247
and oral glucose tolerance test. The insulin resistance accounts more to induce diabetes than the beta cell dysfunctioning [33, 34].
A number of T2D related studies found the DEHP/metabolites as the main perceptible markers in their blood, serum, and urine samples. The dysfunctioning of
β-cells, decreased insulin sensitivity, and increased insulin resistance were detected
when obesogenic and diabetogenic characteristics were co-studied in one such
study [35]. Over the years, concerns have raised due the high chances of phthalate
exposure and their correlations with childhood obesity and insulin resistance.
Because of the growing fast food culture, endocrinal signaling thus could lead to
perturbation of lipid and glucose homeostasis [10].
The molecular docking studies have revealed that the under-given important
nuclear regulators in xenobiotic metabolism are more susceptible to strong interactions with phthalates or their metabolites as compared to their natural ligands [36–
38]. Such unwanted cross-talks adversely affect the synthesis, secretion of hormones,
and consequently the metabolism of lipid and glucose causing their impaired
homeostasis.
– Estrogen and ketosteroid receptors (mineralocorticoids, glucocorticoids, progesterone, and androgens).
– Pregnane-X-receptor (PXR).
– Retinoid X α, β, or γ receptors (RXR).
– PPAR α, β, or γ subtypes.
The phthalates and their metabolites could bind more intensely to these receptors
than their natural agonist thus act as EDCs because they impair normal molecular
signaling processes by disturbing at least one of the links in web of communications. The circulating phthalate/metabolites reach the cytosol in the form of
phthalate- protein complexes (by binding with fatty acid binding proteins (FABP)
and liver (L-FABPs)). In digestive system, the phthalates bind with intestinal
(I-FABP) which facilitate the transport of relatively more soluble phthalates from
intestinal lumen to the sites of metabolism and distribution. The phthalate-HAS
complexes also help in their transportation to hormone receptors. Afterwards, the
phthalates are transferred from such complexes to afore-mentioned nuclear receptor
proteins as co-activators and reside in nucleoplasm. These complexes further
undergo hetero-dimerization to act as a transcription factor and bind to target genes
responsible for xenobiotic metabolism and the biosynthesis of hormones resulting
in their suppression or downregulation [39, 40].
General Health Impacts of Phthalates
In additions to above explained diseases caused by phthalates as EDCs, they have a
lot many other deleterious health impacts in human beings. In males, the phthalate
toxicity accounts for testicular dysgenesis syndrome characterized by infertility,
decrease in sperm quality and its count, undescended testes, and testicular cancer
15 Role of Phthalates as EDCs in Metabolic Disorders
and oral glucose tolerance test. The insulin resistance accounts more to induce diabetes than the beta cell dysfunctioning [33, 34].
A number of T2D related studies found the DEHP/metabolites as the main perceptible markers in their blood, serum, and urine samples. The dysfunctioning of
β-cells, decreased insulin sensitivity, and increased insulin resistance were detected
when obesogenic and diabetogenic characteristics were co-studied in one such
study [35]. Over the years, concerns have raised due the high chances of phthalate
exposure and their correlations with childhood obesity and insulin resistance.
Because of the growing fast food culture, endocrinal signaling thus could lead to
perturbation of lipid and glucose homeostasis [10].
The molecular docking studies have revealed that the under-given important
nuclear regulators in xenobiotic metabolism are more susceptible to strong interactions with phthalates or their metabolites as compared to their natural ligands [36–
38]. Such unwanted cross-talks adversely affect the synthesis, secretion of hormones,
and consequently the metabolism of lipid and glucose causing their impaired
homeostasis.
– Estrogen and ketosteroid receptors (mineralocorticoids, glucocorticoids, progesterone, and androgens).
– Pregnane-X-receptor (PXR).
– Retinoid X α, β, or γ receptors (RXR).
– PPAR α, β, or γ subtypes.
The phthalates and their metabolites could bind more intensely to these receptors
than their natural agonist thus act as EDCs because they impair normal molecular
signaling processes by disturbing at least one of the links in web of communications. The circulating phthalate/metabolites reach the cytosol in the form of
phthalate- protein complexes (by binding with fatty acid binding proteins (FABP)
and liver (L-FABPs)). In digestive system, the phthalates bind with intestinal
(I-FABP) which facilitate the transport of relatively more soluble phthalates from
intestinal lumen to the sites of metabolism and distribution. The phthalate-HAS
complexes also help in their transportation to hormone receptors. Afterwards, the
phthalates are transferred from such complexes to afore-mentioned nuclear receptor
proteins as co-activators and reside in nucleoplasm. These complexes further
undergo hetero-dimerization to act as a transcription factor and bind to target genes
responsible for xenobiotic metabolism and the biosynthesis of hormones resulting
in their suppression or downregulation [39, 40].
General Health Impacts of Phthalates
In additions to above explained diseases caused by phthalates as EDCs, they have a
lot many other deleterious health impacts in human beings. In males, the phthalate
toxicity accounts for testicular dysgenesis syndrome characterized by infertility,
decrease in sperm quality and its count, undescended testes, and testicular cancer
15 Role of Phthalates as EDCs in Metabolic Disorders