## 4 Discussion
Among the three receptors, we observed that Esr2 mRNA levels did not fluctuate with estrogenic challenges regardless of the segment of the gut. Unlike Esr2, Esr1 and Gper1 responded similarly to E2 supplementation in the jejunum and ileum, at the mRNA level. However, these tissues are distinguished by their response to pollutant exposure since in the ileum but not in the jejunum, the mRNA levels of Esr1 and Gper1 are affected in response to exposure to pollutants. It is not currently clear why a mixture of pollutants would mimic the effects of E2 supplementation in the ileum but not in the jejunum. Importantly, exposure to pollutants did not affect the gene expression levels in the intestine of the xenobiotic receptors AHR, PXR, CAR, and of CYP3A11 and CYP2B10, prototypical targets of PXR and CAR, respectively. We previously observed that these genes were also unaffected by exposure to pollutants in the livers of the same mice [19]. Nonetheless, we herein showed that the mRNA expression of Nr3c1 (encoding GR) in the jejunum, Nr1c1 (encoding PPAR\(\alpha\)) in the ileum in addition to Esr1 and Gper1, and Nr1c3 (encoding PPAR\(\gamma\)) and Nr3c2 (encoding MR) in the liver was affected by exposure to pollutants. These data confirm and extend previous findings showing that pollutants of the mixture can target PPAR and GR not only in the liver [27; 53; 54] but also in the gut in addition to estrogen receptors. Furthermore, with the exception of Nr1c3 in the liver, pollutant effects mimicked those induced by E2 supplementation in line with our previous findings that the mixture of pollutants had estrogen-mimetic activities [18; 24; 25]. Whether the Nr1c3 mRNA upregulation detected in the liver of ovariectomized mice exposed to the mixture of pollutants is correlated with the upward trend in liver TG described previously [19], will await further studies. Unlike xenobiotic receptors, CYP3A11 and CYP2B10 mRNA expression was tightly regulated by estrogens in the various intestinal segments analyzed. As PXR and CAR were only regulated by estrogens in the jejunum and not in the ileum, colon, and even in the liver, it is likely that other nuclear receptors and/or cross-talk with other transcription factors contribute to the regulation of the expression of Cyp3a11 and Cyp2b10 in the ileum and colon. This may also indicate that PXR and CAR have functions other than the sensing of xenobiotics in the jejunum and that those functions which might be related to glucose and lipid metabolism as described in the liver [35; 56; 55] would be regulated by estrogens in the jejunum (at least in females). CAR and PXR, which cross-talk by sharing response elements and showing overlapping affinities for certain ligands, also share target genes such as CYP3A11 and CYP2B10 enzymes which show overlapping functions [29]. CYPs metabolize various steroids, fatty acids in addition to xenobiotics,and are subject to a complex regulatory scheme. For example, it has been reported that isoforms of CYP3A, which play an important role in the oxidation of endogenous steroids and toxic hydrophobic bile acids are modulated by exogenous and endogenous ligands not only via PXR and CAR but also via other receptors. These may be ER\(\alpha\)[57], GR, FXR, VDR [58], and PPAR\(\alpha\)[59], some of them have been shown in the current study expression profiles as compatible with estrogen regulation in the jejunum and ileum. However, it is surprising that both estrogen withdrawal and E2 supplementation caused downregulation of CYP3A11 and CYP2B10 in the liver. It highlights that the regulation of these CYPs differ between the liver and the jejunum. The understanding of the estrogenic regulation of these genes which are also expressed in a sex-dimorphic manner [24; 60] and regulated as well by glucocorticoids and GH [61] in the liver, warrants further studies.