Teratogens, TORCH, and Microchimerism

Sensitive Timepoints for Teratogens

• Early: disrupt cleavage, implantation

• Embryonic period:  disrupt organogenesis

• Fetal period:  brain, sensory organs, genitalia

Wilson’s 6 Principles of Teratology

• Susceptibility depends on the genotype of the fetus/embryo and how this genotype interacts with environmental factors

• Susceptibility varies with developmental stage

• Teratogens act in specific ways on developing tissues and cells

• Many factors influence how a teratogen interacts with a fetus/embryo, including the route and degree of exposure, how the substance is absorbed and whether it can cross the placenta

• 4 possible manifestations:  death, malformation, growth retardation, functional defect

• Higher dose = greater defect

Crossing the Placenta

• Smaller drugs (less than 500 Da) can cross

• Lipophilic drugs (opiates and antibiotics) do better than water-soluble drugs

• Weak bases cross to the fetus and do not return as fetal pH is lower than maternal pH

Retinoic Acid

• Found in acne medication, cancer drugs, skin medicines

• 2^nd to 5^th week of gestation

• Miscarriage

• Absent/defective ears

• Small jaws, cleft palate

• Problems with 1^st pharyngeal arch

• Aortic arch abnormalities

• Thymic deficiencies

Thalidomide

• Induces dysregulation of transcription factors, especially Sall4

• Used as a treatment for nausea during pregnancy, 1950s and 1960s

• Now used for leprosy and some cancers

• Primarily affected limb development

• Blindness, paralysis, face

• Internal organs

Minamata Disease

• Methylmercury spill in 1956

• Transmitted across placenta and through mother’s milk

• Selectively absorbed by regions of the developing cerebral cortex

• Neurological defects

• Defects in movement

• Problems with limb and joint development

• Growth and nutritional defects

Diethylstilbestrol or DES

• Synthetic form of estrogen

• Prescribed between 1940s-1970s to prevent miscarriage

• Banned in 1971; adenomas found in reproductive tracts of women whose mothers took DES during pregnancy

• Interferes with sexual and gonadal development in the female reproductive tract

• Mullerian duct often fails to form a cervical canal

• Causes infertility or subfertility

Warfarin

• Vitamin K inhibitor

• Commonly used blood thinner

• 6^th-12^th week

• Low birth weight/slower growth

• Mental retardation; small head

• Deafness

• Deformed bones, cartilage, and joints

Neonatal abstinence syndrome (NAS)

• Tremors (trembling)

• Irritability, including excessive or high-pitched crying

• Sleep problems

• Hyperactive reflexes

• Seizures

• Yawning, stuffy nose, or sneezing

• Poor feeding and sucking

• Vomiting

• Loose stools and dehydration

• Increased sweating

TORCH Organisms

• Toxoplasmosis

• Other (syphilis, Zika, HIV, Listeria)

• Rubella

• Cytomegalovirus

• Herpes

How Pathogens Affect Pregnancies

• Cross placental barrier and grow in fetal tissues

• Infect placental trophoblasts and macrophages, causing placental insufficiency

• Cause placental inflammation

• Maternal immune activation

Toxoplasmosis

• New infection during pregnancy

• Chance of cross-placental infection increases as gestational age increases

• Severity decreases as gestational age increases

Syphilis

• Stillbirth/miscarriage

• Low birth weight

• Meningitis

• Liver and spleen problems

• Bone deformities 

• Rashes

Hutchinson’s triad

• Keratitis

• Deafness

• Hutchinson’s teeth

Long Term Consequences of syphilis

• Fetal death or premature birth

• Microcephaly

• Retina damage

• Hydrocephalus- CSF build up in brain

• Intracranial calcifications

  • Seizures

  • Intellectual disabilities

  • Motor and developmental delays

  • Hearing loss

Zika

• Microcephaly

• Learning disabilities

• Joint problems

Rubella

• Heart defects

• Ocular problems

• Hearing loss

• Microcephaly

• Mental retardation

• Rashes

Cytomegalovirus

• Associated with hearing loss

• Decreased growth

• Vision problems

• Microcephaly

• Low platelet levels

Herpes

• New or reactivated infection in mother (usually in final trimester)

• Most infections occur near time of birth or during labor

• Rashes

• Eye problems/small eyes

• Microcephaly

• Growth restriction

Maternal Immune Activation

• Changes to immune system, gut microbiome

• Fewer interneurons

• Changes in glutamatergic neurons

• Changes in neuronal activation

Susceptibility to MIA

• Maternal hypoferremia and anemia 

• Gestational diabetes mellitus

• Maternal stress during pregnancy

• Gut dysbiosis

• Peripubertal exposure to psychological trauma

• Chronic cannabis use during periadolescence

Resilience

• Vitamin D, iron, zinc, or choline

• Efficient anti-inflammatory and antioxidant response systems

• Omega-3 fatty acids.

Fetal Microchimericism

• Fetal cells or DNA in maternal bloodstream

• Increased after fetal surgery

• Increased in pre-eclampsia, pre-term labor

• Higher levels may be associated with fetal genetic problems

• May be associated with autoimmune diseases or cancer later

• Dizygotic twins may have microchimericism with each other

Maternal Microchemericism

• Maternal cells in fetal blood

• Transferred in pregnancy, breastfeeding

• Non-inherited maternal antigens (NIMAs)

• Helps development of regulatory T cells 

• Can influence future autoimmune responses

• Can influence tolerance to transplant from mother 

• Influences future Rh response

Microchimerism

• Mother to child

• Child to mother

• Twins in utero

• Siblings through mother