3 developmental toxicology I

Question 1

what is developmental toxicology and teratogenesis?

Answer 1

-developmental tox= adverse effects of xenobiotics that occur between conception to puberty (recall diethylstilbestrol)
-teratogenesis= adverse effects of xenos that occur between conception and birth (recall thalidomide)

Question 2

what are the causes of developmental toxicity?

Answer 2

-known genetic factors (25%)
-known environmental factors (10-15%)
-unknown multifactorial causes (causes)

Question 3

what are the known genetic factors?

Answer 3

25%
-most common are chromosomal abnormalities and single-gene defects

Question 4

what are the known environmental factors?

Answer 4

10-15%
-infections (bacteria, viruses) 3%
-maternal factors (ex: disease nutrition) $4
-environmental toxicants and drugs, referred to as teratogens 5%
-ionizing radiation other physical factors (1-2%)

Question 5

what are the unknown multifactorial causes?

Answer 5

60%
-genetic: environmental interactions
-epigenetics: especially important during gametogenesis (formation of egg and sperm) in parents, and subsequently in early development between zygote and blastocyst stage (referred to as “imprinting”) (environmental exposure to parent changes gene)

Question 6

what are are the 6 general principles of teratology (birth defects) of Wilson?

Answer 6

1. susceptibility to teratogenesis depends on the genotype of the conceptus (baby) and the manner in which this interacts with adverse environmental factors
2. susceptibility to teratogenesis varies with the developmental stage (windows) at the time of exposure to an adverse influence
3. teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate sequences of abnormal developmental events (pathogenesis)
4. the access of adverse influences to developing tissues depends on the nature of the influence (agent) (ADME)
5. the four manifestations of deviant development are death, malformation, growth retardation (reduced birth weight) and functional deficit
6. manifestations of deviant development increase in frequency and degree as dosage increases, from no effect to the totally lethal level (dose defines the poison, threshold response)

Question 7

what are principles I & II?

Answer 7

susceptibility
-genotype of embryo-fetus (intrinsic factors) and environment (extrinsic factors, which include maternal factors and external environmental factors) are the major consideration

Question 8

what are the general developmental stages?

Answer 8

1. early development (fertilization to implantation)
2. organogenesis (day 21-56 in humans; first trimester)
3. fetal period

Question 9

what is the early development stage?

Answer 9

fertilization to implantation
-usually lower sensitivity to teratogen exposure at this stage
-gastrulation: formation of ectoderm. mesoderm, and endoderm (cell differentiation), and then migration of these cellular “germ layers”
-teratogens can cause malformations of eye, brain and face during this period

Question 10

what is the organogenesis stage?

Answer 10

day 21-56 in humans; 1st trimester
-highly sensitive developmental stage due to significant cell division, differentiation, migration and “remodeling” during organ and tissue development
-within organogenesis, there are key developmental events that coincide with peaks of sensitivity
-recall thalidomide: amelia (missing limbs) and phocomelia (shortened limbs) due to exposure during this specific period of development (20-36 days after fertilization in humans)

Question 11

what is the fetal period stage?

Answer 11

2nd and third trimester
-pre-differentiation and organogenesis are referred to as the embryonic period; structural/morphological effects of teratogens are most prevalent
-fetal period involves histogenesis and functional maturation of organs and tissues; thus teratogenic effects are more functional in nature (eg: CNS, behavior, immune system, reproductive system)
-significant growth occurs during fetal period and reduced growth (birth weight) is a common effect of teratogens

Question 12

what is the big graph of how dose defines the poison in birth?

Answer 12

dose and timing define the poison

Question 13

what are species differences in organogenesis and functional maturation?

Answer 13

-example: thalidomide causes phovomelia/amelia in humans but not in rats or mice; many other examples
-consider implication for risk assessment when testing chemicals for teratogenicity

Question 14

what are species differences in organogenesis and functional maturation when going back to ADME?

Answer 14

-back to ADME: consider species differences in appearance of smooth endoplasmic reticulum (SER) in liver (CYP expression)
-in humans SER appears early in gestation (1st trimester, day 40-60) whereas in mice and rats SER appears just before birth
-thus human fetus can detoxify xenobiotics early in development compared to rodents
-however if xenobiotic is bioactivated by CY{ it can be more teratogenic in humans during sensitive organogenesis period

Question 15

what is of principle 3?

Answer 15

adverse outcome pathway

Question 16

what are the general teratogenic mechanisms (principle 3)?

Answer 16

-gene mutations and chromosomal abnormalities
-altered mitosis or apoptosis (either increased or decreased)
-altered nucleic acid integrity or function (RNA and DNA)
-reduced precursors or substrates for metabolism (ex: vitamin and nutrient deficiencies)
-reduced energy sources (carbohydrates and lipids)
-osmotic imbalances (eg: edema (fluid accumulation))
-altered cellular membranes
-enzyme inhibition

Question 17

what is pathogenesis (prin3)?

Answer 17

altered cell death is a major effects of teratogens; both increased or decreased apoptosis can be important (ex: apoptosis of cells in hands to create fingers)
-delicate balance between cellular mitosis, apoptosis and differentiation in embryo; any disruption of signaling pathways can cause pathology

Question 18

what are other pathogenic responses (pri3)?

Answer 18

-altered cell-cell interaction
-reduced biosynthesis of endogenous compounds
-inhibition of morphogenesis (dictates shape of organ, tissue, and organism)

Question 19

what are the sources of teratogenesis?

Answer 19

1. direct effects on embryo/fetus (discussed in previous slides)
2. placenta
3. maternal

Question 20

what are the placenta sources of teratogenesis?

Answer 20

-provides nutrition, gas exchange, and waste removal
-produces hormones involved in maintenance of pregnancy
-can biotransform xenos (both detox and bioactivate)
-can be a target organ of xenos

Question 21

what are the maternal sources of teratogenesis?

Answer 21

-genetics (ex: certain terata occur more frequently in humans with different genetic backgrounds)
-disease (ex: hypertension, diabetes, certain bacterial/viral infections (Fever))
-nutrition (ex: calorie restriction, vitamin and trace element deficiencies)
-physiological and psychological stress
-ethanol or tobacco smoke consumption

Question 22

what is the summary of the first three principles?

Answer 22

this complexity is why 60% of developmental toxicities are of an unknown etiology
-age=maternal age is old vs young
-parity=socioeconomic status (can we afford food that fulfills our needed vitamins and antioxidants)