Question

Endocrine disrupting compounds (EDCs) are ubiquitous chemicals that interfere with growth and development. Several EDCs also interfere with epigenetic programming. There is evidence to show that Bisphenol-A is one such compound.”

Critically evaluate the statement above. In your evaluation, make reference to the reported mechanisms by which Bisphenol-A is thought to have an impact, from both an EDC and epigenetic perspective.

i am looking for esssay type answer with detailed information for the above answer with no bullet points. You can put references as well.

Answer 1

Bisphenol A (BPA) is one of the highest produced chemical in the world. It is a building block of polycarbonate plastics and is often used for food and beverage storage. BPA is also a component of epoxy resins which are used to line food and beverage containers. It is a widely known endocrine disruptor and has a estrogenic activity. Humans are exposed to a lot of exogenous chemicals, known as 'endocrine disrupting chemicals' (EDCs), that can interfere with endogenous hormone action. Because hormones often act at very low concentrations, for example estradiol functions at or below the picomolar range, EDCs can often disrupt the endocrine system. EDCs are described as compounds that disrupt almost all types of endocrine signaling in laboratory animals and humans.

It has been shown in a number of studies that BPA acts through several different receptor-mediated mechanisms of action to disrupt the endocrine system and. BPA is a xenoestrogen that binds to an estrogen receptor and activates it. Although it has lower affinity for genomic ER than estradiol, circulating concentrations of BPA are higher than estradiol and are within a biologically active range. BPA is similar to estradiol for a many type of responses, particularly those mediated by nongenomic signaling. It is also an antiandrogen, i.e., it binds to the androgen receptor and blocks the normal action of androgens.It can also alter steroid synthesis and circulating steroid hormone concentrations and disrupt peroxisome proliferator-activated receptor. Thyroid, and glucocorticoid signaling are also altered due to this compound. It is now known that, two steroid synthesizing enzymes are altered: aromatase, the primary estrogen synthesizing enzyme, and 5α-reductase, the androgen-synthesizing enzyme that converts testosterone to the higher potency dihydrotestosterone by acrion of BPA.

Even low circulating concentration of BPA has been associated with many human diseases, such as infertility, recurrent pregnancy loss, insulin resistance, diabetes, obesity, cardiovascular disease, and hypertension in adults; and obesity. EDCs may alter fetal development and lead to disease later in life. Hormones like estradiol and testosterone play key roles in normal development, and small changes in timing or concentration can program the fetus or neonate, resulting in lifelong consequences and BPA intervenes both the hormone signaling and actions. The developing ovary requires precisely orchestrated cues by steroid hormones to establish a competent female germ line, making this process vulnerable to disruption by EDCs. Perinatal BPA has been shown to impact metaphase-II oocytes by increasing aneuploidy rates in mice and monkeys, accelerate follicle development resulting in rapid depletion of the follicular reserve in sheep and accelerate reproductive senescence in rats. Also, folliculogenesis is disrupted in mice and primates after BPA exposure, leading to multioocyte follicles, increased unenclosed oocytes, and nongrowing oocytes in later follicles.

BPA does not directly cause DNA mutation but induce epigenetic developmental events resulting in adult onset disease. It is a epigenetic modulator, i.e., it affects small non coding RNA's expression, DNA methylation and histone modification. In several animal studies it was seen that BPA alters expression of miRNA and is responsible for ovarian dysfuntion. One important pathway that is altered by BPA is the expression of miRNAs that regulate SOX family genes wa altered by its administration, it is a gene family critical in sex determination and embryonic development. Estrogens play key roles in orchestrating fetal development, and estrogenic activity during fetal life has been associated with developmental origins of adult disease in humans, eg, fetal estrogen is positively associated with breast cancer and endometriosis in adulthood. Because BPA can both bind directly to ERs and increase endogenous estrogen, via up-regulation of aromatase, it likely functions to increase the overall estrogenic activity during fetal development.

BPA alteres expression of two key steroidogenic enzymes: aromatase, the primary estrogen-synthesizing enzyme and 5α-reductase, the androgen-synthesizing enzyme that converts testosterone to the higher potency dihydrotestosterone; both of these are up-regulated by BPA's exposure. Aromatase expression is very important for follicle development. miRNA-224, miRNA-378, and miRNA-383 regulate aromatase expression during follicle development in the adult ovary. miRNA-383 is up-regulated by BPA-treatment. miRNAs generally function as negative regulators of protein synthesis by coupling with complementary mRNA sequences and either inhibiting their translation or targeting them for degradation. The direct targets of many specific miRNAs or their role in early development are largely unknown. Additional studies are needed to examine whether BPA modulates miRNA expression to directly regulate aromatase expression in the fetal ovary.

Taken together, perinatal BPA exposure has a significant impact on the developing ovary and results in decreased fertility in adulthood by increasing reproductive senescence and accelerating the rate of atresia in adulthood. Although the current studies neither assessed the adult consequences of fetal exposure to BPA nor examined whether aromatase expression is targeted by any of the miRNAs altered by BPA exposure, it anyhow suggests that increased fetal aromatase expression may be an underlying mechanism via decreased expression of miRNAs.