Reproductive Developmental Toxicology DAVID SHUBERT PH D SHUBERT BUFFALO EDU Importance Estimated that 15 of all recognized pregnancies end in spontaneous abortion United States about 2 3 of babies are born with birth defects recognized in the first year 1 in 33 babies born in US has a birth defect Women over the age of 35 years have a higher chance of having a child with Down s syndrome than women who are younger About 8 percent of babies born preterm had a birth defect New York In an average week 4 771 babies born 314 babies born to teen mothers 581 babies born preterm 391 babies are low birth weight 27 babies die before their first birthday Data from the March of Dimes April 2012 Definitions Developmental Toxicology study mechanism pathogenesis and outcome after exposure to agents or conditions that lead to abnormal development Developmental toxin chemical or physical agent can cause adverse developmental outcome Teratogenesis Production of developmental malformation Teratogen drug or other agent that can cause developmental malformation Pathogenesis of Abnormal Development Development is a hierarchical sequence of carefully timed events molecular cellular tissues organ systems Perturbation at any stage may permanently alter development later Development Time at which exposure occurs determines which structures are most susceptible to damage and to what extent the conceptus can combat survive the insult Gestation is generally considered to consist of three periods of development Pre implantation increase in cell number Gastrulation formation of 3 germ layers ectoderm endoderm mesoderm Organogenesis developmental of internal organs Fetal period growth and maturation Mammalian Embryology Overview Mammalian Embryology Overview The Germ Layers Ectoderm Endoderm Epithelium Lens And Cornea Of The Eye Dorsal Root Ganglia Schwann Cells Facial Cartilage Dentin In Teeth Brain Spinal Cord Motor Neurons Retina Posterior Pituitary Pigment Cells Of Skin GI Tract Inner Lining Respiratory Tract Endocrine Glands Liver Pancreas Mesoderm Bones Most Of The Circulatory System Connective Tissues Of The Gut Gastrointestinal Tract Outer Covering Muscles Peritoneum Organ Coverings Reproductive System Urinary System Dermis Critical Periods http www cerebralpalsychildren com CP1 jpg Human Developmental Toxins Radiation Infections Rubella virus Herpes virus Syphilis Maternal metabolic imbalances Alcoholism Folic acid deficiency Prevents with at least 400 mcg day Diabetes Drugs Androgenic compounds Angiotensin converting enzyme inhibitors Tetracycline Retinoids Lead Mercury Pathogenesis of Abnormal Development General kinds of toxin toxicant interactions Receptor ligand interactions Covalent binding Peroxidation of lipids and proteins Interference with sulfhydryl groups Inhibition of protein function Dose Response Curve Maternally Mediated Effects on Development Developmental effects occur secondarily to some effect on the pregnant mother Susceptibility Factors Genetic background Health uncontrolled hypertension diabetes Age Stress physical stress Etc Folic Acid Folic acid is a B vitamin It is used in our bodies to make new cells If a woman has enough folic acid in her body before she is pregnant it can help prevent major birth defects of her baby s brain and spine These birth defects are called neural tube defects or NTDs Anencephaly absence of brain skull scalp Encephalocele sac like protusions of the brain through opening in the skull brain Spina bifida spinal cords sticks out through openings in the bone Historical Compounds Thalidomide History Amelia absence of limbs Phocomelia reduction of the long bones of the limb Use introduced in 1956 as a sedative hypnotic 1998 approved to treat leprosy multiple myeloma and AIDS wasting syndrome Effects amelia phocomelia congential heart disease Result DR Francis Kelsey 1 FDA mission to keep unsafe products off the market 2 development of animal testing requirements for evaluating effects of drugs on pregnancy outcomes Diethylstilbesterol DES Estriol Historical Compound Diethylstillbesterol DES History use synthetic nonsteroidal estrogen widely used from 1940 1970 in the US to prevent miscarriages Effects Risk for adenocarcinoma of the vagina and cervix in off spring Ethanol Fetal alcohol syndrome FAS History 1968 by P Lemoine and colleagues in France and Jones and Smith in 1973 recognized and accepted as a developmental toxin Effects craniofacial dysmorphism malformation of the cranium intrauterine and post natal growth retardation retarded intellectual development spina bifida hydrocephalus fluid on brain Historical Compound Cocaine History local anesthetic and drug of abuse serotonin norepinephrinedopamine reuptake inhibitor Effects decreased birth weight microcephaly Historical Compound Retinoids Accutane History from the time of its introduction the drug was known to have teratogenic potential Use acne Effects malformation of the face limb heart CNV Historical Compound Valproic acid History 1982 146 cases of spina bifida Use anticonvulsant Effects Spina bifida Methods Whole rodent embryo culture techniques Whole animals Litter collection weights gross exam Soft tissue examination Skeletal exam TESTING MATERNAL AMINSTRATION DURING IN PHONE PICTURE Reproductive Toxicology Reproductive Toxicology Reproductive failure Infertility 10 15 of couples Spontaneous abortion 10 20 of pregnancies Limitations Less attention Adequate sample size Ethical limitations on human studies Data animal What is a Reproductive Toxin Any agent that adversely effects any male or female reproductive structure or function impairment of the ability to conceive and carry to term Manifestations in Humans Reduced Fertility Impotence Menstrual Disorders Spontaneous Abortions Growth Retardation Developmental Effects Premature Reproductive Senescence Genetic Diseases Others Direct Effects Gonads Endocrine competition for receptors or inhibiting steroidogenesis Non endocrine dates back to Roman times lead played a role in increased incidence of still births Indirect Effects Hypothalamic pituitary gonad axis Accessory organ structure and function Behavior Endocrine disruption Testis Anatomy Blood Testis Barrier Blood testis barrier Consist of Sertoli cells and peritubular cells Myofibroblasts and basement membrane Two important functions Prevents spermatozoa from passing into systemic and lymphatic circulation Provides controlled microenvironment for sperm production and development Toxins