165
lipophilic in nature, lipophilicity depends on the number of chlorine molecules in
the biphenyl ring. Owing to this high lipophilic nature especially the highly chlorinated congeners, tend to accumulate in lipid-rich tissues. More amounts of PCBs
are usually found in adipose tissue, breast milk, liver, and skin [17]. PCBs can enter
the nucleus of the cells and binds with numerous nuclear receptors especially that
are associated with lipid metabolism, such as Aryl hydrocarbon receptor (AhR),
Constitutive Androstane Receptor (CAR), and Pregnane Xenobiotic Receptor
(PXR) [18]. Multiple studies are carried out to ascertain the half-lives of the PCBs.
It was assessed to be 21.83 and 133.33 years for Aroclor 1242 and Aroclor 1254,
respectively. However, half-lives of both lower Aroclor 1242 and higher Aroclor
1254 chlorinated biphenyls are 2.6 and 4.6 years, respectively [19].
The metabolism entirely depends on the degree and orientation of chlorination
on the biphenyl rings. They are predominantly metabolized in the liver by cytochrome P-450 system into phenols. In phase 2 of the metabolism hydroxylation and
conjugation of the metobilites with glucuronic acid and sulfates occured, hence
further hydroxylation results into the formation of catechol [20]. Glucuronide and
sulfate conjugates are excreted in the urine and hydroxylated metabolites are
excreted in the bile. Generally, metabolism of the less-chlorinated congeners are
comparatively more rapid. This is also one of the explanations that highly chlorinated congeners tend to remain in the body longer than do less-chlorinated congeners. Conjugation and glucuronidation tend to polarize the PCBs which ultimately
facilitate the elimination by fecal and urinary route [21].
Hepatic Steatosis
The mechanisms through which PCBs can cause hepatic steatosis are still not
understood very well and most probably differ between compounds. Although activation of AhR can lead to hepatic steatosis by several mechanisms. Several in vitro
studies proved mitochondrial dysfunction as a result of their exposure primarily at
the level of Mitochondrial Respiratory Chain complex (MRC complexes), Oxidative
Phosphorylation (OXPHOS), and mitochondrial transcription factor A (mtFA) [22–
25]. These hazardous effects are mostly observed at high concentrations of PCBs
(>10–20 μM). Certain experimental studies reported that some PCBs can cause
fatty liver diseases [26–28]. Possible mechanism of fatty liver disease is the reduction in hepatic PPARα expression. Their expression was associated by a robust
reduction of Carnitine palmitoyltransferase I and II (CPT1 and CPT2) expression
[28]. Erstwhile reported that small concentration (i.e., 1 nM) of PCBs have the ability to strongly decrease PPARα mRNA expression [29].
Steatosis having necro-inflammation and fibrosis is regularly observed in intoxicated animals, [30–34] confirming TCDD potential of steatohepatitis. Mechanism
of TCDD-induced steatosis includes raised fatty acid uptake in liver, decreased
VLDL secretion, and reduced mtFAO [35, 36]. All these effects are completed
through AhR activation [37, 38]. TCDD has the potential to diminish the activity of
11 Role of Polychlorinated Biphenyls as EDCs in Metabolic Disorders
lipophilic in nature, lipophilicity depends on the number of chlorine molecules in
the biphenyl ring. Owing to this high lipophilic nature especially the highly chlorinated congeners, tend to accumulate in lipid-rich tissues. More amounts of PCBs
are usually found in adipose tissue, breast milk, liver, and skin [17]. PCBs can enter
the nucleus of the cells and binds with numerous nuclear receptors especially that
are associated with lipid metabolism, such as Aryl hydrocarbon receptor (AhR),
Constitutive Androstane Receptor (CAR), and Pregnane Xenobiotic Receptor
(PXR) [18]. Multiple studies are carried out to ascertain the half-lives of the PCBs.
It was assessed to be 21.83 and 133.33 years for Aroclor 1242 and Aroclor 1254,
respectively. However, half-lives of both lower Aroclor 1242 and higher Aroclor
1254 chlorinated biphenyls are 2.6 and 4.6 years, respectively [19].
The metabolism entirely depends on the degree and orientation of chlorination
on the biphenyl rings. They are predominantly metabolized in the liver by cytochrome P-450 system into phenols. In phase 2 of the metabolism hydroxylation and
conjugation of the metobilites with glucuronic acid and sulfates occured, hence
further hydroxylation results into the formation of catechol [20]. Glucuronide and
sulfate conjugates are excreted in the urine and hydroxylated metabolites are
excreted in the bile. Generally, metabolism of the less-chlorinated congeners are
comparatively more rapid. This is also one of the explanations that highly chlorinated congeners tend to remain in the body longer than do less-chlorinated congeners. Conjugation and glucuronidation tend to polarize the PCBs which ultimately
facilitate the elimination by fecal and urinary route [21].
Hepatic Steatosis
The mechanisms through which PCBs can cause hepatic steatosis are still not
understood very well and most probably differ between compounds. Although activation of AhR can lead to hepatic steatosis by several mechanisms. Several in vitro
studies proved mitochondrial dysfunction as a result of their exposure primarily at
the level of Mitochondrial Respiratory Chain complex (MRC complexes), Oxidative
Phosphorylation (OXPHOS), and mitochondrial transcription factor A (mtFA) [22–
25]. These hazardous effects are mostly observed at high concentrations of PCBs
(>10–20 μM). Certain experimental studies reported that some PCBs can cause
fatty liver diseases [26–28]. Possible mechanism of fatty liver disease is the reduction in hepatic PPARα expression. Their expression was associated by a robust
reduction of Carnitine palmitoyltransferase I and II (CPT1 and CPT2) expression
[28]. Erstwhile reported that small concentration (i.e., 1 nM) of PCBs have the ability to strongly decrease PPARα mRNA expression [29].
Steatosis having necro-inflammation and fibrosis is regularly observed in intoxicated animals, [30–34] confirming TCDD potential of steatohepatitis. Mechanism
of TCDD-induced steatosis includes raised fatty acid uptake in liver, decreased
VLDL secretion, and reduced mtFAO [35, 36]. All these effects are completed
through AhR activation [37, 38]. TCDD has the potential to diminish the activity of
11 Role of Polychlorinated Biphenyls as EDCs in Metabolic Disorders