Fyziologie působení farmak a
toxických látek
Přednáška č.4
Endokrinní disrupce u obratlovců I.
ER, AR, PR, GR
Výzkum endokrinní disrupce je soustředěn do dvou
oblastí:
• obratlovci, kteří alespoň část svého životního cyklu
tráví ve vodném prostředí – ryby, obojživelníci –
expozice vodou, potravou;
• terestričtí obratlovci – expozice především v rámci
potravního řetězce;
Nejohroženější skupina – vrcholoví konzumenti –
dravci.
http://www.epa.gov/endo/
Biomagnifikace a bioakumulace
Effects of DDT
(Dichlorodiphenyltrichloroethane)
•Invertebrates
•Fish
•Birds
•Mammals
TDS = testicular dysgenesis syndrome
Environmental estrogens
(xenoestrogens)
 Sources
– pesticides
– plastics
– pharmaceuticals
– some cleansers
– contraception
 vs. phytoestrogens
– antiherbivore compounds in many plant
species
– lignans (many fruits, vegetables),
isoflavones (soy)
Možnosti účinků environmentálních estrogenů na
buněčné úrovni
Environmentální estrogeny:
Environmentální antiandrogeny:
Xenoestrogens and xenoandrogens can:
 Mimic or partly mimic
the sex steroid
hormones estrogens
and androgens (the
male sex hormone) by
binding to hormone
receptors or
influencing cell
signaling pathways.
Those that act like
estrogen are called
environmental
estrogens.
 Modify the making and
function of hormone
receptors.
 Block, prevent and
alter hormonal binding
to hormone receptors
or influencing cell
signaling pathways.
Chemicals that block
or antagonize
hormones are labeled
anti-estrogens or
anti-androgens.
 Alter production and
breakdown of natural
hormones.
Interakce AhR a ER:
Hormonální přípravky jako
EDs - ethinylestradiol
 Male fish living near municipal sewage outlets in
England had both male and female sex
characteristics and their livers produced
vitellogenin, a female egg-yolk protein not
normally found in males
 cancers of the female and male reproductive
tract
 malformed Fallopian tubes, uterus and cervix
 altered bone density and structure
 abnormal blood hormone levels
 reduced fertility
 altered sexual behavior
 modified immune system
Biosyntéza steroidních hormonů a endokrinní
disrupce:
aromatáza
In vitro model:
buňky H295R
Buněčná linie odvozená od karcinomu kůry nadledvinek, která je
schopna in vitro produkovat většinu steroidogenních enzymů:
• aktivita enzymů;
• exprese enzymů na úrovni mRNA a proteinu
Effects of test substances on cortisol and 11-deoxycortisol
formation in H295R cells, assumed to represent CYP11B and
CYP21 activity.
Testy estrogenity a antiestrogenity
Mikrobiální syntéza androgenů??
Většina látek narušujících androgenní dráhy
jsou antiandrogeny!!!!
Anti-androgenic compounds in the environment
There are a number of commonly used environmental chemicals
that have been identified as having anti-androgenic properties.
These chemicals have been administered to pregnant rodents
during the period of reproductive tract
development. When the male pups were examined, they displayed
many of the abnormalities associated with flutamide
administration.
Some chemicals (vinclozolin, procymidone, linuron, p,p’-DDE (1,1,1dichloro-2,2-bis(pchlorophenyl)ethane)
act as androgen receptor
antagonists, others (phthalate esters) reduce androgen
synthesis, but it is likely that other modes of action are also
involved in the toxicity induced by these compounds.
There are major problems in comparing the published studies of
the effects of anti-androgenic compounds / inconsistent
protocols.
Human impact????
Polycyklické aromatické uhlovodíky mají
antiandrogenní účinek:
Antiandrogenní účinky PCB:
Interakce polutantů s endokrinní dráhou
= velmi složitý proces:
Bromované zpomalovače hoření – nový typ endokrinních disruptorů??