The document discusses the effects of chemicals on the reproductive system. It describes how chemicals can cause morphological disruptions like reproductive tract malformations and hermaphroditism. Chemicals may also cause endocrine disruption through feminization or altering hormone levels. Specific chemicals that can cause these issues are discussed like DDT, BPA, steroids, and diethylstilbestrol. The mechanisms of endocrine disruption are explained. Concerns about declining male fertility and anti-androgen compounds in plastics are covered. Impacts on germ cells and during development are summarized. Cytotoxicity is discussed as a mechanism for defects, death, and malformations.

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