10 mg/ areas, are relevant to increasing the understanding of the in-
kg), noticeably increases the expression of PPARb with greater teractions among pollutants and transcription factors involved in
outcomes after 4 h of exposure regarding to this expression at 2 h. FAM. In channel catfish (Ictalarus punctatus) exposed to 0, 10, 20,
Meanwhile, PPARa and PPARg gene expressions pertaining to and 40% of the bleached kraft pulp and paper mill effluent for two
controls were reduced; however, the AOX was not different in weeks, increases in the metabolism of two acyl-CoA oxidases
comparison to basal values. Atorvastatin is a cholesterol-lowering (lauroyl-CoA oxidase and palmitoyl-CoA oxidase) belonging to
pharmaceutical product, which is one of the statins released into peroxisomal b-oxidation were documented (Mather-Mihaich and
the aquatic environment mainly through wastewater treatment Di Giulio, 1991). In grey mullet exposed to fresh heavy fuel oil
plants (Khetan and Collins, 2007). Some studies have reported that and weathered heavy fuel oil for 2 and 16 days, increases in the
the concentration of statins is in the range of ng/L to mg/L (Metcalfe expression of AOX, PPARa, cytochrome P450 (CYP 450) isoforms 1A
et al., 2003; Grung et al., 2007; Gracia-Lor et al., 2010; Langford and (CYP 1A), RXR (at day 2) and CAT (at day 16) were observed.
Thomas, 2011). In the gills as in the liver of the rainbow trout Otherwise, reductions in the mRNA were detected for PPARg (at day
exposed for 7 days to atorvastatin acid and atorvastatin lactone at 2 and day 16) and RXR (only at day 16); these effects were similar to
10 and 200 ng/L showed no significant changes in the two genes those elicited by PFOS (2 ppm) reported in the same study (Bilbao
involved in cholesterol biosynthesis and PPARa regarding controls et al., 2010). Using the ingenuity pathway analysis, it was found that
(Ellesat et al., 2012). These reports could be viewed in Table 6. persistent organic pollutants obtained from the liver of burbot (Lota
In the aquatic environment, there are large amounts of OC Lota) from Lake Mjøsa and Lake Losna (Norway) provoked associ-
whose concentrations are able to impact the organisms exposed to ations between the PPARg expression with certain genes involved
Table 6
Reported effects of in flame retardants, plasticizers and others compounds FAM of fish species under controlled conditions.
Plaice Phthalate mono-esters 1 to 50 nM 24 h Not activation Gal4-PPARs; in contrast, Colliar et al., 2011
(see text) mono-1-methyl-hexyl-phthalate and
1-mono-benzylphthlate [ transcriptional
activities of Gal4-PPARa and Gal4-PPARb
at 100 mM in a line cell
Zebrafish DBP 500 mg/L 7 and 15 days [ AOX in liver Ortiz-Zarragoitia and
Cajaraville, 2000
Zebrafish TDCPP and TPP 0.02, 0.2 and 2 mg/L 4 to 120 hpf [ t-r PPARgc1, LPL and PPARa for TDCPP; Liu et al., 2013
similar responses for TPP in embryos/larvae
Gilthead seabream TMCP 0.1, 1.0 or 10 mM 48 h [ PPARa, PPARb, PPARg, RXRa, LXRa, FADS2, Palermo et al., 2016
SREBP-1C, SCD1A, SCD1B and APO-A1 in hepatocytes.
Sea bream DiDP 0.1, 1.0, or 10 mM 48 h [ PPARa, PPARb, PPARg, RXRa, CPT-I, FADS2, Cocci et al., 2015
SREBP, SCD1A, SCD1B, LPL, FABP and APO-A1
in hepatocytes at 0.1 and 1.0 mM
Zebrafish TBBPA and TCBPA 1 mM 48 h [ weight, probably because these compounds Riu et al., 2014
are agonist of PPARg in juvenile of zebrafish
previously exposed as larvae
Atlantic salmon TBT and forskolin 10 mg/kg for TBT and 72 h for TBT and Forskolin with TBT or in alone elicited [ of Pavlikova et al., 2010
after 200 mg/L for forskolin after 4 and 2 h PPARb and Y of PPARa and PARRg and an
or alone forskoline fot forskolin irregular expression of AOX was noted in
the head of kidney
Rainbow trout Atorvastatin acid and 10 and 200 ng/L 7 days No significant changes of two genes of cholesterol Ellesat et al., 2012
atorvastatin lactone biosynthesis and PPARa regarding to controls
in liver and gills
DBP, Phthalate dibutylphthalate; TDCPP, tris(1,3-dichloro-2-propyl) phosphate; TPP, triphenyl phosphate; TBBPA; Tetrabromobisphenol-A; TCBPA, Tetrachlorobisphenol-A;
DiDP, Diisodecyl phthalate; TDCPP, Tris(1,3-dichloro-2-propyl) phosphate; TMCP, tri-m-cresyl phosphate; PPAR, peroxisome proliferator-activated receptor; AOX, acyl CoA-
oxidase; LPL, protein lipase; LXRa, liver retinoid receptor isoform a, RXRa, retinoid X receptor a; FADS2, fatty acid desaturase 2; SREBP-1, sterol regulatory element binding
protein-1; SCD1A and SCD1B, stearoyl-CoA desaturase 1A and 1B; APO-A1, apolipoprotein; CPT-I, cartnitine palmitoyl trasnferase I; t-r, treatment-related; [, induction respect
to controls; Y, inhibition respect to controls.
in the metabolic syndrome and diabetes (Lyche et al., 2011). This different areas and seasons (Zorita et al., 2008). In the liver of three
linkage was related with the adipogenesis in the liver and ovary of tilapia speciesdthe Guinean tilapia (Tilapia guineensis), the Mango
zebrafish treated during its lifespan (Lyche et al., 2011). In the head tilapia (Sarotherodon galileaus) and the Nile tilapia (Oreochromis
kidney of the Atlantic cod (Gadus morhua) exposed to waters con- niloticus)dcollected from areas with different degrees of contam-
taining polycyclic aromatic hydrocarbons, phenol and alkylphenols ination, there were documented increases in the expression of CYP
for 32 weeks, it was found that AOX activity shows potential as a 450 isoforms 1A, 1B and 1C as well as on PPARa, PPARb, PPARg,
biomarker in male fish treated for less than 16 weeks (Holth et al., which were associated with contents of PAHs and PCBs in the
2011). In addition, benzo[a]pyrene, which is a typical PAH, was able muscle of these fish. In addition, a cross-talk between aryl hydro-
to induce the peroxisome proliferation in the ovate sole (Solea carbon receptor and PPARs as a pathway of toxic response was
ovate) after 7 days of intraperitoneal injection with 0.1, 0.5, 1, 5 and suggested (Adeogun et al., 2016a). In the blackchin tilapia (Sar-
10 mg benzo[a]pyrene/Kg, respectively (Au et al., 1999). Due to the otherodon melanotheron) from a freshwater dam (Awba Dam)
epidemiologic concern about the risk of obesity for human health polluted with several OC in the southwest of Nigeria, the hepatic
and the wide knowledge about zebrafish, it has been proposed that expression of the three PPARs and CYP 1A and the activities of
this fish species is an appropriated model for the study of adipo- ethoxyresorufin-, benzyloxyresorufin- and methoxyresorufin O-
genesis and FAM because these physiological processes are deethylase belonging to CYP 450 were more than in fish from a less
conserved between fish species and mammals (Den Broeder et al., polluted site (Modete Dam) (Adeogun et al., 2016b). Findings on
2015). FAM in fish species exposed to mixtures of OC and field studies
A little information prevails about the transcription factors of could also be reviewed in Table 7.
PPARs related to FAM in wild fish species inhabiting environments Detoxifying pathways of OC are of special interest. Enzymes
impacted by pollutants. In the liver of the bullhead (Cottus gobio) belonging to CYP 450 catalyze the initial detoxification of lipophilic
from an Austrian river that receives effluents from a pulp and paper xenobiotics to more hydrosoluble compounds (phase I) favouring
mill, a PP was demonstrated (Bucher et al., 1992). In the herring their excretion (Denison and Whitlock, 1995; van der Oost et al.,
(Clupea harengus) captured in the German Bight in the North Sea, a 2003). Enzymes of the second phase are responsible for binding
greater hepatic peroxisomal volume density was detected the metabolites derived from the biotransformation process (phase
regarding specimens of this fish species from a reference site. In the I) with endogenous substrates, such as glutathione, glucuronic acid
liver of saithe (Pollachius virens) from the Statfjord crude oil or amino acids, among others (Rushmore and Kong, 2002; Ma and
extraction area, some increases were observed in the activity of Lu, 2014). Some of the phase I enzymes are under the activation of
AOX compared with the less polluted station (Bilbao et al., 2006a). PPARs (Denison and Whitlock, 1995). Target genes of PPARa include
In the Atlantic cod, no changes were detected in the liver meta- members of CYP1, CYP2, CYP3, CYP4 and EPHX2 (phase I), and GSTA
bolism of AOX from four stations with different degrees of pollu- and UGT1A9 (phase II) (Johnson et al., 1996; Simpson, 1997;
tion; also, the content of PPARa detected by immunoblotting was Rakhshandehroo et al., 2010; Cizkova et al., 2012). The cross-
not linked with the environmental gradient (Bilbao et al., 2006b). In linking among FAM and the detoxification process (phase I and II)
the red mullet (Mullus barbatus) used as a sentinel for the moni- mediated by PPARa is an interesting topic poorly studied in fish
toring areas of the NW Mediterranean Sea impacted with several exposed to OC since clofibric acid (typical ligand of PPARa) is able to
OC and metals, a differentiated metabolism of AOX was found in down-regulate AhR protein expression and CYP1A1/A2 protein and
Table 7
Reported effects of mixtures of compounds (under controlled conditions) and environmental studies in FAM of fish species.
Fish species Treatment/Site Time Response Reference
Channel catfish Kraft pulp and paper mill effluent (0, 10, 20, and 40%). Two weeks [ two peroxisomal b-oxidation enzymes Mather-Mihaich
was documented and Di Giulio, 1991
Grey mullet Fresh heavy fuel oil and weathered heavy fuel oil 2 and 16 days [ AOX, PPARa, CYP 1A for both days; Bilbao et al., 2010
RXR (at day 2) and CAT (at day 16). Y PPARg
(at day 2 and 16) and RXR only at day
16 in the liver
Zebrafish Organic contaminants from the liver of burbot from Lifelong Associations among genes involved in Lyche et al., 2011
Lake Mjøsa and Lake Losna (Norway) exposure a metabolic syndrome and diabetes with
PPARg in liver and ovary
Atlantic cod Waters containing polyaromantic hidrocarbons, 32 weeks AOX activity shows potential as biomarkers Holth et al., 2011
phenol and alkylphenols in male fish treated for less than 16 weeks
in head kidney.
Bullhead Austrian river that receives effluents from pulp and [ PP in the liver Bucher et al., 1992
paper mill
Herring German Bight in the North Sea [ peroxisomal volume in the liver Bilbao et al., 2006a
Saithe Statfjord oil extraction area in the North Sea [ AOX in the liver
Atlantic cod Statfjord oil extraction area in the North Sea No relations in AOX and PPARa with the Bilbao et al., 2006b
degree of pollution in liver
Red mullet Northwest of Mediterranean Sea impacted with several Differentiated metabolism of AOX was found Zorita et al., 2008
organic contaminants and metals in different areas and seasons
Guinean tilapia, Mango Sites with different degrees of pollution Ogun [ CYP 1A, 1B and 1C as well as PPARa, PPARb Adeogun
tilapia and Nile tilapia River, Nigeria. and PPARg in liver and were associated to et al., 2016a
contents PAH and PCB in the muscle
Blackchin tilapia Awba Dam polluted with severe organic contaminants [ PPARa, PPARb and PPARg and CYP 1A; Adeogun et al., 2016b
compared to less polluted site Modete Dam in [ activity of three enzymes belonging to
Southwest of Nigeria. CYP 450 in the liver
AOX, acyl CoA-oxidase; PPAR, peroxisome proliferator-activated receptor; CYP 1A, 1B and 1C, cytochrome P450 isoform 1A, 1B and 1C; RXR; retinoid X receptor; CAT, catalase;
PP, peroxime proliferation; PAH, polyaromatic hydrocarbons; PCB, polychlorinated biphenyls; [, induction respect to controls or regarding to less polluted site and Y, in-
hibition respect to controls or regarding to less polluted site.
mRNA levels in rats (Shaban et al., 2004). 53, 409e435.

Bernlohr, D.A., Simpson, M.A., Hertzel, A.V., Banaszak, L.J., 1997. Intracellular lipid-
It is important to increase efforts to clarify if PPARs and proteins
binding proteins and their genes. Annu. Rev. Nutr. 17, 277e303.
involved in FAM are suitable biomarkers for exposure to exogenous Bilbao, E., Soto, M., Cajaraville, M.P., Cancio, I., Marigo mez, I., 2006a. Cell and tissue-
ligands of these NRs in wild fish from polluted areas. In this regard, level biomarkers of pollution in wild pelagic fish, herring (Clupea harengus), and
a statistical approach such as the use of multivariate analysis is saithe (Pollachius virens), from the North Sea. In: Hylland, K., Lang, T.,
Vethaak, D. (Eds.), Effects of Contaminants in Pelagic Ecosystems. BECPELAG.
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with the biological responses (Sole et al., 2010; Young et al., 2014; Bilbao, E., Ibabe, A., Zaldibar, B., Soto, M., Cajaraville, M.P., Cancio, I., Marigo mez, I.,
Olivares-Rubio et al., 2015; Dzul-Caamal et al., 2016) as was per- 2006b. Cell- and tissue-level biomarkers of pollution in mussels (Mytilus edulis)
and cod (Gadus morhua) caged along a contaminant gradient in Statfjord (North
formed for FAM in fish species (Adeogun et al., 2016a, 2016b). Sea). In: Hylland, K., Lang, T., Vethaak, D. (Eds.), Effects of Contaminants in
Pelagic Ecosystems. BECPELAG. SETAC press, Brussels, Belgium, pp. 215e234.
Bilbao, E., Raingeard, D., de Cerio, O.D., Ortiz-Zarragoitia, M., Ruiz, P., Izagirre, U.,
5. Conclusion Orbea, A., Marigo mez, I., Cajaraville, M.P., Cancio, I., 2010. Effects of exposure to
Prestige-like heavy fuel oil and to perfluorooctane sulfonate on conventional
Since the 1990s of the last century, the effects of xenobiotics biomarkers and target gene transcription in the thicklip grey mullet Chelon
labrosus. Aquat. Toxicol. 98 (3), 282e296.
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Blackburn, M.A., Waldock, M.J., 1995. Concentrations of alkylphenols in rivers and
perfluoroalkyl acids are the two major groups of chemical com- estuaries in England and Wales. Water Res. 29, 1623e1629.
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tors controlling lipid and lipoprotein metabolism. Ann. N. Y. Acad. Sci. 967,
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7e18.
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Despite these efforts, a weak relationship between gene expression perfluorinated compounds in raw and treated tap water in France. Arch. En-
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Braissant, O., Foufelle, F., Scotto, C., Dauça, M., Wahli, W., 1996. Differential
ants was found, with the exception of those induced by fibrates, expression of peroxisome proliferator-activated receptors (PPARs): tissue dis-
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are required to determine if these biological aspects, as well as (1), 354e366.
Braunbeck, T., Vo € lkl, A., 1991. Induction of biotransformation in the liver of Eel
biomarkers for environmental monitoring in fish species, could be (Anguilla anguilla L.) by sublethal exposure to dinitro-o-cresol: an ultrastruc-
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NE Spain). Sci. Total Environ. 503e504, 48e57.
Carlson, P., Van Beneden, R.J., 2014. Arsenic exposure alters expression of cell cycle
H.F. Olivares-Rubio is DSc. student which receive scholarship and lipid metabolism genes in the liver of adult zebrafish (Danio rerio). Aquat.
from CONACyT and BEIFI-IPN. A. Vega-Lo pez is fellow of Estímulos Toxicol. 153, 66e72.
al Desempen ~ o en Investigacio
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characterization and tissue-specific expression of the acetyl-CoA carboxylase a
vidades Acade micas (Instituto Polite
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Nacional de Investigadores (SNI, CONACyT, Me xico). Chen, P.S., Huang, S.D., 2006. Determination of ethoprop, diazinon, disulfoton and
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coupled with gas chromatography-mass spectrometry. Talanta 69 (3), 669e675.
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Environmental Pollution xxx (2016) 1e16

Contents lists available at ScienceDirect

Fatty acid metabolism in ﬁsh species as a biomarker for environmental

1. Introduction Contaminants (OC), as in the cases of polyaromatic hydrocarbons

Fish species Fibrate Treatment Time Response Reference

Fish species Compound Treatment Time Response Reference

Fish species Metal Treatment Time Response Reference

Fish species Compound Treatment Time Response Reference

Fish species Pesticide Treatment Time Response Reference

Fish species Compound Treatment Time Response Reference

Fish species Treatment/Site Time Response Reference

mRNA levels in rats (Shaban et al., 2004). 53, 409e435.

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