Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview

Abstract

Exposure to potential Endocrine Disrupting Chemicals (EDCs) pose a documented risk to both wildlife and human health. Many studies so far described declining sperm counts, genital malformations, early puberty onset, highlighting the negative impact on reproduction caused by the exposure to many anthropogenic chemicals. In the last years, increasing evidence suggested that these compounds, other than altering reproduction, affect metabolism and induce the onset of obesity and metabolic disorders. According to the "environmental obesogens" hypothesis, evidence exists that exposure to potential EDCs during critical periods when adipocytes are differentiating, and organs are developing, can induce diseases that manifest later in the life. This review summarizes the effects occurring at the hepatic level in different animal models, describing morphological alterations and changes of molecular pathways elicited by the toxicant exposure. Results currently available demonstrated that these chemicals impair normal metabolic processes via interaction with members of the nuclear receptor superfamily, including steroid hormone receptors, thyroid hormone receptors, retinoid X receptors, peroxisome proliferator-activated receptors, liver X receptors, and farnesoid X receptors. In addition, novel results revealed that EDC exposure can either affect circadian rhythms as well as up-regulate the expression of signals belonging to the endocannabinoid system, in both cases leading to a remarkable increase of lipid accumulation. These results warrant further research and increase the interest toward the identification of new mechanisms for EDC metabolic alterations. The last part of this review article condenses recent evidences on the ability of potential EDCs to cause "transgenerational effects" by a single prenatal or early life exposure. On this regard, there is compelling evidence that epigenetic modifications link developmental environmental insults to adult disease susceptibility. This review will contribute to summarize the mechanisms underlying the insurgence of EDC-induced metabolic alterations as well as to build integrated strategies for their better management. In fact, despite the large number of results obtained so far, there is still a great demand for the development of frameworks that can integrate mechanistic and toxicological/epidemiological observations. This would increase legal and governmental institution awareness on this critical environmental issue responsible for negative consequences in both wild species and human health.

Keywords: epigenetic; metabolic disorders; phthalates; reproduction; zebrafish (Danio rerio).

Figure 1

PPAR signaling pathway. PPARs are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPAR α, δ/β, ɤ, show different expression patterns in vertebrates. Each of them is encoded by a separate gene and binds fatty acids, eicosanoids and synthetic ligands. Key genes are reported. PPARα/RXR heterodimer activates the transcription of genes involved in lipid metabolism, including transport, lipogenesis, cholesterol metabolism and adipocyte differentiation. PPARβ/RXR heterodimers activate the transcription of signal involved in fatty acid transport, fatty acid oxidation, and signal triggering final adipocyte differentiation. PPARɤ/RXR heterodimers are involved in different steps of lipid metabolism and regulate the transcription of signal responsible for adipocyte differentiation and gluconeogenesis. ACBP, Acyl-CoA-binding protein; ACS, Acetyl-coenzyme A synthetase; ACO, andacyl-CoA oxidase; ACOX1, Peroxisomal acyl-coenzyme A oxidase 1; ADIPOQ, adiponectin; aP2, adipocyte fatty acid binding protein 2; Apo-AI, apolipoprotein A1; ApoAII, apolipoprotein AII; Apo-AV, apolipoprotein AV; FABP1, fatty acid binding protein 1; FABP3, fatty acid binding protein 1; FATP1/4, Fatty acid transport protein 1–4; GyK, glycerol kinase; LPL, lipoprotein lipase; LXRα, Liver receptor α; Pepck, phosphoenolpyruvate carboxykinase; SCD-1 stearoyl-CoA desaturase-1.

Figure 2

Activation of lipogenic and adipogenic pathways. PPARs (α, β/δ, and γ) belong to the nuclear hormone receptor superfamily and are ligand-activated transcription factors activated by fatty acids, fatty acid derivatives (e.g., eicosanoids), endocannabinoids and potential EDCs. PPAR and RXR dimers form important transcription activators which upon binding PPAR response elements can modulate many important cell functions, e.g., PPARα-RXR dimers activate genes controlling peroxisome proliferation, fatty acid metabolism and lipid homeostasis; PPARγ-RXR dimers affect adipocyte differentiation. C/EBPs are a family of nuclear activators, transiently expressed very early during adipocyte differentiation. C/EBPβ/δ activate the expression of of C/EBPa. Furthermore, the expression of C/EBPa and PPARγ is sustained by apositive feedback loop. Both proteins cooperatively promote downstream adipocyte-related genes transcription. SREBPs are activators of the complete program of hepatic cholesterol and fatty acid synthesis. SREBP-1 preferentially activates genes of fatty acid and triglyceride metabolism, whereas SREBP-2 preferentially activates genes of cholesterol metabolism. SCAP transports SREBPs from the ER to the Golgi apparatus, where is cleaved by two proteases, Site-1 protease (S1P) and Site-2 protease (S2P). nuclear SREBP (nSREBP), translocates to the nucleus, where it activates transcription of multiple target genes. SREBP-2 responsive genes include those for the enzymes HMG-CoA synthase, HMG-CoA reductase, farnesyl diphosphate synthase, and squalene synthase. SREBP-1 responsive genes include those for ATP citrate lyase and acetyl-CoA carboxylase and fatty acid synthase, the fatty acid elongase complex, (27) stearoyl-CoA desaturase, and glycerol-3-phosphate acyltransferase (28) Finally both SREBP forms activate three genes required to generate NADPH, which is consumed at multiple stages in these lipid biosynthetic pathways (29).

Figure 3

Modulation of lipid content and metabolism in Seabream fed xenobiotics. (A) False color images of liver sections from C, NP, t-OP, BPA, and xenobiotic mixtures representing the topographical distribution of lipids. Adapted from Carnevali et al. (72). (B) mRNA variations in the different experimental groups. “+” upregulation, “–” downregulation, “/” no changes respect to control values. Experimental groups C, control fish receiving the commercial feed; NP, fed the commercial feed enriched with 5 mg/kg bw NP; t-OP, fed the commercial feed enriched with 5 mg/kg bw t-OP; BPA, fed the commercial feed enriched with 5 mg/kg bw BPA; NP + t-OP, fed the commercial feed enriched with 5 mg/kg bw NP + 5 mg/kg bw t-OP; BPA + t-OP, fed the commercial feed enriched with 5 mg/kg bw BPA + 5 mg/kg bw t-OP; BPA + NP, fed the commercial feed enriched with 5 mg/kg bw BPA + 5 mg/kg bw NP; NBO, fed the commercial feed enriched with 5 mg/kg bw NP + 5 mg/kg bw BPA + 5 mg/kg bw t-OP. Seabream picture by Dr. Marco Graziano http://tiktaalikillustrations.com.