VIBS 422 Lecture 13

What are phytoestrogens?

plant-derived xenoestrogens (“dietary estrogens”)

Why are phytoestrogens considered endocrine disruptors?

structurally similar to estradiol —> mimic or block estrogen signaling

Do phytoestrogens act as agonists or antagonists?

BOTH —> can stimulate or block estrogen receptors

Main classes of phytoestrogens?

• isoflavones (genistein, diazein)

• ligans

• coumestanes

• flavonoids

• stilbenes (resveratrol)

• mycotoxins (zeralenol)

Major food source of phytoestrogens?

soy products (tofu, soy, milk, tempeh)

Other phytoestrogen-containing foods

• broccoli, cabbage

• garlic

• grapes

• green tea

• tumeric

Primary mechanism of phytoestrogens?

bind to estrogen receptors (ERa, ERb)

Additional mechanisms of phytoestrogens?

• alter ER structure

• change gene transcription

• interfere with steroid metabolism

• pass through membranes (low MW)

Why can phytoestrogens enter cells easily?

• low molecular weight

• stable structure

What is genistein?

isoflavone phytoestrogen (most abundant in soy)

Where is genistein found?

• soybenads

• tofu, soy milk

• legumes

Key molecular actions of genistein?

• ERa/ERb binding

• inhibits steroidogenesis enzymes

• inhibits tyrosine kinase

• inhibits DNA topoisomerase

• epigenetic changes

Enzymes inhibited by genistein?

• 3B-HSD

• 17B-HSD

• Aromatase

Major ovarian effect of genistein?

anovulation (no ovulation)

What happens to corpora lutea?

absent —> disrupted ovarian function

Hormonal mechanism causing anovulation?

low LH due to low pituitary response to GnRH

What unique ovarian abnormality does genistein cause?

multi-oocyte follicles (MOF)

Why doe MOFs occur?

failure of oocyte nest breakdown —> cells remain clustered

Effect on primordial follicles?

• low primordial follicles

• increased unassembled follicles

Effect on estrous cycle?

irregular cycles & prolonged estrous phase

What brain pathway is disrupted?

HPG axis (hypothalamus-pituitary-gonadal)

Effect on oocytes?

• increased oocyte number

• decreased apoptosis

• abnormal development

Effect on fertility?

• infertility or reduced fertility

• decreased pregnancy success (50%)

Pregnancy effects of genistein?

fewer implantation sites

increased resorption (loos of embryos)

Structural uterine changes?

• hyperplasia

• cysts

• polyps

What happens to uterine lumen?

increased size + fluid accumulation

Can genistein effects be passed to future generations?

YES (epigenetic inheritance)

Evidence of transgenerational effects?

MOFs persist in F1 & F2 generations

Effect on embryos (zebrafish)?

• reduced size

• malformations

• neural damage

Effect on male reproductive system?

• decreased testis weight

• decrease prostate size

• decreased epididymal mass

What happens to AGD (anogenital distance)

decreases —> feminization marker

Effect on sperm?

• decreased sperm count

• increased apoptosis

• decreased fertility

Behavioral changes in males?

• decreased aggression

• increased defensive behavior

Effect on mammary gland development?

• increased ductal branching

• increased alveolar growth

Cancer risk associated with genistein?

• increased mammary tumors

• increased breast cancer risk

Potential benefits of phytoestrogens?

improved menopause symptoms & lipid profile

Major risks of phytoestrogens?

• reproductive disruption

• cancer risk

• hormonal imbalance

Which EDC causes multi-oocytes follicles (MOFs)? & is most abundant phytoestrogen in soy?

Genistein

Why are phytoestrogens endocrine disruptors?

mimm/block estrogen —> alter signaling