2 EDCs I

Question 1

what is the other nomenclature of EDCs?

Answer 1

-reading: WHO (2012) Executive summary (pp. vii-xvii)
-research-active and controversial topic in toxicology

other nomenclature
-endocrine active compounds/chemicals (EACs)
-endocrine modulating compounds/chemicals (EMCs)

Question 2

what is the history and foundation of EDCs?

Answer 2

observations in wildlife began over 60 years ago
-rachel carson, silent spring (1962)
-diethylstilbestrol (DES) (1972)

wingspread conference (1991)
-organized by theo colborn (our stolen future)
-chemically-induced alterations in sexual development: the wildlife/human connection

since the wingspread conference, extensive research around the endocrine disrupting potential of synthetic chemicals. Recent report released by the WHO (2013)
-some substances can alter hormonal system
-“we urgently need more research to obtain a fuller picture of health and environment impacts of endocrine disruptors”-Dr. Maria Niera

Question 3

so what are EDCs?

Answer 3

USEPA:
-exogenous agents that interfere with the synthesis, secretion, transport, binding, action, elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development and/or behavior

National Institute of environmental health services:
-chemicals that may interfere with the body’s endocrine system and produce adverse developmental, reproductive, neurological, and immune effects

Question 4

what is the major concern of EDCs?

Answer 4

-EDCs may have effects on developmental processes in embryos/neonates resulting in subtle long-term irreversible effects
-effects may not manifest until long after exposure has ceased

Question 5

what are the effects of EDCs?

Answer 5

-impaired fertility
-delayed development/malformation of reproductive organs
-cancer in hormone-responsive organs (e.g. breast, ovary, uterus, testicle, prostate)
-altered sex ratios
-neurobiological/behavioral alterations
-epigenetic changes

Question 6

what are parts of the endocrine system?

Answer 6

-glands
-hormones
-target tissue that responds to the hormone

-endocrine homeostasis is maintained by feedback loops

Question 7

what are the glands of the endocrine system?

Answer 7

secrete hormones into circulation
-neuroendocrine cells are able to secrete these hormones via neurotransmitters

Question 8

what are the hormones of the endocrine system?

Answer 8

“a chemical substance produced by a ductless endocrine gland and secreted into blood, which carries it to a specific target organ to produce an effect”

synthesis, secretion, transport, target, mechanism depend on:
-hydrophilic (target receptor would most likely be on plasma membrane)
-hydrophobic (target would perhaps be within the cell or the nucleus)

Question 9

what are the target tissue responds to the hormone?

Answer 9

hormones are distributed to target tissues with cells that express hormone receptors
-hormones bind to a specific hormone receptor->activate signal transduction pathway->change in cell function

Question 10

what biological processes are hormones involved in?

Answer 10

-growth
-development
-energy homeostasis
-reproduction
-water/electrolyte homeostasis

Question 11

what is the HPG axis?

Answer 11

hypothalamus-pituitary-gonadal (HPG) axis
-feedback loop

-GnRH: gonadotropin releasing hormone
-LH: luteinizing hormone (a gonadotropin)
-FSH: follicle stimulating hormone (a gonadotropin)

Question 12

what is an example of the HPG axis?

Answer 12

in oviparous (egg producing animals)

Question 13

what are the targets of EDCs?

Answer 13

-hormone synthesis (ex: steroidogenesis)
-hormone transport
-hormone degradation
-hormone action

Question 14

what is the example of targeting hormone synthesis?

Answer 14

steroidogenesis
-StAR: steroidogenic acute regulatory protein
-brings cholesterol into inner mitochondrial membrane (allows for production of steroids)

important/note worthy enzymes:
-P450scc (scc=side chain cleavage) (converts cholesterol to precursor steroids)
-aromatase (testosterone to estradiol)
-5alpha-reductase (testosterone to dihydrotestosterone)

Question 15

EDCs target hormone synthesis by:

Answer 15

-availability of precursors (target StAR)
-alter enzyme activities (target P450scc)

Question 16

what are free and protein bound hormones?

Answer 16

HORMONE transport
most peptide hormones are not bound to plasma proteins in circulation (free/unbound)
-hydrophilic hormones
-ex: peptides and proteins, catecholamines

other types are noncovalently bound to transport proteins in plasma (protein bound)
-hydrophobic hormones
-ex: steroids, thyroid

Question 17

what is dangerous about unbound hormones?

Answer 17

HORMONE TRANSPORT
only free (unbound) hormone is able to diffuse into cells and bind receptors
-endogenous hormones can be displaced by EDCs through competition for receptor binding sites

Question 18

what can happen once hormones are transported to target?

Answer 18

HORMONE DEGRADATION
free (unbound) fraction of hormones can diffuse into target tissues to be metabolized (biotransformed) or be excreted:
-biotransformation is similar to xenobiotics-> phase 1 (hydroxylation, demethylation, deamination), phase 2 (glucuronidation, sulfation)
-urinary or biliary excretion

Question 19

what do hormones mostly interact with?

Answer 19

HORMONE ACTION
EDCs mostly interact with hormones that bind nuclear receptors

nuclear receptors
-ligand-activated transcription factors
-responsible for sensing specific hormones and regulate the expression of specific gene (transcription factors)

Question 20

what are the hormones that bind nuclear receptors?

Answer 20

-steroid hormones (estradiol, testosterone, progesterone, cortisol)
-thyroid hormones (T3, T4)
-retinoic acid (vitamin A)
-peroxisome proliferators
-orphan receptors (AhR)

Question 21

how does hormone action get affected?

Answer 21

EDCs can bind hormone receptors and “mimic” endogenous hormone
-can act as antagonist, agonist, partial agonist
-receptor affinities (i.e. potency) vary, depending on EDC structure

some EDCs bind multiple receptors
-e.g. DDE, BPA

species differences
-due to different ligand binding domains of the receptor

-“cross-talk” between signaling pathways=complex

Question 22

what is the summary of EDCs?

Answer 22

-hormones are chemical messengers that regulate many physiological processes
-thousands of anthropogenic chemicals are known to interfere with endocrine homeostasis
-EDCs can interfere with hormone synthesis, transport, degradation or action