246
to show their obesity association mainly with DEHP. While low molecular weight
phthalates and their metabolites have shown association with obesity in adolescent
and male children. The phthalates have established their direct linked on obesitydevelopment independent of subject’s physical activity and diet intake. The obesity
in senior citizens was positively correlated with the prevalence of DEHP and its
metabolites [22–24]. The lipid metabolism and its homeostasis is mainly regulated
by hormone-assisted coordinated molecular signaling in normal physiological conditions. The phthalates interfere and disrupt the signaling mechanisms for the lipid
metabolism through different channels and pathways [25, 26].
1. Thrifty phenotype-epigenetic modulation channel.
2. Phthalate-PPARγ-adipogenesis.
3. Phthalate-thyroid hormone channel.
4. Phthalates-PPARα-androgen channel.
Mainly hypothalamic-pituitary-gonad/thyroid along with PPAR channel the disrupted signaling for lipid metabolism and subsequent homeostasis. The PPAR
mediate the nuclear signaling for lipogenesis in coordination and control of endocrine messaging. The phthalate binding to PPAR especially to PPARγ results in
perturbed nuclear receptor signaling. The impaired glucose-homeostasis generally
leads to lifestyle disease syndrome, obesity, and type II diabetes. The fatty acid
metabolism processes often experience multiple disturbances in insulin-resistant
individuals; as a result the fats get accumulated in skeletal muscles, endothelial
cells, adipose tissues and liver; the insulin targets cells and tissues. Consequently,
the situation leads to oxidative stress due to resultant acquired mitochondrial dysfunctions [27–30]. Generally, diet is considered as the main cause of obesity.
However, phthalates and its metabolites alter the cell signaling mechanisms of
nuclear receptors of obesity-related pathways well mechanized for lipid homeostasis.
Insulin Resistance, Type 2 Diabetes, and Phthalate Exposures
The higher level of blood sugars due to improper utility of insulin or due to inadequate insulin production has been considered as a major metabolic disorder.
According to WHO report in 2016, the T2D is the main prevalence diabetes mellitus
around the world [31]. In contrary to insulin-based considerations, many environmental factors do account for the onset and progression of chronic type 2 diabetes.
In fact, numerous environmental toxicants like phthalates are supposed to act as
activators of PPARs thus pose serious risks of diabetes. In fact, the development
of β-beta cells get impaired due to the undesirable off-target interactions of PPARs
(key regulators of glucose and lipid homeostasis) with phthalates [32]. In a number
of studies, the urine and blood samples represented the presence of a number of
phthalates/metabolites as markers in epidemiological studies. The impaired functioning of beta cells, decreased insulin sensitivity, and increased insulin resistance
could be confirmed by the perceptible phthalate/metabolite levels along with fasting
T. Farooq et al.
to show their obesity association mainly with DEHP. While low molecular weight
phthalates and their metabolites have shown association with obesity in adolescent
and male children. The phthalates have established their direct linked on obesitydevelopment independent of subject’s physical activity and diet intake. The obesity
in senior citizens was positively correlated with the prevalence of DEHP and its
metabolites [22–24]. The lipid metabolism and its homeostasis is mainly regulated
by hormone-assisted coordinated molecular signaling in normal physiological conditions. The phthalates interfere and disrupt the signaling mechanisms for the lipid
metabolism through different channels and pathways [25, 26].
1. Thrifty phenotype-epigenetic modulation channel.
2. Phthalate-PPARγ-adipogenesis.
3. Phthalate-thyroid hormone channel.
4. Phthalates-PPARα-androgen channel.
Mainly hypothalamic-pituitary-gonad/thyroid along with PPAR channel the disrupted signaling for lipid metabolism and subsequent homeostasis. The PPAR
mediate the nuclear signaling for lipogenesis in coordination and control of endocrine messaging. The phthalate binding to PPAR especially to PPARγ results in
perturbed nuclear receptor signaling. The impaired glucose-homeostasis generally
leads to lifestyle disease syndrome, obesity, and type II diabetes. The fatty acid
metabolism processes often experience multiple disturbances in insulin-resistant
individuals; as a result the fats get accumulated in skeletal muscles, endothelial
cells, adipose tissues and liver; the insulin targets cells and tissues. Consequently,
the situation leads to oxidative stress due to resultant acquired mitochondrial dysfunctions [27–30]. Generally, diet is considered as the main cause of obesity.
However, phthalates and its metabolites alter the cell signaling mechanisms of
nuclear receptors of obesity-related pathways well mechanized for lipid homeostasis.
Insulin Resistance, Type 2 Diabetes, and Phthalate Exposures
The higher level of blood sugars due to improper utility of insulin or due to inadequate insulin production has been considered as a major metabolic disorder.
According to WHO report in 2016, the T2D is the main prevalence diabetes mellitus
around the world [31]. In contrary to insulin-based considerations, many environmental factors do account for the onset and progression of chronic type 2 diabetes.
In fact, numerous environmental toxicants like phthalates are supposed to act as
activators of PPARs thus pose serious risks of diabetes. In fact, the development
of β-beta cells get impaired due to the undesirable off-target interactions of PPARs
(key regulators of glucose and lipid homeostasis) with phthalates [32]. In a number
of studies, the urine and blood samples represented the presence of a number of
phthalates/metabolites as markers in epidemiological studies. The impaired functioning of beta cells, decreased insulin sensitivity, and increased insulin resistance
could be confirmed by the perceptible phthalate/metabolite levels along with fasting
T. Farooq et al.