Transcript Developmental Toxicity - Lectures For UG-5

Occurrence of adverse effects on the
developing organism occurring anytime
during the lifetime of the organism that
may result from exposure to environmental
agents prior to conception (either parent),
during
prenatal
development,
or
postnatally until the time of puberty.
Central Nervous System
Heart
Ears
Eyes
Limbs
Palate
External Genetalia
1
2
Implantation
Prenatal
Death
3
4
5
6
7
8
12
16
20
38
Emryonic period
Fetal Period
Major Morphological abnormalities
Physiological and Functional
Defects
Red - most sensitive, Gray - Less
 Reproduction – issues associated with
the egg and sperm
 Pregnancy – the critical environment
of early development
 Development of the infant.
 Many ancient cultures had fertility
goddess
 Many ancient documentation of
malformations
 Malformations rich aspect of mythology
 6500 BC – Turkey - figurine of conjoined
twins
 4000-5000 BC – Australia drawings of
twins
 2000 BC - Tablet of Nineveh – describes
62 malformations and predicts the future
 15th-16th centuries malformations
caused by the Devil, mother and child
killed
 1830’s - Etienne Geoffroy Saint-Hilaire
experimented with chicken eggs
 1900’s began acceptance of
malformations related to genetics
 1940’s - Josef Warkany – environmental
factors affect rat development
 1941 – Human malformations linked
to rubella virus
 1960’s – Thalidomide (a sedative and
anti-nausea drug) found to cause
human malformations
 1950’s – Methylmercury recognized
as developmental toxicant
 1970’s – Alcohol related to
developmental effects – Fetal
Alcohol Syndrome (FAS)
• Approximately 80,000 chemicals listed by EPA
• Most of these chemicals have not been
tested for developmental toxicity
• For example, High Production Volume (HPV)
Chemicals
• Chemicals produced at >1 million lbs/year
• Approximately 3,000 chemicals identified
internationally
• Few tested for both reproductive and
developmental toxicity
• 50% of pregnancies end in miscarriage
or spontaneous abortion often before
pregnancy is recognized
• 15% of couples of reproductive age are
infertile
• The occurrence of biologically adverse
effects on the reproductive systems of
females or males that may result from
exposure to environmental agents.
• The toxicity may be expressed as alterations
to the female or male reproductive organs,
the related endocrine system, or pregnancy
outcomes.
REPRODUCTIVE Toxicity
Reproductive toxicity involves toxic damage to either male or
female reproductive system. Toxic effects may cause
Decrease LIBIDO and IMPOTENCE
INFERTILITY
Interrupted pregnancy ( abortion, fatal death, or premature
delivery)
Infant death or childhood morbidity
Altered sex ratio and multiple birth
Chromosome abnormalities and birth defects
Childhood cancer.
Endocrine disruptors
DDT, Dioxin, Phthalates
Heavy metals
Lead (decreased sperm)
Organic Solvents
Toluene, benzene
Drugs
Alcohol
• Cardiovascular
• Increased - cardiac output heart rate, blood
pressure, blood volume expands
• Oxygen consumption increases by 15-20%
• Urine volume increases
• Gut absorption changes
• Increases in iron and calcium (toxic lead
substitutes for calcium)
• Liver metabolism decreases for some
drugs or chemicals (caffeine)
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Teratology (physical malformations)
Birth weight
Growth
Neurobehavioral
 Decreased intelligence
 Decreases learning and memory
Lower doses  toxic effects
Repro system more sensitive to ~33% toxicants
evaluated

Three structures
› Hypothalamic-pituitary-gonadal axis
› Ovary
› Fallopian tube
Signals ovulation
Disrupted by
Xenobiotics
Excess hormones
Insufficient hormones
Cyclic production of gonadotropins
› FSH, LH, prolactin produced, released
 Feedback loops controlled by endogenous
hormones
 BUT environmental chemicals can influence
feedback loops
Neuronal influences
› Affected by anesthetics, cannabinols,
sedatives
Site of gamete maturation
 Controls proliferation

› Endometrium
› Oviductal function
› Uterus

Oocytes at birth
› Suspended meiosis (birth to maturity)
Recruitment at maturity
 Meiosis
 Release at ovulation
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
Primary oocytes during suspended meiosis
› Susceptible to drugs, environmental agents
› PAH’s toxic to ovary, oocytes
 Dose toxic to mouse oocytes sim to
mutagenic/carcinogenic dose
 Dependent on strain, species, age, dose,
metabolism

Some agents act indirectly
› DES, DDT
› PAH= Polycyclic aromatic hydrocarbons
Activation of some toxins  reactive
intermediates
Ex: DES- Diethylstilbestrol activation

› Harmful to developing fetus
›  infertility in mature females
Ex: Benzopyrene
› Systemic and ovarian metabolism
› Some metabolites ootoxic
› Cigarette smoking linked to disruption
reproduction
Gamete propulsion, fertilization,
implantation of embryo
 Congenital structural problems

› May be linked to xenobiotic exposure
› DES- Diethylstilbestrol

Hormonal imbalance, immunologic
alterations
› Xenobiotics??
› Unexplained infertility

Preimplantation embryo in oviduct
› Signals endometrium biochemically
› Site for interruption 
 Disruption implantation
 Improper hormones
 Improper hormone levels @ crucial time

Sperm count decrease?
› 1951 – 44% subjects > 100x106/mL
-- 5%
< 20x106/mL
› 1975 – 24% subjects > 100x106/mL
›
-- 7%
< 20x106/mL
›
Other indicators decreasing following
repro toxicants
› Libido
› Impotence
FORMS fertile sperm, deliver to female tract
› Must be functional
DiBromoChloroPropane (DBCP) (1970’s)
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Azoospermia
Oligospermia
Incr’d plasma LH, FSH
Atrophy seminiferous tubular epithelium
 Human testes affected
 Sim in lab animals, but to lesser extent
› Recovery w/in 18-21 mos
Convoluted seminiferous tubules
arranged in lobules
 Surrounded by interstitial cells (Leydig
cells)
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
Lined w/
› Germ cells
 Proliferative
 Mature to spermatozoa
 Migrate basement membr  tubule lumen w/ maturation
› Sertoli cells
 “Hold” sperm
 Form blood-testis barrier
 Help protect sperm from some toxicants

Sperm dev’t prior to
release from Sertoli cells
› Flagellum develops
› Nucleus condenses
› Acrosomal cap w/
digestive enzymes
develops

GnRH (hypothalamus)
› FSH
 From anterior pituitary
 Required to initiate spermatogenesis
› LH
 From anterior pituitary
 Stim’s testosterone synth/release from Leydig
cells

Testosterone
› Spermatogenesis progression, maturation,
maintenance
› Accessory sex glands
› Negative feedback to anterior pituitary

Alterations
› Anesthetics, Stimulants, Drugs of Abuse
 Alter hypothal-pit-gonadal (so GnRH, FSH, LH)
› Exogenous Steroids, Alcohol
 Interfere w/ steroid metabolism
 May affect hormonal balance
Toxicants selective for sperm dev’t
stage(s)
 DNA repair mech’s stage-specific
 Sperm metabolism alteration may affect
fertilizing capacity


Cd
› Testicular necrosis
› Concentrates in interstitial tissues

Polyaromatic Hydrocarbons
› Metabolized in testes
› Cyt P450’s.
› Metabolites may be toxic
DES -Diethylstilbestrol
› Hypoplastic testes
› Microphallus
› Cryptorchidism
› Oligospermia
› Azoospermia