313
linear isomers [126] and exhibit more effects on decreasing birth weight of infants
[127], which is related greater chances of obesity [128].
PFASs Association with Diabetes and Oxidative Stress
Mixed evidence has been reported regarding the association of PFAS exposure and
the risk of T2DM. C8 Health Project was the largest cross-sectional analysis, in
which no association was found between lifetime exposure and fasting glucose or
T2D [129], while plasma concentrations of different PFASs such as PFOS, PFOA,
PFHxS, and PFNA were inversely related to diabetes prevalence [130]. On the other
hand, a positive association was found between PFASs exposure and prediabetes,
diabetes in an investigation of Wisconsin male anglers [131]. In a study of Chinese
of Taiwan, a positive association of T2DM and serum PFOS was seen [132].
Underlying mechanisms that show PFASs and T2DM associations are not clear.
Investigations have cleared that PFASs stimulate PPARγ and PPARα [133], which
control homeostasis of energy, adipocyte differentiation and its functional regulation, glucose and lipid metabolism [134]. It has also been shown that PFASs also
interfered by PPAR-independent pathways. Such as, PFOA changes the expression
of liver cell proteins of human being that are controlled by hepatocyte nuclear factor
4α4α [135], which is a most important regulator of gluconeogenesis and lipid
metabolism [136] and also stimulate homeostasis of thyroid hormone [137]. Current
confirmation from in vitro investigations has additionally shown estrogenic and
antiestrogenic properties of PFASs [138]. Moreover, PFOA enhances mitochondrial
dysfunction and oxidative stress that cause cytotoxicity and apoptosis in rat β-cellderived RIN-m5F cells [139]. The sub-chronic effects of PFASs exposure included
the disturbed homeostasis of thyroid hormone, body weight gain and liver toxicity
have been observed in experimental animal studies [17]. Further latest studies have
reported that PFOS exposure in perinatal stages in rats causes abnormalities in the
homeostasis of glucose and lipid at adulthood [140]. Furthermore, adult mice treatment with PFOA for 4 weeks interfered with the metabolism of glucose and insulin
hypersensitivity induction [141]. In vivo study in mice exhibited that PFOA produced histopathological alternations in the pancreas by enhancing oxidative stress
[142]. Abnormal development of the pancreas in zebrafish observed after PFOS
exposure [143]. A strong correlation was not observed between levels of PFAS and
markers of diabetes risk, for example, insulin or HbA1c, adiponectin. Human crosssectional studies have revealed a strong connection between exposure to the PFAS
and changes in liver or thyroid functions [144]. Hence, defective liver or thyroid
functions may also have a role, while estrogenic effects and increased oxidative
stress illustrated the PFASs–T2DM links. Moreover, PFASs may have strong effects
among those individuals who are at high diabetes risk (such as overweight) or
change in weight during childhood and puberty [145].
18 Role of Perfluoroalkyl Substances as EDCs in Metabolic Disorders
linear isomers [126] and exhibit more effects on decreasing birth weight of infants
[127], which is related greater chances of obesity [128].
PFASs Association with Diabetes and Oxidative Stress
Mixed evidence has been reported regarding the association of PFAS exposure and
the risk of T2DM. C8 Health Project was the largest cross-sectional analysis, in
which no association was found between lifetime exposure and fasting glucose or
T2D [129], while plasma concentrations of different PFASs such as PFOS, PFOA,
PFHxS, and PFNA were inversely related to diabetes prevalence [130]. On the other
hand, a positive association was found between PFASs exposure and prediabetes,
diabetes in an investigation of Wisconsin male anglers [131]. In a study of Chinese
of Taiwan, a positive association of T2DM and serum PFOS was seen [132].
Underlying mechanisms that show PFASs and T2DM associations are not clear.
Investigations have cleared that PFASs stimulate PPARγ and PPARα [133], which
control homeostasis of energy, adipocyte differentiation and its functional regulation, glucose and lipid metabolism [134]. It has also been shown that PFASs also
interfered by PPAR-independent pathways. Such as, PFOA changes the expression
of liver cell proteins of human being that are controlled by hepatocyte nuclear factor
4α4α [135], which is a most important regulator of gluconeogenesis and lipid
metabolism [136] and also stimulate homeostasis of thyroid hormone [137]. Current
confirmation from in vitro investigations has additionally shown estrogenic and
antiestrogenic properties of PFASs [138]. Moreover, PFOA enhances mitochondrial
dysfunction and oxidative stress that cause cytotoxicity and apoptosis in rat β-cellderived RIN-m5F cells [139]. The sub-chronic effects of PFASs exposure included
the disturbed homeostasis of thyroid hormone, body weight gain and liver toxicity
have been observed in experimental animal studies [17]. Further latest studies have
reported that PFOS exposure in perinatal stages in rats causes abnormalities in the
homeostasis of glucose and lipid at adulthood [140]. Furthermore, adult mice treatment with PFOA for 4 weeks interfered with the metabolism of glucose and insulin
hypersensitivity induction [141]. In vivo study in mice exhibited that PFOA produced histopathological alternations in the pancreas by enhancing oxidative stress
[142]. Abnormal development of the pancreas in zebrafish observed after PFOS
exposure [143]. A strong correlation was not observed between levels of PFAS and
markers of diabetes risk, for example, insulin or HbA1c, adiponectin. Human crosssectional studies have revealed a strong connection between exposure to the PFAS
and changes in liver or thyroid functions [144]. Hence, defective liver or thyroid
functions may also have a role, while estrogenic effects and increased oxidative
stress illustrated the PFASs–T2DM links. Moreover, PFASs may have strong effects
among those individuals who are at high diabetes risk (such as overweight) or
change in weight during childhood and puberty [145].
18 Role of Perfluoroalkyl Substances as EDCs in Metabolic Disorders