OBI 814 - RD4 - Exam 2

• RD-4 covers fetal development, teratogens, sex differentiation, and intersex conditions.
• The learning objectives include explaining primary sex organ differentiation in utero, puberty's physical changes and oral health issues in adolescents, causes and symptoms of precocious puberty, and the biological basis of primary and secondary sex characteristics in an XY subject with complete androgen-insensitivity syndrome.

Fetal Development

• Organogenesis is generally complete by the end of the first trimester.
• Gestational age is calculated as fetal age + 2 weeks.
• The 1st gestational trimester is 1-12 gestational weeks.
• The 2nd trimester is 13-28 gestational weeks.
• The 3rd trimester is 29-40 gestational weeks.
• A teratogen is a substance that interferes with normal fetal development and causes congenital disabilities, with the most detrimental effects occurring during the 1st trimester.
• Examples of drugs causing detrimental effects on fetal development include thalidomide.
• Acceptable and unacceptable drugs are categorized based on their risk to the fetus, ranging from category A (no fetal risk in controlled studies) to category X (contraindicated in pregnancy).

Fetal Mandible Formation

• The mandible forms via intramembranous bone formation.
• At the 6th week, the mandibular division of the trigeminal nerve leads to mesenchymal condensation, forming osteoblasts, which then become osteoid and ossify.
• By the 7th week, intramembranous bone lies lateral to Meckel's cartilage and continues until the posterior aspect is covered with bone.
• At 8-12 weeks, mandibular growth accelerates in length.
• Endochondral bone formation occurs at the condylar, coronoid, and mental regions.
• From 10-12 weeks, accessory cartilage forms.
• By the end of the first year, cartilage is replaced by bone.

Tooth Development In Utero

• Dental lamina develops from epithelial-mesenchymal interaction.
• Tooth development stages include bud stage, cap stage, bell stage, and crown and root formation.
• In epithelium development, thickening of dental epithelium progresses to budding of dental epithelium, formation of the 1st enamel knot, formation of the 2nd enamel knot, differentiation of ameloblasts, and finally, formation of enamel.
• Mesenchyme development involves migration of neural crest ectomesenchyme, condensation of mesenchyme, and dental mesenchyme, leading to dental papilla (which differentiates into odontoblasts and pulp cells) and dental follicle (which differentiates into PDL cells, cementoblasts, and osteoblasts).
• Enamel knots are the signaling center for tooth formation.
• Signal molecules like BMP, WNT, SHH, and FGF control the expression of transcription factors that are important in forming teeth.
• Lack of these signal molecules can lead to agenesis, such as severe tooth agenesis (oligodontia) caused by a lack of Eda in XLHED.
• Dental pulp is connective tissue with four layers: the most external odontoblast layer with odontoblasts, a cell-free zone rich in collagen fibers, a cell-rich zone with fibroblasts and undifferentiated mesenchymal cells, and the innermost core with blood vessels and nerves.
• Dentin epithelium becomes secretory ameloblasts, secreting enamelin and amelogenin which is mineralized to create tooth enamel.
• Deciduous and permanent teeth form in utero but erupt after birth.
• The tooth germ starts from ectoderm through interaction between the oral epithelium and ectomesenchyme.
• Epithelium assumes an odontogenic capacity and forms a continuous band, known as the primary epithelial band.
• The band extends into the mesenchyme, forming dental laminae, which are classified as continual and successional laminae.
• The continual lamina forms horizontally from the posterior extension of the dental lamina and forms primary dentition during the 6-8th week of development.
• The successional lamina forms vertically from the lingual side of the dental lamina and forms a second dentition (permanent dentition) during the 12th week of development.

Development of Primary Sex Characteristics In Utero

• Primary sex characteristics, needed for reproduction, differentiate in a sex-dependent manner during fetal development.
• In males, the testes include the epididymis, and vas deferens; the seminal vesicle includes the scrotum, prostate, and penis.
• In females, the ovaries connect to the fallopian tube, uterus, cervix, and vagina; external structures include the labia and clitoris.
• At 4 weeks, the early human embryo is at an indifferent stage, possessing the potential to develop either female or male primary sex characteristics.
• Every embryo (XX or XY) has bipotential primordial gonads that become female ovaries or male testes, Mullerian ducts that develop into female internal genitalia, Wolffian ducts that develop into male internal genitalia, and a bipotential urogenital sinus.
• Gonads become ovaries, Mullerian ducts develop into female internal genitalia, Wolffian ducts regress, and the bipotential urogenital sinus becomes female external genitalia and urethra.
• At ~4 weeks, the SRY gene (sex-determining region on the Y-chromosome) is activated.
• SRY causes bipotential gonads to develop into testes.
• Testes secrete Mullerian Inhibiting Hormone (MIH) and testosterone (T).
• MIH causes the Mullerian ducts to regress.
• T causes Wolffian ducts to become male internal genitalia, which requires AR.
• At ~8 weeks, T is converted to DHT by 5-reductase in the urogenital sinus.
• DHT causes the bipotential urogenital sinus to develop into male external genitalia and the prostate, requiring AR.
• In the 3rd trimester, T facilitates the descent of the testis into the scrotum, requiring AR.

Androgen Insensitivity Syndrome (AIS)

• AIS, also known as testicular feminization syndrome, manifests in varying degrees of severity.
• There are seven grades of AIS, ranging from Grade 1 (mildest, with male external genitalia) to Grade 7 (most severe, with female external genitalia).
• It stems from primary defects in AR-mediated signaling caused by genetic mutations.
• Neither T nor DHT can adequately activate AR-required steps, influencing the individual phenotype.
• The XY subject would possess normal testes and normal MIH.
• Also an XY subject would exhibit normal MIH action and testosterone.
• Due to androgen insensitivity, normal testosterone action occurs, but no internal genitalia develops.
• Both normal DHT levels and normal DHT action is also found along with female genitalia, and undescended testes.
• These individuals are typically considered girls at birth and would not experience menstruation during puberty.
• The testes are in body cavity (cryptochidism), leading to increased risk of testicular cancer.
• These individual typically goes though female secondary sex characteristics.
• The Oral-health professionals need to be prepared to provide equitable care to the often-stigmatized population, transgenders, and intersex people.
• XY subjects typically have larger bone structures where their permanent teeth grow bigger and are squarer.
• Genes determine tooth size as well as tooth crown and root.
• Permanenttooth has bigger roots and crowns females with XY, where (XY = XY Male >> XX Female)

This lesson covers fetal development stages, teratogens and their effects, sex differentiation, and intersex conditions. It includes gestational age calculation, trimester specifics, and the impact of teratogens on fetal development during the first trimester. Also covered are drugs that cause detrimental effects on fetal development.