Intoxicated Babies

1
Intoxicated Babies

• Biology of Toxins
• Dr. Toolson
• Justin Trujillo
• Julian Davis

2
Contraception, protection, and guns

• Sperm are vectors for pathogens to enter the
  female reproductive system. Pathogens that use
  sperm as a vehicle for transport include
• Chlamydia trachomatis
• E. coli
• Streptococcus viridans
• Staphylococcus aureus
• Neisseria gonorrheae
• Menstruation is a defense that the female body
  has against these pathogens While in menses the
  uterus
• Provides macrophages and phagocytes
• Lacks functional clotting factors

• After sperm fertilizes the egg, the zygote
  implants itself in the uterus. How does this
  happen without the mothers immune system
  attacking this foreign body?
• Hybrid zygotes, which are only half similar to
  the mother, are able to bypass the uterus
  defense mechanisms
• This suggests there is a mechanism to bypass the
  mothers immune system.
• Trophoblast cells are not attacked

3
Development of the Placenta

• In eutherian mammals the fertilized embryo
  implants in the uterus and forms part of the
  placenta for a 40 week gestation period within
  the mother. 
• Implantation in the endometrium allows chorion
  formation. This forms the vascular connections
  to the uterus necessary for transport of
  nutrients.
• This complex connection between the mother and
  the embryo will direct maternal endocrine,
  immune, and metabolic functions to the embryos
  advantage.
• The chorin secretes hormones that prevent
  menstruation.

4
Development of the Placenta cont

• These complex connections are sensitive and can
  be easily disrupted by the environment.
• The fetus will be exposed to everything present
  in the mothers body, including all the nutrients
  necessary for proper development, and any harmful
  toxins.

Abnormal development and birth defects may result
from exposure to toxins.
5
Parent-offspring conflict in the uterus

• Once the embryo is implanted it is difficult, but
  not impossible, for the mother to deprive the
  embryo of resources.
• Trophoblast and other extraembryonic cells are
  designed by natural selection to implant in the
  endometrium and manipulate maternal spiral
  arteries to make the constriction of arteries
  more difficult.
• If constriction does occur the outer layer of the
  endometrium becomes starved and dies off i.e.
  mentruation.

6
Parent-offspring conflict in the uterus

• The developing embryo must do this without being
  detected by macrophages and lymphocytes.
• If it is successful the embryo gains direct
  access to maternal arterial blood which it can
  then release hormones and other substances into
  the maternal bloodstream.
• Human placental lactogen (HPL) and human
  chorionic gonadotropin (HCG) alter the in-utero
  environment in a manner that benefits the fetus
  at the cost of the mother.

7
Teratogen -Any substance or exposure
that causes birth defects

• Substances that have adverse effects on the
  ontogeny of fetuses and children include
• Thalidomine
• Alcohol
• Nicotine
• Lead
• Mercury
• PCB
• Dioxin
• Water

8
Endotoxin (Lipopolysaccharide,LPS)

• IP injection into pregnant mice increased
  cytokine production in maternal organs and
  placental tissue. No increases of cytokines
  occurred in fetal membranes, however after 12
  hours the concentrations of cytokines in the
  amniotic fluid increased.
• Acute inflammation spread from the mother to the
  placenta but never reached the fetus.
• severe vascular congestion in the placenta and
  abnormalities in fetal cardiovascular function
  occured.
• Congestion caused an increase in placental
  resistance to blood flow and a higher volume of
  blood remained in the ventricles of the
  fetus after each beat.
• Congestion in the maternal compartment caused
  increased resistance to flow in the fetus, which
  ultimately led to reduced cardiac output by the
  fetus. However since the inflammatory response of
  the mother did not reach the fetus, the fetus was
  able to maintain high enough pressures to
  circulate blood.
• When LPS was injected directly into the amniotic
  sac the mouse fetus cytokines were expressed in
  the membranes and inflammation occured. These
  fetuses could not maintain high enough systemic
  pressures leading to heart failure.

9
Endotoxin (LPS)

• These results suggest the placenta acts as a
  barrier to any substances that may harm the
  fetus. The fetuses heart begins to function at
  week 5 of gestation and is the first functional
  organ. Thus it is seems likely the placenta would
  prevent any substance that may interfere with
  cardiac function from crossing the mother/fetus
  interface. There is evidence however that the
  placenta also facilitates the transfer of certain
  substances across the membrane. How is it
  possible for some substances to be blocked while
  others are facilitated?

10
Exchange across the interhemal membrane of the
placenta

• Via diffusion
• Oxygen
• Carbon dioxide
• Urea
• Blood

• Via active transport
• Glucose
• amino acids
• large organic molecules

Oxygen consumption by the embryonic compartment
of the placenta is higher than that of the
maternal compartment suggesting metabolic costs
associated with active transport of molecules.
The hemoglobin (oxygen-carrying) molecule
contains 4 globin proteins that change
structurally and functionally during development.
Embryonic heme groups have a much higher affinity
for oxygen compared to that of adult heme groups,
setting up a gradient of exchange (to the embryos
advantage) between the maternal compartment and
the developing embryo.
11
Omeprazole (Losec)

• Anti-ulcer drug (gastric and duodenal ulcers)
• Helicobactor pyroli
• Inhibition of HCL secretion
• ATPase inhibitor
• Histamine H2-receptor antagonist
• Highly correlated with hepatotoxicity and
  nephrotoxicity in rats and mice.
• Omeprazole administered to a man of 69 years lead
  to kidney tissue damage and impaired renal
  function.
•  Interstitialnephritis may cause renal failure in
  patients using anti-ulcer drugs to treat duodenal
  and gastric ulcers.

12
Omeprazole

• Mice were injected with omeprazole for 7 days and
  14 days (before pregnancy) and 21 days (14 days
  prior to pregnancy and 7 days during pregnancy).
•  Maternally treated fetuses revealed
• decreases in fetal body weight and body length.
• reduced skeletal growth/osteoclast activity
• reduced ability to remove the anti-ulcer drug
  from the proximal convulated tubule due to
  inflammation/congestion of the tissue in the
  kidney.
• increases in liver isoenzyme activity ie P450.
• The group injected for 21 days (14 days prior to
  gestation and 7 days during gestation) revealed
  the most pronounced nephrotoxicity.

13
Morning Sickness Defense against Teratogens

• Hook (1976)and Profet (1988) hypothesized that
  morning sickness protects the embryo by causing
  pregnant women to physically expel and
  subsequently avoid foods that contain teratogenic
  and abortifacient chemicals Flaxman

14
Industrial Risks

• "The Occupational Safety and Health
  Administration (OSHA) has determined that
  excessive lead exposure is linked to both male
  and female reproductive disorders. In men, these
  disorders include reduced sexual drive,
  impotence, decreased semen count, and sterility.
  In women, disorders include abnormal ovarian
  cycles, premature births, menstrual disorders,
  sterility, spontaneous abortions and stillbirths"
  (Jones 199040)

15
Heavy metal and sperm concentration

• Cadmium, Lead, Molybdenum, and Methylmercury have
  been linked with poor semen quality, DNA damage,
  and sperm abnormalities. Others such as Zinc are
  enzyme cofactors, necessary at low concentrations
  for functional enzymes and normal semen motility.
  At high concentrations Zinc may also inhibit
  sperm motility.
• Effects are dose-dependant
• higher concentrations in semen result in reduced
  sperm quality.
• the majority of cases have low concentrations of
  metals in the plasma but showed no reduction in
  sperm quality.
• With increasing plasma metal concentrations,
  there are parallel increases in semen metal
  concentrations.  

• Toxicants affect the reproductive health of men
  and women at equally devastating rates.
• In 1974 General motors permitted women from
  working in their warehouses in light of the
  growing threat of lead poisoning to them and
  their fetuses.
• Nurses are exposed to infectious agents daily.

16
Lead

• In the circulatory system lead is held mainly
  within red blood cells. Less than 1 is held in
  the plasma. (1)
• Lead has a half life of 7 to 20 years once in the
  bones of an adult human. A pregnant woman is in
  danger of poisoning her unborn child with lead
  regardless of when she was exposed. (1)
• Lead is a pseudo-calcium and during pregnancy is
  released along with the other essential minerals
  to aid in the development of the skeleton and
  tissues of the fetus even though it is harmful.
  (1)

(1) Washam, Cynthia. 2001. Leacy of Lead Babies
at Risk Decades after Mothers Exposed.
Environmental Health Perspective. 109A224 (2)
Chuang, H., Schwartz, J., Gonzales-Cossio, T.,
Lugo, M.C., Palazuelos, E., Aro, A., Hu, H.,
Hernandez-Avila, M. 2001. Interrelations of Lead
in Bone, Venous Blood, and Umbilical Cord
Blood with Exogenous Lead Exposure through
Maternal Plasma Lead in Peripartum Women.
Environmental Health Perspective. 109527-532
17
Lead cont

• Fetal lead exposure is asociated with delayed
  embryinic development of several organs and
  cognitive deficiencies in early
  childhood."-Cynthia Washam 2001 (1,2)
• Maternal lead bone levels correlates with
• declined infant birth weight
• Smaller head circumference
• Shorter length at birth (1,2)

(1) Washam, Cynthia. 2001. Leacy of Lead Babies
at Risk Decades after Mothers Exposed.
Environmental Health Perspective. 109A224 (2)
Chuang, H., Schwartz, J., Gonzales-Cossio, T.,
Lugo, M.C., Palazuelos, E., Aro, A., Hu, H.,
Hernandez-Avila, M. 2001. Interrelations of Lead
in Bone, Venous Blood, and Umbilical Cord Blood
with Exogenous Lead Exposure through Maternal
Plasma Lead in Peripartum Women. Environmental
Health Perspective. 109527-532
18
Mercury

• Mercury is the 80th element on the periodic table
  of elements. It is an inorganic heavy metal that
  is poisonous to humans.(1,2)
• There is an increase of inorganic Hg present in
  the hydrosphere biosphere via acid rain and
  industrial mining activities.(1)
• In the ocean inorganic mercury is converted to
  methylmercury by methanogenetic bacteria
  present.(2)
• Bioaccumalation of this compound throughout the
  food chain has adverse affects on developmenting
  fetuses. (1,2)
• Food Agriculture Organization/World Health
  Organization report a tolerable weekly intake of
  the organic form of Hg to be 3.3 µg/kg/week or
  200 µg/week for adults and breast-feed
  infants.(2)

(1) Chapman, Laurie, Chan, Hing Man. 2000. The
Influence of Nutrition on Methyl Mercury
Intoxication. Environmental Health Perspective.
10829-56 (2) Meyers, Gary, J., Davidson, Philip,
W. 2000. Does Methylmercury Have a Role in
Causing Developmental Disabilities in Children?.
Environmental Health Perspective. 108413-420
19
Methylmercury MeHg

• Methylmercury is a powerfull neurotoxin that in
  high levels has been shown to cause
• mental retardation
• cerebral palsy
• seizures
• low birth weight
• early sensorimotor dysfunction (1,2)

• MeHg in vitro directly affects
• microtubule formation
• protein synthesis in nerve cells.
• DNA synthesis
• In vivo MeHg
• Impairs mitosis
• Disrupts neuronal migration (2)

• Chapman, Laurie, Chan, Hing Man. 2000. The
  Influence of Nutrition on Methyl Mercury
  Intoxication. Environmental Health Perspective.
  10829-56
• (2) Meyers, Gary, J., Davidson, Philip, W. 2000.
  Does Methylmercury Have a Role in Causing
  Developmental Disabilities in Children?.
  Environmental Health Perspective. 108413-420

20
Polychlorinated BiphenylsPCB

• PCB is a class of chemicals that has 209 cogeners
  with varying chlorine substitutions. The
  different substitutions affect different
  biological pathways. (2)
• These environmental contaminants are found
  throughout various human populations. (2)

• PCBs can
• interfere with IQ levels of children
• interfere with normal endocrine functions of
• weight and height of children (1,2)

(1) Stewart, P.W., Lonky, E., Reihman, J.,
Pagano, J., Gump, B.B., Darvill, T. 2008. The
Relationship between Prenatal PCB Exposure and
Intelligence (IQ) in 9-Year-Old Children.
Environmental Health Perspective.
1161416-1422 (2) Lamb, M.R., Taylor, S., Liu,
X., Wolff, M.S., Borrell, L., Matte, T.D.,
Susser, E.S., Factor-Litvak, P. 2006. Prenatal
Exposure to Polychlorinated Bibenyls and
Postnatal Growth A Structural Analysis.
Environmental Health Perspective. 114779-785
21
PCB cont

• The adverse affects that can result from PCB
  exposure during pregnancy include
• Lower IQ in children
• 3 point drop in IQ for every 1 ng/g of exposure
• Childhood height and weight
• increased girls and boys height up to 17 years
  of age
• Reduced girls weight up to 17 years of age (1,2)

(1) Stewart, P.W., Lonky, E., Reihman, J.,
Pagano, J., Gump, B.B., Darvill, T. 2008. The
Relationship between Prenatal PCB Exposure and
Intelligence (IQ) in 9-Year-Old Children.
Environmental Health Perspective.
1161416-1422 (2) Lamb, M.R., Taylor, S., Liu,
X., Wolff, M.S., Borrell, L., Matte, T.D.,
Susser, E.S., Factor-Litvak, P. 2006. Prenatal
Exposure to Polychlorinated Bibenyls and
Postnatal Growth A Structural Analysis.
Environmental Health Perspective. 114779-785
22
Water intoxication of the mother and her new-born
baby

• Excessive water intake immediately before and
  during delivery may cause water intoxication of
  the mother and harm the newborn child.
• Oxytocin, a hormone released during labour, is
  thought to have vasopressin-like action and cause
  the mother to retain water.
• In one case the mother developed seizures and an
  emergency caesarean was performed to prevent the
  infant from harm. Her sodium serum levels were
  115 mmol/L, which is extremely low salt
  concentration in the plasma. The infant required
  assisted ventilation after birth.
• Other cases have been reported by Johansson et
  al. in which the infant experienced seizures and
  severe hyponatremia (electrolyte imbalance) which
  may result in swelling of the brain and
  permanent brain damage. Mothers and young women
  must be informed of the dangers of consuming
  large quantities of water.

23
Is Pregnancy "Normal"?

• The metabolic demands of the fetus impose a
  considerable burden on the mother and certain
  risks (ie trauma and infection) are significant. 
  
• Development of the placenta improves the survival
  chances of the embryo with an associated increase
  in risk to the mother.
• If the mother is at increased risk of trauma and
  infection as a result of pregnancy, should her
  condition be considered normal? If the pregnancy
  is endangering the mother's life should she be
  allowed to abort?
• Should expecting mother's receive preferential
  treatment and/or be discriminated against due to
  their delicate condition?
• President Reagan was the first American
  president to make outlawing abortion one his
  primary goals of his political agenda and
  promised a pro-life administration.
• Since then Americans have developed a morbid
  fascination with the fetus and much controversy
  exists over the emotional pivot point.