Presentation given by Isha Ruhela

1.  Topic –Reproductive
Toxicology
Presented By:-
Isha Ruhela (M. Pharm ІΙnd sem.)

2.  Effects of chemicals on the reproductive and
neuroendocrine systems
› the embryo, fetus, neonate and prepubertal
mammal.

3.  Morphology Disruption
› Reproductive tract malformation :-
Development abnormalities of the reproductive system
represent some of the most fascinating disorders.
A wide variety of malformation can occur when this system is
disrupted.
› Hermaphrodite :-
In biology a Hermaphrodite is an organism that has
reproductive organs normally associated with both male and
female.

4.  Endocrine Disruption:-
Endocrine disrupter are chemicals that can interfere with endocrine (or hormone)
system at certain doses.
› Feminization :-
In biology Feminization is the development in an organism of physical characteristics
that are usually unique to the female of the species.
This may represent a normal developmental process, contributing to sexual
differentiation.
Feminization can also be induced by environmental factors.
› Altered circulating hormones

5.  Dichlorodiphenyltrichloroethane
› DDT
› Pesticide
 Bisphenol A
› BPA
› Plastics
› Found in polycarbonate

6.  Steroids –
affect feed back control
 Alkylating agent –
affect spermatogenesis
 Tranquillisers –
affect sexual performance

7.  Ethanol-
Affects puberty/cycling by activity on ovary
/pitutary feed back.
 Estrogens/progesterone-
Affect gamete transport.
 Prostaglandins-
Affect uterine environment

8.  Aminoglutethimide-
Affect steroidogenic enzymes
 Tranquillisers-
Affect maternal behaviour/lactation

9.  Synthetic estroegn
› Developed in 1938
› Prescribed to prevent miscarriages/premature
births (1938-1971)
› 5-10 million exposed
 DES Daughters
› Reproductive tract malformation
› Cancer ( breast and cervical)

10.  Several modes of disruption
› Mimic
 Bisphenol A
› Block
 Flutamide
› Metabolize
 Dexamethasone

11.  Similar
affinity
 Activate
pathway
 No
regulation
 Changes in
hormone levels

12.  Bind to receptor
 Compete with hormone
 Block feedback
 Changes in hormone level

13.  Up-regulation of hepatic and renal clearance
› Dexamethasone
 Up-regulates CYP 3A
 Testosterone to 6β- hydroxytesterone
› Polybrominated diphenyl ether (PBDE)
 Increased hepatic enzyme activity

14.  Decline in male fertility (101 studies in 28
countries)
› 113 million sperm/ml in 1938
› 66 million sperm/ml in 1991
› 1.5% / year decline in the US

15.  Anti-androgen compounds
 Make plastics flexible
› Children’s toys
› Medical equipment
› Enteric coating of pharmaceuticals
 Malformation of reproductive tissue
 Multinucleated germ cells
 Decreased Sperm Count

16.  Primary support for germ cells
› Paracrine
 Anti-Mullerican Hormone
 Follicle Stimulating Hormone
› Structural
 Tight Junctions
 Immune protection

17.  In Utero
› Decreased Anti-Mullerian Hormone
› Germ cell death
› Retracted cytoplasic processes
 Pre-Pubertal
› Disruption of tight junction proteins
 Vimentin
 Connexin 43

18.  Cytotoxicity can lead to Death, Malformation
and Growth retardation
 Focal or diffuse cell death results in focal or
diffuse lesions
 Inflammatory response to necrosis is unlikely to occur
until the later half of gestation
 Before this time the immune system is still immature.
 Plasticity of the early embryo allows for
compensatory growth after nonlethal exposure
 Attempts at repair often follows which ends in
congenital anomalies—deformations
 DEFORMATIONS exemplified by intestinal atresia as a
result of fibrosis following ischaemic bowel injury
Embryonic Faetal Death

19.  Embryonic death--
 Approximately 50-70% of all conceptuses are lost during
the first 3 weeks of pregnancy
 By the end of pregnancy 78% will die due to severe
morphological abnormalities
 Ten times more malformed foetuses are born dead than
alive
 Chromosomal anomalies are apparent in 60% of abortuses
at less than 12 weeks of gestation
 Terathanasia--
 Riddance of dead or deformed nonviable embryos and
fetuses
 Mortality does not stop at birth--
 Human babies (8%) with major malformations die during
the neonatal period and early childhood
Mechanism of Defect Formation

20. Cytotoxicity is a mechanism of defect formation
› The most susceptible cell populations are those with high
proliferative rate and those beginning to differentiate
› DNA sensitivity is due to genome exposure and is most likely to be
damaged by xenobiotic injury
› Correlation between incidence of embryonic death and cytotocity is
not always apparent
 Because cytotoxic effect may be counterbalanced by embryonic
regeneration
› Eg., excessive cell death has a dramatic effect on limb
development–
 May lead to too few cells with a consequent limb reduction eg.
cyclophosphamide exposure.
 May lead to limb defect (thalidomide) because it affects mesonephric
mesenchyme which is the inducer of limb tissue hormone
Cell death

21.  Cell death (PCD) is needed for–
 Separation of digits
 Limiting size of digits
 Decreasing superfluous neurons
 Degeneration of primitive structures
 PCD may be induced by lysosomal activity or
altered nuclear activity through local, hormonal
or chemical messages
 Eg., Apical ectodermal maintenance factor, released by
necrotic mesodermal cells may cause polydactyly in
offsprings
Reduced Proliferative Rate