OBI 814 - RD4 - Exam2

Fetal Development and Teratogens

• Organogenesis is mostly complete by the end of the first trimester.
• Gestational age is calculated by adding 2 weeks to the fetal age.
• The first gestational trimester spans from 1-12 weeks.
• The second gestational trimester spans from 13-28 weeks.
• The third gestational trimester spans from 29-40 weeks.
• A teratogen is a substance that can interfere with normal fetal development.
• Teratogens can cause congenital disabilities and have the most detrimental effects during the first trimester.

Fetal Mandible Formation

• At 6 weeks, the mandibular division of the trigeminal nerve leads to mesenchymal condensation, osteoblast formation, and then osteoid and ossification.
• By the 7th week, the intramembranous bone lies lateral to Meckel's cartilage, continuing until the posterior aspect is covered by bone.
• Between 8-12 weeks, mandibular growth accelerates in length.
• Endochondral bone formation occurs at the condylar, coronoid, and mental regions.
• Accessory cartilage forms between 10-12 weeks.
• Cartilages are replaced by bone, from 12 weeks to the end of the first year.

Tooth Development In Utero

• Dental lamina develops from epithelial-mesenchymal interaction.
• The stages include: Bud, Cap, Bell, and Crown & Root Formation.
• Enamel knots serve as signaling centers for tooth formation.
• Molecules such as BMP, WNT, SHH, and FGF control transcription factors for tooth formation.
• A lack of signal molecules can lead to agenesis, such as severe tooth agenesis (oligodontia) caused by a lack of Eda in XLHED.
• Dental pulp, the soft connective tissue of the tooth, develops with 4 layers.
• The outermost layer is the odontoblast layer, with odontoblasts producing dentin.
• The second layer is a cell-free zone, rich in collagen fibers.
• Third is a cell-rich zone, containing fibroblasts and undifferentiated mesenchymal cells.
• The innermost layer of the pulp contains blood vessels and nerves.
• The inner dental epithelium becomes secretory ameloblasts, secreting enamelin and amelogenin, which mineralize into enamel.
• Primary teeth (deciduous) and permanent develop in utero but erupt after birth.
• Tooth germ originates from ectoderm via interaction between oral epithelium and ectomesenchyme.
• Epithelium becomes odontogenic and proliferates to form a continuous primary epithelial band.
• This band invades underlying mesenchyme, forming dental laminae (classified as continual and successional).
• The continual lamina forms horizontally from the posterior extension of the dental lamina and forms primary dentition, occuring around the 6-8th week of development.
• The successional lamina forms vertically from the lingual side of the dental lamina and form a second dentition (permanent), occuring around the 12th week of development.

Development of Primary Sex Characteristics

• Genetic sex is determined by XX or XY chromosomes at fertilization.
• Biological sex is determined by the differentiation of sex organs during weeks 4-12 of fetal development.
• Primary sex characteristics, structures needed for reproduction, differentiate in a sex-dependent manner during fetal development.
• Male primary sex characteristics include testes, epididymis, vas deferens, seminal vesicle, scrotum, prostate, and penis.
• Female primary sex characteristics include ovaries, fallopian tube, uterus, cervix, upper vagina, labia, clitoris, and lower vagina.
• In early human embryos (4 weeks), there is an indifferent stage where the embryo can develop either female or male characteristics.
• All embryos (XX or XY) have bipotential primordial gonads (becoming ovaries or testes), Mullerian ducts (becoming female internal genitalia), Wolffian ducts (becoming male internal genitalia), and a bipotential urogenital sinus (becoming external genitalia and urethra).
• An XX embryo follows a default pathway during weeks 4-12:
  • Bipotential gonads become ovaries.
  • Mullerian ducts develop into female internal genitalia.
  • Wolffian ducts regress.
  • The bipotential urogenital sinus develops into female external genitalia and urethra.
• In XY embryos, male sex characteristics development is initiated around week 4.
• The SRY gene (sex-determining region on the Y chromosome) is activated.
• SRY causes the bipotential gonads to become testes.
• Testes then secrete Mullerian Inhibiting Hormone (MIH) and Testosterone (T).
• MIH causes Mullerian duct regression.
• Testosterone causes Wolffian ducts to become male internal genitalia and requires AR, androgen receptor.
• Around week 8, testosterone is converted to DHT in the urogenital sinus via 5-reductase.
• DHT causes the bipotential urogenital sinus to become male external genitalia and prostate along with the urethra and requires AR
• During the third trimester, testosterone causes testes descent into the scrotum and requires AR

Androgen Insensitivity Syndrome (AIS)

• Pathophysiology: Testicular feminization syndrome in an XY subject.
• There are seven grades of AIS, depending on the severity;
  • Grade 1 is the mildest with male external genitalia,
  • grade 7 is the most severe with female external genitalia.
• Women with AIS have testes in the body cavity (cryptorchidism), with a predisposition to testicular cancer.
• AIS involves primary defects in AR-mediated signaling.
• Phenotypes depend on the severity of the defect, as neither T nor DHT can adequately activate AR-required steps.
• A complete androgen insensitivity in an XY subject has the following characteristics:
  • Normal testes & MIH
  • MIH action is normal, with Mullerian duct regression (no female genitalia)
  • Normal T, however, T action is not normal, and there is no male internal genitalia
  • The individual lacks male external genitalia and exhibits female external genitalia.
  • The testes will not descend.
• XY subjects with complete AIS:
  • Are considered girls at birth.
  • Will not menstruate at puberty.
  • Have testes located in the body cavity (cryptorchidism).
  • Develop secondary sex characteristics that are female.
  • The testes secrete testosterone, which results in T action on LH secretion to be decreased.
  • Increased or constant more or less LH can lead to increased or constant levels of testosterone secretion.
  • T is converted to estradiol by aromatase in peripheral tissues, causing to increased estradiol.

Sexual Dimorphism of Jaw in Teeth

• XY subjects have a larger bone structure.
• Permanent tooth (root and crown) grows bigger and squarer as genes on the Y chromosome influence the growth of the tooth crown and root.