Developmental Toxicology

Developmental Toxicology

* Structural malformations
* Growth retardation
* Functional impairment
* Death of the organism
4 manifestations of developmental toxicity

Teratology
1. the study of malformations or serious deviations from the normal type in organisms

2. the branch of science concerned with the production, development, anatomy, and classification of malformed fetuses.

* Teratogen
o Any agent that causes a birth defect
o After Greek “monster creating”
* Environmental conditions (1200)
* Maternal nutritional deficiencies (1930)
* Rubella virus infection (1941)
* Thalidomide (1961)

Adverse Outcomes in Pregnancy
Cause of human birth defects
Chemical teratogenicity
Pregnancy Risk Categories
Therapeutic Drugs Teratogenic to Humans
* Anticonvulsants
o Phenytoin, primidone, trimethadione, valproic acid, carbamazepine
* Anticancer agents
o Alkylating agents –busulfan, cyclophosphamide, chlorambucil, mechlorethamine
o Antimetabolites-aminopterin, methotrexate, cytarabine
* Androgenic hormones-danazol
* Coumarin anticoagulants-warfarin
* Retinoids-accutane, isotretinoin, etretinate, acitretin
* Antihyperlipidemic agents-lovastatin, atorvastatin
* Other drugs-diethystilbestrol, thalidomide, penicillamine, lithium, fluconazole, misoprostol
Thalidomide
Diethylstilbesterol (DES)
Alcohol (Ethanol)
Fetal Alchohol Syndrome (FAS)
Fetal Alchohol Effects (FAE)
* Cranial facial dysmorphism
* Intrauterine and postnatal growth retadation
* Retarded psychomotor and intellectual development
* IQ 68

Tobacco smoke
* Spontaneous abortions
* Perinatal deaths
* Lower birth weight
* Increased risk of
o Sudden infant death syndrome
o Behavioral attention disorders
o Orofacial cleft (particular xenobiotic gene polymorphisms)
o Gastroschisis (with variant alleles N053, ICAM1, NPPA)
o Branching morphogenesis and maturation of the lung
* Nicotine-related adverse nerodevelopmental outcomes
Cocaine
* At risk for premature labor, spontaneous abortion, increased perinatal mortality and fetal death.
* intrauterine growth retardation, microcephaly, altered presencephalic development, decreased birth weight, a neonatal neurologic syndrome of abnormal sleep, tremor, poor feeding, irritability, and occasional seizures.
* Genitaouinary tract malformation
* Impaired uditory process

Retinoic Acid
Retinoic acid is the active ingredient in “Accutane”, a drug used to treat severe acne. Since its introduction in September of 1982, an estimated 160,000 women of child bearing age have ingested the drug. Between 1982 and 1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions and 5000-7000 elective abortions are due to Accutane exposure. Exposed children may have hydrocephaly, ear malformations, cardiovascular defects and decreased IQ. Accutane carries a pregnancy category X warning, meaning it is a known human teratogen.
c acid
Retinoids
* Malformations of the face, limbs, heart, CNS, and skeleton
* RXR α receptor
* Schizophrenia
Retinoid Therapies
Tretinoin/ATRA (Vesanoid)
Leukemia
Adapalene (Differin),
Tretinoin (Renova),
Isotretinoin (Accutane)
Acne
Tazartene (Zorac),
Etritinate (Tegison)
Psoriasis
Drugs
RAR and RXR (Simple Version)
* Nuclear Receptors (like ER, PPAR, VDR and others)
* RXR/RAR Heterodimer is functional unit
* Bind selectively to REs in genome
* Act as transcription factors
* Up-regulate or Repress the expression of particular genes

Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy. Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid. By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day).

Valproic Acid
* spina bifida with menigomyelocele or menigocele
* The proposed mechanism of action is that valproic acid influences folate metabolism

Angiotensin Converting enzyme inhibitors and angiotensin antagonists
* 2-3 trimester
* related reduced amniotic fluid volume and impaired fetal renal function
o Oligohydromnios
o Fetal growth retardation
o Pulmonary hypoplasia
o Renal failure
o Hypotension
o Death
* First trimester
o Congenital malformation

Wilson’s General Principles of Teratology (Table 10-2)
* Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with environmental factors.
* Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure.
* Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis).
* The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.
* The access of adverse environmental influences to developing tissue depends on the nature of the influences (agent).
* Manifestations of deviant development increase in degree as dosage increases from the no-effect to the totally lethal level.
Critical periods of susceptibility and endpoints of toxicity
* Gametogenesis and Fertilization

Mechanism unclear, may be related to imprinting
Cytosine methylation and change in chromatin conformation ethylene oxide, ethylmethane sulfonate, ethylnitrosourea→malformed fetus

DNA Methylation vs Genomic Imprinting
Mechanisms and pathologenesis of developmental toxicology

* Mutations
* Chromosomal breaks
* Altered mitosis
* Altered nucleic acid integrity or function
* Diminished supplies or precursors of substrates
* Decreased energy supplies
* Altered membrane characteristics
* Osmolar imbalance
* Enzyme inhibition
Example of cyclophosphamide (CP)
Single strand DNA break
A teratogenic chemotherapeutic agent
CP induces DNA damage
Advances in the Molecular basis of dysmorphogenesis
1.Using either singly or double gene knockout Retinoic acid receptor family (syndactyly)
2. Antisense oligonucleotide Wnt-1, Wnt-3a (mid and hindbrain malformation)
3. Reporter transgenes

Pharmacokinetics and metabolism in pregnancy
1.Changes in maternal physiology
hepatic metabolism, GI tract, cardiovascular system, excretory system, respiratory system
2.Overall decrease in hepatic xenobiotic transformation
3.Roles of placenta in influence embryonic exposure help to regulate blood flow
-offer a transport barrier-pH gradient, weak acid rapidly transfer
-metabolize chemicals
2-acetylaminofluorene (proteratogen)
7-hydroxyl metabolites(proximate teratogen)
4.Maternal metabolism of xenobiotics 2-methoxyethanol 2-methoxyacetic acid

Placental toxicity
* Metals, Cd, As, Hg, ethanol, cocaine, cigaratte, sodium salicylate
* Maternal injection vs fetal injection of Cd
* Production of metallothionein
* Interaction with Zn

Maternal toxicity-
* acetazolamide inhibits carbonic anhydrase forelimb ectrodactyly

* diflunsial results in anemia skeleton defects in rabbits
* phenytoin affects folate metabolism and heart rates
* metallothionein synthesis inducer-urathane, mercaptopurine, valproic acid Zn deficiency

Develpmental toxicity of endocrine-disrupting chemicals
Definition of endocrine-disrupting chemicals
“Exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and the regulation of developmental processes.”
Endocrine-disrupting chemicals
Four modes of action
1. Serving as steroid receptors ligands
2. Modifying steroid hormone metabolizing enzymes
3. Perturbing hypothalamic-pituitary release of trophic hormones
4. Uncharacterized proximate modes of action

Fetal Basis and Transgenerational Transmission of Reduced Fertility
Environmental Epigenetics
Decreased spermatogenic capacity and decreased fertility ..as well as increased prevalence of other diseases transferred via MALE germ line

Summary
* A transient embryonic exposure to endocrine disruptors at the time of gonadal sex determination can cause epigenetic transgenerational disease state of subfertility and spermatogenic defects in F1 through F4 generations
* Transgenerational disease phenotype was primarily transmitted through the male germ line
* Exposure appears to have caused an epigenetic reprogramming of the germ cell line that is “permanent” and transferred transgenerationally to subsequent generations

Modern safety assessment
* Regulatory guidelines for in vivo testing
* Multigeneration tests
* Children’s health and the food quality protection act
o Tenfold safety factor for children
* Alternative testing strategies
* Epidemiology
* Concordance of data (among species)
* Elements of risk assessment
use-in pregnancy rating: A, B, C, D, X

In Vivo Regulatory Protocol Guideline
The 17 intercellular signaling pathways by most metazoans
* Early development and later
* 1. Wnt pathway
* 2. Receptor serine/threonine kinase (TGFb) pathway
* 3. Hedgehog pathway
* 4. Receptor tyrosine kinase (small G proteins) pathway
* 5. Notch/Delta pathway
* Mid-development and later
* 6. Cytokine receptor (cytoplasmic tyrosine kinases)
* pathway
* 7. IL1/Toll NFkB pathway
* 8. Nuclear hormone receptor pathway
* 9. Apoptosis pathway
* 10. Receptor phosphotyrosine phosphatase pathway
* Larval/adult physiology
* 11. Receptor guanylate cyclase pathway
* 12. Nitric oxide receptor pathway
* 13. G-protein coupled receptor (large G proteins) pathway
* 14. Integrin pathway
* 15. Cadherin pathway
* 16. Gap junction pathway
* 17. Ligand-gated cation channel pathway

Sonic Hedge-hog signal pathway
cyclopamine
jervine
Holoprosencephaly
Cholesterol synthesis inhibitor
Consequences of Folate Deficiency
* Result of low dietary intake, genetic error of folate metabolism, lifestyle exposures
* DNA Hypomethylation
o Gene overexpression, uncontrolled cell growth, genomic instability
* Hyperhomocysteinemia
o Excessive accumulation of Hcy
* Base Misincorporation
o Decrease in thymine synthesis; replaced by uracil
o DNA strands prone to nicks, breaks and vulnerable to mutagen insertion
Homework

1. Describe the possible mechanisms for teratogenic effects of the following chemicals.
a. aminoglycosides
b. ethylene oxide
c. captopril
d. danazol
e. aminopterin
f. Accutane

Developmental Toxicology.ppt

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Forensic Anthropology

Forensic Anthropology
Why Forensic Anthropology

* Forensic pathologists are trained to analyze soft tissue and organs. Their experience with hard tissue (bone) is limited.
* The forensic anthropologist specializes in hard tissue morphology, structure and variability. In those cases in which soft tissue has been degraded by time, temperature, environment or other external forces, the only tissue remaining more or less intact is bone.
* Physical Anthropologists and Archeologists study human remains-and have become part of solving crimes.

What Questions Can Forensic Anthropology Answer?

* What is the race of the individual?
* What is the sex of the individual?
* What is the age of the individual?
* What is the stature of the individual?
* What pathologies did the individual have?
* What traumas did the individual have?
* What individual traits did the individual have?

Identity of Decomposed or Skeletal Remains

* Are the remains human or animal? (butchers remains and skeletal remains of dead pets etc. may be found in unlikely places)
* Are they really bones? (wood, stones)
* Are they human?
* How many bodies?
* How long dead? - recent or ancient (e.g. construction or digging at an old burial site)
* Cause of death?
How does this Work?

* Forensic anthropologists use regression equations to determine sex, age, stature, and race of skeletal remains.
* Regression equations are mathematical equations developed from studies of bones of individuals of known sex, age, race, and stature, and are used to predict such things of even fragmentary skeletal remains."

Sex Estimation
* The sex of an individual is determined, when soft tissue is not present, by a number of skeletal indicators.
* The more indicators used to determine sex, the more accurate the results.
* A forensic anthropologist is analytically limited by the bones present and the condition of the bones.
* In general, the muscles in a man are stronger and more developed than in a woman.
* Bones of men are larger and more robust than bones of women.
* Some bones display specific features which can be used to help determination of the sex of the skeleton. The best indicators are the:
o Skull
o Pelvis
o Head of the Femur
Sex Estimation – Adult
* Usually related to size in adult long bones
* Male bones: usually larger, longer in a single population – be cautious if different populations are involved
* Maximum diameter of head of humerus and head of femur may be used (Bass).
* Much more difficult to estimate sex in children’s skeletons.
Sex Estimation: Skull

* Good area for sex determination
* Generalization: male skull more robust, muscle-marked than female: ABSOLUTE
* DIFFERENCES SELDOM EXIST (Bass)
* Sex estimation: face, mandible, vault

Sex Estimation: Face
1. Supraorbital (Brow) ridges: more prominent in males
2. Superior orbital margin: sharper in females
3. Palate: larger in males
4. Teeth: larger in males (Bass)
5. Mastoid process: more prominent and rugged in males.
6. Orbit (Eye socket): Rounder in females, more rectangular in males
7. Chin: more pronounced in males and larger jaws.

Pelvis
* Women give birth. For this reason, the pelvis of a woman is larger than the pelvis of a man.
* The pelvis of a woman is wide and circular whereas the pelvis of a man is narrow and heart-shaped.
* Two angles, the sub-pubic angle and the sciatic notch, cause the differences in the shape of the pelvis.
* In women, the sub-pubic angle and sciatic notch are wide. In men, the sub-pubic angle and sciatic notch are narrow.

Male Pelvis Subpubic Notch
Female Pelvis Subpubic Notch
Pubis Bone Traits Related to Sex
Subpubic angle (degrees) angle made by the inferior borders of the articulated pubis bone
Pubis body width (mm)
Ventral arc: a roughened projection of bone visible on the anterior surface of the pubis bone
Head of the Femur
* In men, the diameter of the head of the femur is larger than 51 mm.
* In women, the diameter of the head of the femur is less than 45 mm.

Determining Ages of Skeletons
* Bone growth stops at about 20 yrs. of age in humans.
* Adult bone continuously adapts to prevailing stresses by appropriate deposition and resorption.
* Deposition and resorption are under hormonal control - integrated with regulation of blood calcium levels.
Skeletal Age
* Skeletal age is the estimated age at which a person died. Skeletal age can be determined by looking at the following:
o sutures of the skull
o teeth
o ribs
o vertebrae
o growth areas of the long bones: epiphyses
Sutures of the Skull
* When a baby is born, the skull is still growing.
* To accommodate this growth, the different bones of the skull are separate.
* By the age of 7, all the different bones have finished growing and the fontanelles have disappeared.
Skull Sutures

The Teeth
* The teeth are arranged in upper and lower arches. Those of the upper are called maxillary; those of the lower are mandibular.

Dental Tissues.
* Enamel. The protective outer surface of the anatomic crown. It is 96% mineral and is the hardest tissue in the body.
* Dentin. Located in both the crown and root, it makes up the bulk of the tooth beneath the enamel and cementum. It lines the pulp cavity.
* Cementum. This substance covers the surface of the anatomic root.
* Pulp. The central, innermost portion of the tooth. It has formative, sensory, nutritive, and functions during the life of the tooth.

* There are four types of teeth with very different shapes:
* Incisors (2)
* Canines (1)
* Premolars (bicuspids) (2)
* Molars (2-3)
* Individual teeth are quite distinct, even when lost from a jaw.

Dental Formula (from the midline)

* Primary (deciduous) teeth.
* It is said as: incisors, two upper and two lower; canines, one upper and one lower; molars two upper and two lower equals ten per side.
* Permanent teeth.
* It is said as: incisors, two upper and two lower; canines, one upper and one lower; premolars, two upper and two lower; and molars, three upper and three lower.

Teeth
* The first teeth to appear are the incisors, which are followed by canines and molars.
* When chewing food, teeth grind down.
* Comparing different teeth gives an idea of how long the teeth have been used.
* Eventually teeth may be lost, due to caries or attrition.

X-Rays Are Used to Date Skulls
* This is the side view of the dentition of a six year old boy.
* There is still some variation from person to person in the order in which the teeth erupt.

Baby Teeth Permanent Teeth
Dental Disease - Cavities, Abscesses, and Attrition
Ribs
* Because of breathing, the front part of the ribs is constantly moving.
* As a person gets older, the front part of the ribs begin to change and form bony spikes.
Vertebrae
* As a person gets older, bony spikes can also start growing on the vertebrae.
* This starts at approximately 40 years of age.
Growth areas of the long bones
(epiphysis)
* From birth to ą25 years of age, a person grows at a relatively constant rate.
* Growth takes place at the ends of the long bones.
* At a certain age, growth is completed and this can also be seen on the bone.

Epiphyseal Fusion
* The pattern of fusion of bone ends (epiphysis) to bone shaft (metaphysis) in each bone indicates age.
* Charts & tables are used.
* The upper arm stops growing at the shoulder at approximately age 20 and at the elbow at approximately age 14.5.
* The upper leg stops growing at the hip at approximately age 17.5 and at the knee at approximately age 18.

Determining Ages of Skeletons
* Cranial suture fusion is less reliable.
* Pubic symphysis changes slightly with age.
* Arthritic changes and osteoporosis give further clues.

Arthritic changes and osteoporosis give further clues to the ages of skeletons.
Ossification Centers
* Useful only in fetuses and babies.
* May be determined radiologically or by cutting into ossification centers.
* May be confirmed histologically.
* Most important center in medico-legal work is the distal center of the femur.
* This is present at birth and indicates a full term baby.
Age Determination from Skeleton
* Long bone length (femur, tibia, humerus) is proportional to height.
* Tables are used.
* Fairly reliable up to the age of epiphyseal fusion.
* There are sex, race, nutrition and personal variations to consider.
Individual Characteristics
Fractures
Head Injuries
Individual Characteristics
* Bone disease (Paget's disease, tumors)
* Previous injury to bone (fracture callus, prosthesis, metallic fragments).
* Comparison of trabecular pattern of bone.
* Pattern of skull's frontal air sinuses. Outline is unique and comparisons with clinical X-rays are useful.
Forensic Dentistry
* Teeth are commonly used to establish identity of deceased.
* Dental X-rays and dental casts are available often for 10 years after a patient visits the dentist last..
Height
Body Type
Race or Ethnic Group Determination
Minimum Number of Individuals
Dating of Human Skeletal Remains
Age of Human Remains
* Naked eye appearance is unreliable:
* Tags of soft tissue, periosteum, ligaments etc, indicate less than 5 years old.
* Soapy texture of surface indicates age less than a few decades.
* Light, crumbling bones are likely to be a century or more old.

Laboratory Tests Can Help
* Immunological reaction between bone extract and anti human serum ceases within months of death.
* If blood pigments are present bones are usually less than 10 years old.
* Up to 20 amino acids may be identified in bones less than a century old.
* Fluorescence of freshly sawn bone surface under UV light diminishes after 100 years.
* New bones contain 4.0 - 4.5 gms% nitrogen; 2.5 gms% indicates approximately 350 years.
* Radioactive carbon dating indicates which century.
Taphonomy
* Coined from the Greek words taphos, for "burial," and nomos, for "law."
* Forensic Taphonomy : The Postmortem Fate of Human Remains
* Skeletal trauma, decomposition, and dispersal of remains.
* Weathering, a taphonomic process, is very useful in determining the elapsed time since death.
Facial Reconstruction
* Skull can be scanned into a computer and "fleshed" by computer reconstruction to give likely facial appearance in life.
* Unfortunately eye color, hair color and lips are independent of bony structure.
* Pearl was a female who died in her early forties approximately three hundred years ago.
* She was Caucasian, of European ancestry and stood about 5'1".
* Her dental health was extremely poor and she had lost 63 per cent of her teeth prior to death. She had no teeth on either side of her jaw. This was most important as the loss of those teeth would evidence themselves in the final reconstruction as sunken cheeks. Of her remaining teeth, the condition was poor and she had several abscesses.
* During her lifetime, there are indicators that she also suffered from acute infections, rickets, sinusities, an upper respiratory infection, arthritis, and gout. Whew--all this in an era when aspirin didn't exist!
* On the other hand, it was determined that she was very muscular, as the ridges on her long bones were very developed.

Various items (glasses, clothing, hats) may be applied to better accentuate the features of the individual.
This method can be very successful.
Cause of Death
* Anthropologists can distinguish between marks from the result of a weapon attack and those resulting from the gnawing and biting of bones by scavenging animals.
* They can also determine the exact kind of weapon and animal, and they can tell if a wound is old or if it occurred at death.
* They can be called upon to testify as to the type of weapon used (saw vs. knife).

Lizzie Bordon’s Father’s skull: Ax Whacked.

* Two outstanding cases of the use of forensic anthropology to successfully solve unsolved mysteries are the cases of Francisco Pizarro.

Pizarro conquered the Incas.
* Pizarro was hated by the Peruvians because he was a brutal ruler. On June 26, 1541 (at age 66), he was stabbed to death by a crowd of angry subjects and in view of many witnesses (Dickerson 1993).
* His brutal death is not questioned due to the well documentation at the time. It was his remains that were questioned.
* In the 1890's, Peruvian officials decided to put Pizarro's remains on exhibit. "They asked officials at the Cathedral of the Plaza de Aramis in Lima for Pizarro's body and were directed to a mummy, which they put on view." (Dickerson 1993)
* In 1978 workers discovered a secret niche that had been walled over in the cathedral, and on a shelf in the niche was a box with a skull and an inscription that identified it as the head of Pizarro.
* Another box was found containing the bones of several unidentified individuals (Dickerson 1993).

* An investigation of the bones in the second box led to the discovery that the postcranial bones matched the skull in the first box.
* These bones and the skull were then placed together and prepared for study to determine if they had marks consistent with sword or knife wounds.

Forensic Anthropology.ppt

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Vitamins

Definition and Classification
* Non-caloric organic nutrients
* Needed in very small amounts
* Facilitators – help body processes proceed; digestion, absorption, metabolism, growth etc.
* Some appear in food as precursors or provitamins

Definition and Classification
* 2 classes, Table 7.1
o Fat soluble:
o Water soluble:
* Fat soluble vitamins
o Found in the fats and oils of food.
o Absorbed into the lymph and carried in blood with protein transporters = chylomicrons.
o *Stored in liver and body fat and can become toxic if large amounts are consumed.
* Water soluble vitamins
o Found in vegetables, fruit and grains, meat.
o Absorbed directly into the blood stream
o Not stored in the body and toxicity is rare. Alcohol can increase elimination, smoking, etc. cause decreased absorption.

Fat Soluble Vitamins
* Vitamin A (precursor – beta carotene)
o 3 forms: retinol (stored in liver), retinal, retinoic acid
o Roles in body:
+ Regulation of gene expression
+ Part of the visual pigment rhodopsin, maintains clarity of cornea (yes eating carrots is good for your eyesight)
+ Required for cell growth and division - epithelial cells, bones and teeth
+ Promotes development of immune cells, especially “Natural Killer Cells”
+ Antioxidant
* Vitamin A
o Deficiencies cause:
+ Night blindness, xerophthalmia (keratin deposits in cornea), macular degeneration.
+ Skin and mucous membrane dryness and infection, keratin deposits.
+ Anemia
+ Developmental defects – bones, teeth, immune system, vision

o Toxicities (RetinA/Accutaine, single large doses of supplements, eating excessive amounts of liver) cause:
+ Fragile RBCs, hemorrhage
+ Bone pain, fractures
+ Abdominal pain and diarrhea
+ Blurred vision
+ Dry skin, hair loss
+ Liver enlargement
o DRI: 700(women)-900(men) micrograms/day, UL 3000 micrograms
o Sources, see snapshot 7.1

* Vitamin D – precursor is cholesterol, converted by UV from sunlight exposure, therefore is a “non-essential” vitamin.
o Roles:
+ Increases calcium absorption in bone, intestines, kidney. Promotes bone growth and maintenance.
+ Stimulates maturation of cells – heart, brain, immune system, etc.

o Deficiencies: rickets (children), osteomalacia (adults). What are some of the causes of deficiencies?
o Toxicities (5X DRI)
+ Loss of calcium from bone and deposition in soft tissues.
+ Loss of appetite, nausea and vomiting, psychological depression.

Bowed legs – Characteristic of rickets

Beaded ribs – Characteristic of rickets
* Vitamin D
o DRI – 5 micrograms/day for ages 19-50, 10 for ages 51-70, 15 for ages >70.
o Sources, see snapshot 7.2

Fat Soluble Vitamins
* Vitamin E – tocopherol, *alpha-, beta -, gamma-, and delta-
o Roles:
+ Antioxidant (protects polyunsaturated fats)
+ Prevention of damage to lungs, RBCs, WBCs (immunity), heart
+ Necessary for normal nerve development
* Vitamin E
o Deficiencies (decreased absorption of fats- liver disease, low fat diets)
+ Premature babies – fragile RBCs (hemolysis)
+ Loss of muscle coordination, vision, immune functions
o Toxicities (more than 1000 milligrams/day)
+ Increases the effects of anticoagulants (Coumadin, Warfarin)
o DRI 15 milligrams/day (alpha-tocopherol)
o Sources, see snapshot 7.3
* Vitamin K – produced by bacteria in large intestine
o Roles
+ Promotes synthesis of blood clotting proteins (**Interferes with Coumadin)
+ Bone formation
o Deficiencies are rare but seen in infants, after prolonged antibiotic therapy, and in patients with decreased bile production.
o Toxicities (>1000 mg/day): rupture of RBCs and jaundice

o DRI: 90(women) – 120(men) micrograms/day
o Sources, see snapshot 7.4

Water Soluble Vitamins
* 8 B vitamins – Tender Romance Never Fails with 6 to 12 Beautiful Pearls (Thiamin, Riboflavin, Niacin, Folate, B6, B12, Biotin, and Pantothenic acid)
o Aid in metabolism of and energy release from carbohydrates, lipids, amino acids.
o Mode of action – coenzymes or parts of coenzymes that are necessary for the proper activity of enzymes, Without the coenzyme, compounds A and B don’t respond to the enzyme.

With the coenzyme in place, compounds A and B are attracted to the active site on the enzyme, and they react.
The reaction is completed with the formation of a new product. In this case, the product is AB.
Muscles and other tissues metabolize protein.
Brain and other tissues metabolize carbohydrates.
Bone tissues make new blood cells.
Liver and other tissues metabolize fat.
Digestive tract lining replaces its cells.

* Thiamin and Riboflavin
o Roles – energy metabolism in cells, part of nerve cell membranes.
o Deficiencies
+ Beri beri, edema &/or muscle weakness
+ Alcohol abuse – Wernicke-Korsakoff syndrome
o DRI thiamin:1.1(women) – 1.2(men) mg/day; riboflavin 1.1(women) – 1.3(men) mg/day
o Sources: All food groups except fats and oils
* Niacin – can be produced from the amino acid tryptophan.
o Roles: energy metabolism
o Deficiencies: Pellagra – dermatitis, diarrhea, dementia, death
o Toxicities (2 - 3X DRI): *prevents blood clotting, causes liver damage, enhances action of Coumadin
* Niacin
o DRI 14(women) -16(men) mg/day
o Sources, snapshot 7.8
+ Meats
+ Some vegetables and grains
* Folate
o Role: required for synthesis of DNA - ***pregnancy
o Deficiencies (drug interactions, smoking)
+ Anemia
+ Decreased immunity
+ Decreased digestive and cardiovascular function
+ Colon and cervical cancers
+ *Neural tube defects, ?other birth defects
o Toxicities (>1000 mg/day): rare, interferes with anticancer drugs.
o DRI 400 milligrams/day
o Sources, snapshot 7.8

* Vitamin B12 (requires intrinsic factor for absorption)
o Roles: works with folate, part of insulating sheath around nerves.
o Deficiencies:
+ Pernicious anemia
+ Paralysis
+ Nerve damage in fetus
o DRI 2.3 micrograms/day
o Sources, see snapshot 7.9
+ Meat and dairy
+ Implications for vegans??
* Vitamin B6
o Roles:
+ Conversion of amino acids to other amino acids
# Ex.: Tryptophan to niacin
+ Synthesis of hemoglobin and neurotransmitters
+ Release of glucose from glycogen
+ Immune function
+ Promotes steroid hormone activity
+ Development of nervous system
o Deficiencies
+ Anemia
+ Dermatitis
+ Muscle weakness
+ Behavioral problems
+ ?Heart disease
o Toxicities (>100 mg/day) – muscle weakness, nerve damage
o DRI 1.3 milligrams/day
o Sources, see snapshot 7.10
+ Meat and dairy
+ Vegetables and fruits
* Biotin and Pantothenic acid
o Roles:
+ Metabolism of carbohydrates, fats and proteins
+ Synthesis of lipids, neurotransmitters, steroid hormones, hemoglobin.
* “Non-B vitamins”: choline, carnitine, inositol, lipoic acid, etc. No beneficial effects proven!!

* Vitamin C, ascorbic acid – history of controversy
o Roles:
+ Connective tissue development, collagen
+ Antioxidant
+ Promotes iron absorption, immunity?
+ Protects vitamin E

o Deficiency – Scurvy (skin and mucous membrane damage), anemia.
o Toxicity (> 2grams/day) – pro-oxidant, activates oxidizing agents.
o DRI – 75(w) – (90(m) milligrams/day. Increased for smokers.
o Sources, see snapshot 7.11
o Notes: can interfere with diagnostic tests for diabetes, and blood clotting
o ??Prevents colds

Vitamin/Mineral Supplements

* Who needs them?
* Who does not need them?
* Oyo read - Controversy

Vitamins.ppt

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