3 developmental toxicology II Flashcards
what is the summary of principles 1-3?
I. susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors
II. susceptibility to teratogenesis varied with the developmental stage at the time of exposure to an adverse influence
III. teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate sequences of abnormal developmental events (pathogenesis)
what is principle IV?
the access of adverse influences to developing tissues depends on the nature of the influence (agent)
-same “rules” apply for ADME (toxicokinetics)
-lipophilic xenos follow concentration gradient and passively diffuse across placenta from maternal to fetal circulation; for certain xenobiotics facilitated and active transport mechanisms can also play a role
-during pregnancy, maternal cardiac output 50% greater and plasma proteins decrease: implications for volume of distribution and uptake by fetus
-placenta expresses phase 1 and phase 2 biotransformation enzymes (can be bioactivated)
-fetus expresses phase 1 and 2 biotransformation enzymes by end of 1st trimester, albeit to a reduced (20-40%) extent than mother
-fetal blood has slightly lower pH (more acidic) than maternal blood: implications for xenobiotics that are weak acids or bases (like pesticides) (weak base diffuses across placenta into bloodstream of fetus and would get trapped, bc it would get ionized by slightly acidic blood and therefore more will be unable to diffuse out of fetal circulation)
what is principle V?
the four manifestations of deviant development are death, malformation, growth retardation and functional deficit
-death: common effect during early embryonic stage
-malformation: mainly during first trimester (organogenesis)
-growth retardation: 2nd and especially 3rd trimester
-functional deficit: mainly exposure during 2nd and 3rd trimester; mainly effects on CNS, reproductive system and immune system
what is principle VI?
manifestations of deviant development increase in frequency and degree as dosage increases,, from the no effect to the totally lethal level
-the frequency and severity of teratogenic effects is proportional to (a) timing of exposure (principle II), (b) dose, and (c) duration of exposure
-teratogenicity is generally considered a “threshold phenomenon” i.e. no effect occurs below a certain dose; this is due to the maternal and fetal defense/repair mechanisms, and the high growth potential of the embryo/fetus
-the degree of teratogenic effect also exhibits a strong relationship with dose for most xenos i.e. lower doses cause growth retardation and more subtle functional deficits, whereas higher doses cause lethality
what are the historical examples and lessons learned?
-thalidomide
-diethylstilbestrol (DES)
-ethanol
tobacco smoke
-drugs of abuse
-pharmaceuticals: retinoids
-pharmaceuticals: antiepileptic drugs (AEDs)
-endocrine disrupting chemicals (EDCs)
what is thalidomide?
-between 1957-1961, pregnant women in many countries were prescribed thalidomide to prevent morning sickness
-over 10,000 children were both with structural defects to arms and legs (amelia and phocomelia); became the largest human medical disaster in history (many more than this died in utero)
-further research showed that almost all organs and tissues in the body could be adversely affected (e.g. heart, kidney, genitalia, GI tract, skeleton)
-completely changed the way humans test drugs (and other chemicals) for toxicities such as teratogenesis
what is diethylstilbestrol (DES)?
-synthetic non-steroidal estrogen used from 1947 to 1971 to prevent miscarriage; prescribed to over 5 million women
-epidemiological studies (coal miners as an example) linked maternal exposure to a rare form of vaginal cancer (clear cell adenocarcinoma) in daughters (“DES daughters”)
-other reproductive tract effects in daughters and sons also became apparent
-recent studies show transgenerational epigenetic effects in 3rd generation offspring (“DES granddaughters”) such as increased risk of cancers in estrogen-responsive organs (e.g. breast. ovary. cervix, uterus)
-relevant to contemporary issue of xenoestrogens (endocrine disrupting chemicals)
what is ethanol?
-developmental toxicity arising from ethanol consumption during pregnancy has been known for over 2000 years but was formally recognized in 1971 as fetal alcohol syndrome (FAS)
-initial focus on FAS was on structural (facial) effects and growth reduction, with some evidence of delayed development and mental deficiency
-50 years later, we now know that FAS is at the higher dose range of what is termed as fetal alcohol spectrum disorders (FASD)
-FASD is now considered a disorder of the brain with profound effects on cognitive, behavioral, and motor functions that persist throughout the life of affected individuals (and their families, and indeed society)
-prevalence estimated at 2-5% of children in USA and Europe
-ethanol affects all stages of brain development
-mechanisms include altered gene expression, cell-cell interactions, oxidative stress and growth factor signaling
what is tobacco smoke?
-smoking during pregnancy may currently be the leading cause of environmentally-induced developmental toxicity
-outcomes include abortion, perinatal mortality, lower birth weight, sudden infant death syndrome, and brain/behavior disorders
-although nicotine is a well known neuroteratogen, there are hundreds of other toxic xenos present in tobacco smoke
what are drugs of abuse?
-cocaine, methamphetamine, and heroin use during pregnancy also cause a spectrum of disorders such as effects on the brain and behavior
-recent studies indicate that exposure to 9-tetrahydrocannabinol (THC; psychoactive ingredient in cannabis) during pregnancy can cause a range of CNS-associated deficits in offspring
what are retinoids?
-vitamin A (retinol) used in acned drugs such as accutane can cause a broad range of structural and functional deficits when used at recommended dose during first trimester
what are antiepileptic drugs (AEDs)?
-several current use AEDs (valproic acid, phenytoin, and carbamazepine) are known to increase the risk of embryo/fetal mortality and structural and functional deficits in offspring when administered during pregnancy
what are endocrine disrupting chemicals (EDCs)?
-“xenos that interfere with the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction, development, and/or behavior “
-“the key issue is the concern that prenatal and childhood exposure to EDCs may be responsible for a variety of abnormalities in human sexuality, gender development and behaviors, reproductive capabilities, and sex ratios”
-main research focus has been on “xenoestrogens” of which there are hundreds known (e.g. bisphenol A, phthalates, organochlorine insecticides, alkylphenols)
-also several known anti-androgens (e.g. DDE, fungicides)
what is the definition of sexual differentiation?
sexual differentiation is the embryonic process of developing into a male or female (internal and external genitalia. brain)
-alfred jost (1940s) discovered the paradigm of sexual differentiation:
what is sexual differentiation?
-early embryonic development id identical in both sexes (“bipotential gonads)
presence of Y chromosome drives male development
-SRY gene in mammals
-no Y chromosome (XX)=female development
males secrete anti-mullerian hormone (AMH) and testosterone
-mullerian duct (primordial female reproductive system) regresses
-wolfian duct (primordial male reproductive system) forms
what is the graph of the internal genitalia differences?
what is the graph of external genitalia?
