## 4 Discussion  
In the present study, we used a previously validated in vivo mouse protocol [19] to explore the metabolic consequences of ovarian withdrawal and E2 replacement on peripheral metabolic tissues, as well as to study the impact of a low-dose mixture of pollutants containing a dioxin, PCB153, DEHP, and BPA. The main objectives of this study were to complement the recently published data on liver and adipose tissues [19] by focusing on the different segments of the intestine: Jejunum, ileum, and colon. Indeed, the gut is the main route by which pollutants enter the body and it is the second detoxifying tissue after the liver [17]. In addition, estrogens have been shown to play important roles in the organization and architectural maintenance of the gut [40], to protect from intestinal \begin{table}
\begin{tabular}{c c c} \hline \hline  & **Genes Affected by OVariectomy** & **Genes Affected by Pollutant** \\  & **and/or E2 Replacement** & **Exposure Showing E2-like Effects** \\ \hline \multirow{3}{*}{Jejunum} & _Cd36; Cyp2b10; Cyp3a11; Esr1; Ghr;_ & \\  & _Got2; Gper1; Mmp7; Nr11; Nr12;_ & _Nr3c1; Muc2_ \\  & _Nr13; Nr3c1_ & \\ \hline \multirow{3}{*}{Ileum} & _Cyp2b10; Cyp3a11; Esr1; Fgf15;_ & \\  & _Gper1; Nr1c1; Nr11; Muc2; Slc10a2_ & _Esr1; Gper1; Nr1c1; Muc2; Tjp1_ \\ \hline \multirow{3}{*}{Liver} & _Ach01; Cyp2b10; Cyp3a11; Esr1; Tjp1_ & _Esr1_ \\ \cline{1-1}  & _Ach011; Athr; Cyp2b10; Cyp3a11;_ & \\ \cline{1-1}  & _Insig2; LepR; Nr1c3; Nr3c2; Slc10a1;_ & _Nr1c3; Nr3c2_ \\ \cline{1-1}  & _Vnn1_ & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Summary of the findings. List of genes in which the mRNA gene expression level is altered by ovariectomy and/or E2 replacement or following pollutant exposure. “E2-like effects” mean that the effects exerted by the mixture of pollutants mimicked the effects shown in the group “Ovx + E2 replacement”. In this case, the name of the genes is in bold type. Figure 5: Effect of ovariectomy alone (Ovx) or with 17\(\beta\)-estradiol (E2) supplementation (Ovx+E2) or with exposure to pollutants (Ovx + Poll) on the expression of genes encoding various nuclear receptors and target genes, and BA transporters in the liver. Values are means \(\pm\) SEM with \(n\) = 6–8. *** \(p\) < 0.001; *** \(p\) < 0.01; * \(p\) < 0.05. Sham: Sham-operated mice. inflammation [41] and contribute to bile acid biosynthesis through the enterhohepatic circulation [14]. First, we studied the intestinal expression of a large range of receptors, not only estrogen receptors, but also xenobiotic receptors and receptors previously identified as interfering with the signaling machinery of estrogen receptors such as PPARs, VDR, GHR, and GR [32; 42; 43; 44; 45]. Indeed, the pollutants in the mixture were individually identified as metabolic disruptors [27; 46; 47] and estrogen-mimicking activities were demonstrated in the mixture [18; 24; 25]. Individually, BPA was originally described as pro-estrogenic due to its binding to estrogen receptors. However, modes of action involving a large repertoire of nuclear receptors including the PPARs and GR, as well as non-genomics modes of action closely related to metabolic health and body weight have also been described [2; 48; 49]. Phthalates, which are other short-lived chemicals used to soften plastics and to which humans are also chronically exposed, can bind to xenobiotic receptors and PPARs as described for BPA, and exert anti-androgenic effects [7; 27]. Dioxins and PCBs, which belong to the group of persistent organic pollutants (POPs), can bind to AHR or interact with its signaling mechanisms such as PCB153, which do not bind to AHR. They may activate PXR and CAR as well, and interact with estrogen and thyroid signaling pathways, respectively [27; 47; 50; 51; 52; 53]. We demonstrated differential estrogen receptor expression along the gastrointestinal tract with the highest level of expression of all three receptors in the colon, which was also the segment that reacted least to estrogen withdrawal or E2 supplementation.