Human development and sex determination PINSET ISLAABAD

Introduction

•Zygote is formed as a result of fusion of sperm (male gamete) and oocyte (female gamete)

•Gametes are produces in gonads •Gonads are paired organs with associated

ducts and accessory glands •The fertilization of the male and female

gamete lead to the formation of zygote

Human Life cycle

Fertilization • Fertilization means

the sperm joins the egg, creating the zygote, which is the first cell of the new individual person.

• 23 chromosomes from sperm plus 23 from the egg restores the total of 46 chromosomes.

• And, the new individual is now either 46,XX (female) or 46,XY (male)

Overview of the male reproductive system

Features of male reproductive system

• Testes form in the abdomen during embryonic development but later descend into Scrotum- sac keep testes external to body

• Septum divides scrotum into two sacs• Dartos helps maintain position and internal temperature• Well vascularized (pudendal,cremasteric branch of

inferior epigastric artery)• Testes descend into scrotum through inguinal canals

during development• Duct systems which transport the sperms out of body • Three sets of glands which secrete fluids to keep sperms

viable and motile• The penis which is the organ of sexual intercourse

Structure and function of the testis (plural: testes)

• Divided into lobules• Seminiferous tubules

are tightly packed within them and sperms are produced

• Cells within tubules:▫ Spermatogenic cells divide

via spermatogenesis or meiosis to produce sperm

▫ Sertoli cells regulate sprem formation

• Leydig (interstitial) cells secrete testosterone

Sperm

• Once produced sperms moves from the seminiferous tubules into the epididymis where sperms are stored

• Sperm formation takes 8-10 weeks (but 300M are formed every day)

• Adapted for “swimming” to an oocyte

Transport of sperm from the testis

• Lumen of seminiferous tubule• Rete testis• Efferent ducts• Ductus epididymis• Ductus deferens• Ejaculatory ducts• Urethra• During the transport of the sperm there are different

secretions which are added 1. Seminal vesicles contribute fructose as an energy

source for sperm 2. Prostaglandins locally acting chemical messengers

that stimulate contraction of female reproductive system for the assistance in movement of sperm

3. Bulbourethral glands which are present for the lubrication of the glands during intercourse

Accessory glands in males

• Seminal vesicles-alkalinity, sugar, coagulants

• Prostate- citric acid, enzymes; PSA (breaks down clot)

• Bulbourethral glands- neutralize acidity of urethra

• Semen contains these secretions and sperms

Spermatogenesis

Overview of the female reproductive system

Female reproductive system • Female gonads are a pair of oval shaped ovaries

about 3cm long located in the abdomen • Ovary contains many follicles consisting of a

developing egg surrounded by an outer layer of follicle cells

• Developing egg is a primary oocyte and begins meiosis in the third month of female prenatal development

• At birth the female carries a lifetime supply of developing oocytes each of which is in the first stage of the meiosis development

•The first developing egg called as a secondary oocyte is released from a follicle at puberty by ovulation and over a females reproductive lifetime about 400-500 gametes will be produced

•The ovulated cell or the secondary oocyte is swiped into the oviduct also called as the fallopian tube

•The oviduct is connected to the uterus which is 7cm long and 5cm wide

Histology of the ovary

Structure of the uterine (fallopian) tubes

Ciliated cellshelp move ovumFertilization usuallyoccurs in ampulla

Features of the uterus• Muscularity is prominent in

the outer layer called myometrium

• Perimetrium is part of peritoneum

• Myometrium- three layers of smooth muscle

• Endometrium- highly vascularized; secretory

• This blood rich endometrium is shed during menstruation if fertilization has not taken place

• The lower neck of the uterus is termed as cervix that opens into the vagina

Human development • During fertilization a sperm binds to the

receptors on the oocyte and other sperms bring about changes in the oocyte

• We all begin as a single cell, the zygote, produced by the fusion of a sperm and oocyte

• Zygote ; Fertilized egg that develops into a new individual

• Zygote travels via ciliary movements into uterus body in 3-4 days

• Cell divisions occur and gives result into a blastocyst

•Blastocyst is 100 celled •Consist of internal cavity and a cell lining

called troposphere •The cells of the endometrium enlarge and

prepare for the attachment of the embryo •The trophoblast attaches to the

endometrium and releases the enzymes which digests some endometrial cells and provide space for the attachment of embryo

• 12 days after fertilization the two layered structure is formed over the embryo

• This structure with a trophoblast covered with two layers is called as chorion

• Once settled chorion releases hCG human chorionic gonadotropin hormone which nourishes the endometrial lining and prevents the cells of endometrium from degeneration

• This also releases other hormones necessary for the establishment of pregnancy

• As chorion develops it makes finger like projections which gets vascularized and filled with maternal blood

• The capillaries of the developing embryo also runs in the same villi separated via single sheath of cells from the maternal blood

• The villi then eventually forms the placenta• A disc shaped structure which nourishes the embryo and

helps providing a suitable environment or the development and growth of embryo

•Membranes which connect embryo to the placenta forms the umbilical cord

•This contains 2 umbilical arteries and an umbilical vein as an extension to the embryonic circulatory system

Stages of development

•The development of human fetus is divided into 3 trimesters

•First trimester•Second trimester•Third trimester

1st trimester • Organ formation • Three tissue layers form starting from first

week and at the end of third week the organ systems begin to take shape

• by 4th week the body is 5mm long and composed of paired segments of body

• In 5th week the embryo dramatically increase in size of about 3cm long. Most of the organ systems like heart are formed

• Limb buds develop into complete arms and legs with fingers and toes

• Head is larger than other body due to rapid development of the nervous system

•After 7 weeks the embryo is called as a fetus •Though the sex of the fetus is determined at

the time of fertilization but the physical appearance of sex is not strict until start of the 9th week

•After 9th week a set of genes is activated which initiates the sexual development

•Ultrasound scans can reveal the external sex organs by 12th to 13th week

•At the end of first trimester the fetus is 9cm long

•It weighs about 15g •All the major organ systems are formed and

are functional to their full extent

2nd trimester •Major changes include the increase in the

size and maturation of the respiratory system •Bony parts of skeleton begin to form •Heartbeat becomes notable with aid of a

stethoscope •Fetal movements become notable •At the end of 2nd trimester the fetus weighs

700g and is 30-40cm in length •A well formed face arms and legs with finger

nails and toe nails are prominenet

3rd trimester • Fetus grows rapidly • Respiratory and circulatory system grow and

prepare to get functional for air breathing • Maternal nutrition in this period accounts for the

skeletal system development and nervous development

• Fetus doubles in size in the last two months • The last month accounts for the immune system

development as maternal antibodies pass into fetus these antibodies are utilized to be safe from the diseases until baby’s immune system develops shortly after birth

Birth is hormonally induced

•Oxytocin induces birth •It is released from the pituitary and

stimulate the uterine contractions •These contractions stimulate the birth of

the fetus

Teratogens Are a Risk to the Developing Fetus

•The embryo and fetus are sensitive to chemical and physical agents that can cause birth defects

•Teratogen ▫Any physical or chemical agent that brings

about an increase in congenital malformations

▫Radiation, viruses, medications, alcohol

Alcohol is a Teratogen

•Fetal alcohol syndrome (FAS)

• Alcohol is the most common teratogenic problem and leading cause of preventable birth defects▫There is no “safe”

amount of alcohol consumption during pregnancy

Other teratogens

•Important: not all have severe effects: consultation with health care provider critical!▫Anticonvulsants▫Antipsychotics▫Antimicrobials▫Anti hypertensives▫Anticoagulants▫Factors: maternal health; maternal

infections (esp. viruses), radiation exposure

Human Sex Ratios

• The proportion of males to females, which changes throughout the life cycle

• The ratio is close to 1:1 at fertilization• The ratio of females to males increases as a

population ages• 105 males for every 100 females at birth • 1:1 at the age of 20-25• Accidents are major cause of death of

males worldwide during 15-30 years of age

Factors in Sexual Differentiation

•The formation of male and female reproductive structures depends on:▫Gene action▫Interactions within the embryo▫Interactions with other embryos in the

uterus▫Interactions with the maternal environment

Levels of sex development• There are 3 levels to sexual development:1. chromosomal sex: presence or absence of the Y

chromosome2. gonadal sex (primary sex determination): whether the

gonads develop as testes or ovaries depends on the presence or absence of the SRY gene, usually found on the Y chromsome

3. phenotypic sex (secondary sex determination): all of the internal and external structures develop along male or female lines depending on which hormones are secreted by the gonads.

• Phenotypic sex also has a couple of distinct systems: the internal ducts, and the external genitalia

• Two important times: pre-natal development and puberty

Chromosomal sex determination •We have 46 chromosomes: 23 pairs, one

set from each parent.•One pair of chromosomes is the sex

chromosomes, X and Y.•the other chromosomes just have

numbers: 1-22.•A person with 2 X chromosomes (46,XX) is

female, and a person with an X and a Y (46,XY) is male.

Chromosomal basis of sex determination

Male or female?

SRY Gene How the Y chromosome determines sex.The SRY gene, located on the Y chromosome, is the primary determinant of sexual development.That is, if a developing embryo has a functional SRY gene in its cells, it will develop as a male. And, if there is no functional SRY, the embryo develops as female.Although the SRY gene is usually on the Y chromosome, it occasionally gets transferred to the X.this leads to 46,XX malesAlso, sometimes the SRY gene is inactivated by mutation.Leading to 46,XY females (Swyer syndrome)it is also possible to have a partially inactive SRY gene, leading to ambiguous genitalia

• Testosterone ▫ A steroid hormone

produced by the testis

▫ Male sex hormone

• Müllerian inhibiting hormone (MIH) ▫ Hormone produced

by developing testis that causes breakdown of Müllerian (female) ducts in the embryo

Early Gonad Development• Before 6-7 weeks of

development, the gonad is indifferent: neither male nor female.

• It develops from the same tissue as the kidneys and adrenal glands.

• Also developing by this time: 2 sets of ducts that will eventually lead to the outside world.▫ Wolffian ducts = male▫ Mullerian ducts =

female

Gonad Differentiation• If SRY is present in

the indifferent gonad at 6 weeks, it gets activated. This in turn activates other genes, and the indifferent gonad is converted to a testes.

• In the absence of SRY, a different set of genes is activated, and the indifferent gonad becomes an ovary.

• The germ cells, which actually become sperm or eggs, migrate into the gonad about this time.

Development of Phenotypic Sex• The cells of the newly formed testes start secreting

the hormone testosterone.▫ Testosterone secretion peaks about week 16, with levels

similar to those found in adult males. After this, the testosterone level drops to about the same level as female fetuses.

▫ The testes also secrete another hormone: Mullerian inhibiting substance (MIS) (aka anti-Mullerian hormone, AMH).

• Another important process in the developing male: during the last trimester of pre-natal life, the testes migrate (“descend”) from the kidney region into the scrotum.▫ Under the control of a third testes hormone: “insulin-like

hormone 3”

• The developing ovary secretes estrogen, which is important after birth, but estrogen from the mother completely swamps it out before birth.

Internal Ducts• In the early embryo, two

duct systems form. After the gonad differentiates into a testis or ovary, one set of ducts develops further while the other set degenerates.

• Testosterone causes the Wolffian ducts to develop into male structures: epididymus, vas deferens, seminal vesicles.▫ In the absence of

testosterone, the Wolffian ducts disappear (except a bit becomes the adrenal glands in both sexes)

• Mullerian inhibiting substance causes the Mulerian ducts to disappear.▫ In the absence of MIS, the

Mullerian ducts develop into the Fallopian tubes, uterus, and upper vagina.

Another Duct Picture

Development of the External Genitalia

• This process is controlled by the presence or absence of dihydrotestosterone (DHT).

• Testosterone gets converted into DHT by the enzyme 5-alpha reductase, which is found in the testes and the skin.

• Both sexes start out with the same structures, which develop along different lines under the influence of testosterone and DHT.

• The default condition in female: in the absence of DHT, the external genital structures develop along female lines.

• DHT also causes hair loss: male pattern baldness. Testosterone is converted to DHT locally. Rogaine works by blocking 5-alpha reductase

External Development• In the absence of DHT, the genital swellings form the labia majora; the genital folds remain unfused and form the labia minora; the genital tubercle forms the clitoris and the urogenital sinus forms the lower part of the vagina.

• With DHT present, the genital swellings migrate and become the scrotum; the urogenital folds enlarge and enclose the penile urethra and become the shaft of the penis; the genital tubercle becomes the glans penis; and the urogenital sinus forms the prostate gland

Androgen Insensitivity

•A mutation in the X-linked androgen receptor gene (AR) causes XY males to become phenotypic females▫Testosterone is produced, but not testosterone

receptors; cells develop as females

•Androgen insensitivity (CAIS) ▫An X-linked genetic trait that causes XY

individuals to develop into phenotypic females

Mutations can cause Sex Phenotypes to Change at Puberty

•Pseudohermaphroditism ▫An autosomal genetic condition that causes

XY individuals to develop the phenotype of females

▫Caused by mutations in several different genes

▫Affected individuals have both male and female structures, but at different times of life

▫At puberty, females change into males

Equalizing the Expression of X Chromosomes in Males and Females

•Human females have one X chromosome inactivated in all somatic cells to balance the expression of X-linked genes in males and females

Dosage Compensation

•Females have two X chromosomes, males have one; yet the amount of gene product is the same

•Dosage compensation ▫A mechanism that regulates the expression

of sex-linked gene products

Barr Bodies and X Inactivation• Lyon hypothesis (proposed by Mary

Lyon) ▫Dosage compensation in mammalian females▫Random inactivation of one X chromosome in

females equalizes the activity of X-linked genes in males and females

• Barr body ▫A densely staining mass in the somatic nuclei

of mammalian females ▫An inactivated X chromosome, tightly coiled

Female Mammals are Actually Mosaics for X Chromosome Expression

• In females, some cells express the mother’s X chromosome and some cells express the father’s X chromosome▫Inactivated chromosome can come from either

mother or father▫Inactivation occurs early in development▫Inactivation is permanent; all descendants of a

particular cell have the same X inactivated▫Genetic regulation (Xic) of which chromosome

is inactivated

Effects of Random X-Chromosome Inactivation

• Random X inactivation can cause twins with identical genotypes to have different phenotypes (also calico cats!)

Fig. 7-20, p. 171

7.8 Sex-Related Phenotypic Effects

•In sex-influenced and sex-limited inheritance, the sex of the individual affects: ▫whether the trait is expressed▫the degree to which the trait is expressed

•This is true for autosomal and sex-linked genes▫Sex hormone levels modify expression of

these genes, giving rise to altered phenotypic ratios

Sex-Influence Traits

•Sex-influenced traits ▫Traits controlled by autosomal genes that

are usually dominant in one sex but recessive in the other sex

A Sex-Influenced Trait

•Pattern baldness ▫Acts like an autosomal dominant trait in males

and an autosomal recessive trait in females

The difference istestosterone

Sex-Limited Traits

• Genes that produce a phenotype in only one sex▫ Example: Precocious puberty in heterozygous males but

not in heterozygous females

• Traits expressed only in females because males die before birth▫ Example: Male-lethal X-linked dominant traits

• Traits expressed only in males▫ Example: Duchenne muscular dystrophy (X-linked

recessive); males do not have offspring and don’t pass their X onto daughters

▫ Result: very rare in females

Imprinting

•One copy of a gene is inactivated, depending on whether it comes from the father or the mother▫Example: NOEY2 gene; paternal copy is

expressed in normal breast and ovarian cells•Imprinting

▫A phenomenon in which expression of a gene depends on whether it is inherited from the mother or the father Chemical modification of DNA (more common) Uniparental disomy (rare)

Thanks