Table 1.

Endocrine Disrupting Chemicals (EDCs): Mechanism, Source and Effects on Ovarian Function.

Compound/Potential Targets/Source	Does of exposure/species	Main Effects	References
Bisphenol-A (BPA) ESR Plastics industry	1, 10 and 100 μg/ml in vitro, mice cultured antral follicles	Inhibits follicular growth, induces atresia, and inhibits steroidogenesis and expression of steroidogenic enzymes in antral follicles from adult FVB, C57BL/6, and CD-1mice.	127
	500 μg per pup PND1-10 daily rat sc injection	Alters the hypothalamic-pituitary-gonadal axis in female Sprague-Dawley rats and induces development of follicular cysts in the ovary, leading to infertility. Increases testosterone and estradiol levels and decreases progesterone.	51
	20 μg/kg PND7-14 daily mice hypodermic injection	Inhibits methylation of imprinted genes during oogenesis via the ER signaling pathway, affecting the development of oocytes and folliculogenesis.	106
	50 mg or 50 μg/kg PC14-E9.5 or PC14-E12.5 daily mice diet	Disturbances in tissue-specific DNA methylation and gene expression in imprinted loci, leading to abnormalities in placental development.	78
	0.5 mg/kg E30-90 daily ewe sc injection	Decreases miRNAs targeting SOX family genes (sex determination and embryonic development), kit ligand (follicular assembly establishment of reserve pool of primordial follicles) and insulin related genes (follicular development and steroid production).	121
	150 μg/pup PND 1-5 daily mice sc injection	Induces polyovular follicles or multi-oocyte follicles (having more than one oocyte in a follicle).	47
	0.05 and 20 mg/kg PND 1, 3, 5, and 7 rats sc injection	Reduces primordial follicles and increased growing follicles. Primordial and recruited showed increased ERβ and proliferation in recruited follicles.	15
	50 ug/kg and 50 mg/kg PND 1 rats sc injection	Produces early pubertal onset. Large antral-like follicles and follicular cysts, lower numbers of corpora lutea and acyclicity.	54
	2, 20, and 200 μg/kg E1-19 daily mice orally	Dose-dependent, brain region-specific and sex-specific effects of BPA on gene expression of ERs, ERα, ERβ and estrogen-related receptor-γ that varied across brain regions, and changes DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus. Changes in behavior: hyperactive phenotype in males and hypoactive phenotype in females.	104
	4.4, 44, and 440 uM in vitro cultured antral follicles PND 32 mice	BPA (440 μM) inhibits follicle growth. BPA (44 and 440 uM) inhibit progesterone, dehydroepiandrosterone, androstenedione, estrone, testosterone, and estradiol production.	115
	3 nM and 300 nM in vitro cultured Metaphase II oocytes mice	Exposure to 3 nM BPA was associated with slightly accelerated follicle development, increased allele methylation errors in differentially methylated regions of maternally imprinted genes, and decreased histone H3K9 trimethylation and interkinetochore distance.	124
	10 and 100 ug per pup PND1-5 daily mice sc injection	Blocks cyst breakdown and rise polyovular follicles and primordial follicles.	46
Methoxychlor (MXC) ESR1 ESR2 AR Pesticide	50, 100, or 500 mg/kg PND3-10 daily rats sc injection	Inhibits early ovarian development and stimulates AMH production directly in the ovary.	17
	100 mg/kg E19 to PND7 daily rats ip or sc injection	Induces hypermethylation of the promoter region of Esr2 in the adult ovary with a decrease in the ESR2 protein and induces Dnmt3b expression in the ovary.	101
	0.5 or 1mg per pup PND 1-14 daily mice ip injection	Produces ovarian atrophy, relative ovarian weight loss, depletion of corpora lutea and follicular cysts in 0.5 mg doses	55
	20 μg/kg and 100 mg/kg E19 to PND7 daily rats ip or sc injection	Hypermethylation and/or downregulation in: regulatory subunit p85 of phosphoinositide-3-kinase, insulin-like growth factor-1 receptor, Harvey rat sarcoma viral oncogene, insulin receptor, and FOXO3 in the ovary.	102
	20 μg/kg and 100 mg/kg E19 to PND7 daily rats ip or sc injection	Reduces ovulation and induces early puberty, irregular cyclicity, sub-fertility, and premature reproductive aging.	52
Di(2-ethylhexyl) phthalate (DEHP) ESR Androgen production Plastic Industry medical devices building products containing polyvinyl chloride	20 and 40 μg/kg PND7-14 daily mice hypodermic injection	Decreases number of the primordial follicles at pubertal and adult age. Decreases methylation of maternal imprinted genes Igf2 and Peg3 in oocytes, which leads to abnormalities in oocyte and embryo development.	50
Genistein ESR Phytoestrogen (soy)	1 nM to 100 uM in vitro cultured ovaries for 7 days PND1 mice	Impairs formation of primordial follicular pool in the ovary.	42
	10 and 100 μg/pup PND1-5 daily mice sc injection	Increases number of multi-oocyte follicles.	48
Estradiol valerate (EV) and Estradiol Benzoate (EB) ESR Synthetic estradiol	10 mg/kg PND1, 7 and 14 rats sc injection	Reduces follicular growth and maturation in the ovary, decreases steroidogenesis, disrupts estrous cyclicity, and impairs reproductive performance.	53
	5 mg/kg PND 1-14 daily mice ip injection	Induces multi-oocyte follicles in adult ovaries.	42
	10 μg/kg PN1-34 day rats sc injection	Advances vaginal opening, and induces multi-oocyte follicles in the ovary.	49
	0,1 mg per pup PND1 sc injection	Increased ovarian expression of nerve growth factor (Ngfb) and p75 low-affinity neurotrophic receptor (Ngfr) mRNAs. Early vaginal opening, disrupted cyclicity, appearance of follicular cyst, absence of corpus luteum, infertility and reduced number of primordial follicles	16
	25 ug per pup PND 1 rats sc injection	Early pubertal onset. Ovaries undersized and absence of folliculogenesis. Absense of sexual receptivity after ovariectomy and hormone replacement.	54
Diethylstilbestrol (DES) ESR Synthetic estrogen	0, 0.75, 1.25, 2.5, or 25ug per pup PND1-5 daily Rats sc injection	Dose-dependent increase in miR-29a, miR-29b, and miR-29c expression, this resulted in a decrease in DNMT1, DNMT3a, and DNMT3b expression in testes	105
	5 μg/kg PND 1-14 daily lambs sc injection	Decline in the stock of primordial follicles, increase in number of multi-oocyte follicles and increase in the number of antral atretic follicles	14
	0.2 and 20 ug/kg PND 1,3,5 and 7 rats sc injection	Produce a decrease in primordial follicles and increased growing follicles. Increase the incidences of multi-oocyte follicles.	15
	1 ug per pup PND1-5 daily mice sc injection	Produces a higher incidence in polyovular follicles and the oocytes from polyovular follicles have a smaller capacity for fertilization.	44
	3 ug per pup PND1 and 2 mice sc injection	Induces appearance of polyovular follicles.	45
	10 and 100 ug per pup PND1-5 daily mice sc injection	Blocks the cyst breakdown and rises polyovular follicles and primordial follicles.	46

AMH, anti-Mullerian hormone; E, embryonic day; PND, postnatal day; PC, pre-coital day.