Reproductive Toxicology Flashcards
final exam
what is the reproductive cycle?
- gamete production and release
- fertilization
- zygote transport
- implantation
- embryogenesis
- fetal development
- parturition
- Lactation and postnatal development (rest period for humans)
- growth and development
- sexual maturation
what are the different testing phases for a reproductive toxicant? what do each contain?
- Fertility Segment (includes gamete production and release, fertilization, zygote transport, implantation)
- Embryotoxicity, Teratogenicity (includes embryogenesis, fetal development, parturition)
- Pre- postnatal toxicity (includes Lactation and postnatal development, growth and development, sexual maturation)
explain the fetal prepubertal female germ cell development
- all oocytes are made during gestation (many actually die before birth)
- germ cell becomes primordial follicle (after a few steps), where they enter prophase
- but, it then stays dormant until puberty
explain the pre-ovulatory phase of female germ cell development.
starts when puberty begins:
- becomes a primary follicle
- then through action of FSH/LH, becomes early secondary follicle (and can then secrete androgens and estrogens)
- becomes advanced secondary follicle
- 2ndary oocyte with polar body (start of meiosis II)
explain the ovulatory phase of female germ cell development.
- becomes ovulatory follicle:
- if fertilized, becomes corpus luteum
- if not, corpus albicans
explain the female hormone signaling pathway starting from the CNS.
- CNS signals to hypothalamus
- hypothalamus releases GnRH, which signals anterior pituitary
- releases LH (signals to Theca cells), FSH (signals to granulosa cells), and prolactin (signals corpus luteum)
- granulosa cell makes estradiol and corpus luteum, progesterone.
- a) both signal to vagina, cervix, uterus, and oviduct
- b) also they both negative feedback on hypothalamus and anterior pituitary.
explain the menstrual cycle
increase of FSH as follicle matures, until there is a surge (means that there is a surge of estradiol), and around the same time, there is the LH surge, which marks the release of the egg. Now the corpus luteum is developing and releasing high amounts of progesterone. Eventually, it dies, which decreases the progesterone levels (then menses occurs)
potential useful targets for female reproductive toxicants (12).
- body weight
- ovary
- hypothalamus
- pituitary
- endocrine
- oviduct
- uterus
- cervix
- vulva
- vagina
- fertility
- IVF
what are some things we can measure/look at in the ovary for toxicants? (9)
- organ weight (helpful but there is a natural decline so hard to know if the change is relevant)
- histology
- number of oocytes
- rate of follicular atresia
- follicular steroidogenesis (look at progression of folllicles)
- follicular maturation
- oocyte maturation
- ovulation
- luteal function
what are some chemicals linked to adverse reproductive outcomes in females? (8)
- phytoestrogen: natural products that have estrogenic activity
- heavy metals (cooper, cadmium, lead)
- solvents (benzene, chloroform)
- industrial chemicals
- pesticides
- cigarette smoke (major effects on fertility)
- vaping (less evidence but clearly an effect on follicles to grow normally)
- chemotherapeutic agents: granulosa cells are those that grow and secrete estrogen, these will inhibit cell division, which prevents the granulosa cells from dividing, which will decreases estrogen (and prevent ovulation – infertility)
- chem agents: prednisone, 5-FU, cyclophosphamide, …
what are the feedback mechanisms operating in the male?
- LH signals to Leydig cells, that makes testosterone, and it can signal back to anterior pituitary and hypothalamus
- FSH signals to Sertoli cells, that mike inhibin, that signals back to anterior pituitary
where are Leydig cells located?
in between seminiferous tubules, so high testosterone concentration there
how long is spermatogenesis in humans? what about other species?
- 64 days
- varies: rat is between 48-52 and rabbit is 49 for example
potential target sites for male reproductibe toxicants
- liver, nutrition, testicular vasculature, pituitary, CNS, epididymal maturation, fertilization, pineal
- sperm motility, chromatin integrity
- semen
- accessory glands
which part of the germ line cycle does cyclophosphamide affect?
when it loses some of its repair mechanisms in the beginning
which part of the germ cell cycle does chlorambucil affect?
the condensing of the chromatin
which part of the germ cell cycle does acrylamide affect?
affects chromatin, that it cannot impact at fertilization (already condensed here)
which part of the germ cell cycle do x-rays affect?
the very first step
Cellular Sites of Action of Excess Heavy Metals on the Male Reproductive System
most affect the germ cells, Leydig cell, and Sertoli cells either directly or indirectly
what is looked at in semen analysis?
- volume
- total number of sperm
- sperm concentration
- total motility
- progressive motility
- vitality
- sperm morphology
epididymal function (that may be targets for toxicants)
- absorption
- secretion
- transport
- maturation
- storage
how does the sperm chromatin look like (how is it packaged and how does it compare to other somatic cells)?
- from somatic cells, there is histone displacement, replaced temporarily by transition proteins, and eventually protamines
- it is 6x more compact than somatic cells
what are chromatic biomarkers for sperm quality?
- Sperm decondensation
- Breaks and cross-links and integrity of chromatin
- Chromatin template function
- Chromatin structure
- Chromatin epigenome
what is the limitation and value of using fertility as a male reproductive endpoint?
- limitation: insensitive
- value: integrates all reproductive function
what is the limitation and value of using Testicular histology as a male reproductive endpoint?
- limitation: subjective, not quantitative
- value: information on target cells
what is the limitation and value of using Testis weight as a male reproductive endpoint?
- limitation: less sensitive than sperm count, affected by edema
- value: rapid, quantitative
what is the limitation and value of using gene expression as a male reproductive endpoint?
limitation: overly sensitive, hard to assess what matters
- value: comprehensive
how is the general trend sperm concentration over the years?
it is declining (at rate of about 1%/yr)
what are the conditions seen with testicular dysgenesis syndrome?
- decrease sperm quality
- testicular cancer
- hypospadias
- testicular maldescent
how does testicular dysgenesis cause the related conditions?
- it disturbs Sertoli function and decreases Leydig function
- leads to decrease germ cell differentiation (and therefore decrease sperm quality and cancer)
- also, decreases androgens, which leads to hypospadias and testicular maldescent
how does cyclophosphamide affect sperm concentration, production, and morphology?
- lower concentration with higher abnormal sperm
- abnormal forms (abnormal tail growth) and loss of cytoplasmic droplet
what did the FISH aneuploidy assay show in relation to sperm quality with CPA?
increase sperm aneuploid with CPA treatment, showing decreases integrity of the chromatin
what did the Comet assay show in relation to sperm quality with CPA?
increased DNA damage
How does Paternal CPA exposure impact on early embryos?
- increases pronuclear formation in both male and female
- more abnormal histone acetylation patterns
Core histone acetylation is correlated with what?
activation of zygotic genome in early embryonic development
Are the effects of paternal CPA exposure on progeny outcome heritable?
yes since paternal CPA affects F2 generation and increased apoptotic germ cells as far as F4 when F0 treated with vinclozolin
