Endocrine disrupters

Endocrine disruption Endocrine disrupters (ED) or endocrine disrupting chemicals (EDC) are exogenous chemical agents that interfere with the pathways of natural hormones (estrogens, androgens): –Synthesis –Secretion –Transport –Binding –Action –Metabolism –Elimination

Pituitary-gonad axis

How do hormones act? Cross membrane into cytoplasm and nucleus Cross membrane and bind receptor in cytoplasm --> carried to nucleus Bind to receptor on cell surface --> carried into the cytoplasm Bind receptor on cell surface and activate second messages cascade (hydrophilic hormones: peptides eg. insulin) Inside nucleus, they affect gene expression of hormone-dependent genes by binding to special sites on regulatory regions of DNA (estrogen- responsive elements: ERE)

Basic facts about hormones Timely synthesis and action Negative feedback control of production Small amounts usually needed for action Small perturbations of concentration have effects Developmental implications Include reproductive, thyroid and immune system effects

Endocrine disrupters Mimic or Block natural hormone action Can be synthetic (most) or naturally occurring (phytoestrogens, animal hormones) May or may not have structural similarity with endogenous hormone Alter gene expression not structure (not mutagens) Are lipophilic and cross membranes

Mode of action of EDs Mimics - bind and activate receptors just as the natural hormone Antagonists - bind but do not activate receptors Inhibitors of synthesis of natural hormone Inhibitors of degradation/removal of natural hormone (HO-PCBs) Interfere with transport from production site to action site

Xenoestrogens Phytoestrogens –Lignans –Isoflavons Synthetic –DES (diethylstilbesterol) –PCBs –Dioxins –DDT/DDE –Alkylphenols –Phthalate esters –Bisphenol-A

Implications of ED toxicity Developmental - estrogen/androgen ratio disturbed (placental barrier crossing) –Two sets of partially developed sex organs (imposex) ( TBT ; aromatase suppression) –Improperly developed sex organs (DDT) Sterility (DES) –Male: sperm counts and quality (fertilizing ability); structural abnormalities –Female: structural abnormalities of reproductive organs Cancer - in utero exposure –Female: CCA (DES), breast (and endometriosis) –Male: prostate, testicular Hypothyroidism - PCBs ?

Progesterone a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstrual cycle, differentiation factor for mammary glands Testosterone an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone Estradiol an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics Sex hormones are products of cholesterol basic structure

From: 3b-DH is 3b- dehydrogenase, P450c11 is 11b- hydroxylase, P450c17 is 17a- hydroxylase, P450c21 is 21b- hydroxylase. Synthesis of the various adrenal steroid hormones from cholesterol

Synthesis of major female hormones in the ovary

P450SSC, 3b-DH, and P450c17 are the same enzymes as those needed for adrenal steroid hormone synthesis. 17,20- desmolase is the same as 17,20-lyase of adrenal hormone synthesis. Synthesis of the male sex hormones in Leydig cells of the testis.