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irregularities, ovarian cycle leads to impaired, Fertility
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female||non-adjacent||Moderate||Allie Always (send email)||Open for citation & comment||EAGMST Under Review|
|Inhibition of ALDH1A (RALDH) causing reduced all-trans retinoic acid levels leading to impaired fertility, females||adjacent||High||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
The ovarian cycle irregularities impact on reproductive capacity of the females that may result in impaired fertility:
1. Irregular cycles may reflect impaired ovulation. Extended vaginal estrus usually indicates that the female cannot spontaneously achieve the ovulatory surge of LH (Huang and Meites, 1975). The persistence of regular vaginal cycles after treatment does not necessarily indicate that ovulation occurred, because luteal tissue may form in follicles that have not ruptured. However, that effect should be reflected in reduced fertility. Conversely, subtle alterations of cyclicity can occur at doses below those that alter fertility (Gray et al., 1989).
2. Persistent or constant vaginal cornification (or vaginal estrus) may result from one or several effects. Typically, in the adult, if the vaginal epithelium becomes cornified and remains so in response to toxicant exposure, it is the result of the agent’s estrogenic properties (i.e., DES or methoxychlor), or the ability of the agent to block ovulation. In the latter case, the follicle persists and endogenous estrogen levels bring about the persistent vaginal cornification. Histologically, the ovaries in persistent estrus will be atrophied following exposure to estrogenic substances. In contrast, the ovaries of females in which ovulation has been blocked because of altered gonadotropin secretion will contain several large follicles and no corpora lutea. Females in constant estrus may be sexually receptive regardless of the mechanism responsible for this altered ovarian condition. However, if ovulation has been blocked by the treatment, an LH surge may be induced by mating (Brown-Grant et al., 1973; Smith, E.R. and Davidson, 1974) and a pregnancy or pseudopregnancy may ensue. The fertility of such matings is reduced (Cooper et al., 1994).
3. Significant delays in ovulation can result in increased embryonic abnormalities and pregnancy loss (Fugo and Butcher, 1966; Cooper et al., 1994).
4. Persistent diestrus indicates temporary or permanent cessation of follicular development and ovulation, and thus at least temporary infertility.
5. Prolonged vaginal diestrus, or anestrus, may be indicative of agents (e.g., polyaromatic hydrocarbons) that interfere with follicular development or deplete the pool of primordial follicles (Mattison and Nightingale, 1980) or agents such as atrazine that interrupt gonadotropin support of the ovary (Cooper et al., 1996). Pseudopregnancy is another altered endocrine state reflected by persistent diestrus. The ovaries of anestrous females are atrophic, with few primary follicles and an unstimulated uterus (Huang and Meites, 1975). Serum estradiol and progesterone are abnormally low.
6. Lengthening of the cycle may be a result of increased duration of either estrus or diestrus.
Evidence Collection Strategy
Evidence Supporting this KER
In females, normal reproductive function involves the appropriate interaction of central nervous system, anterior pituitary, oviducts, uterus, cervix and ovaries. During the reproductive years the ovary is the central organ in this axis. The functional unit within the ovary is the follicle which is composed of theca; granulosa cells and the oocyte. The somatic compartment synthesizes and secrets hormones (steroids and growth factors) necessary for the orchestration of the inter-relationship between the other parts of the reproductive tract and the central nervous system. Oestrus cycle is under strict hormonal control, therefore perturbations of hormonal balance lead to perturbations of normal cyclicity (change in number of cycles or duration of each phase) and/or ovulation problems leading to impaired female reproductive function. However, there are other mechanisms that might result in impaired fertility (e.g cellular maturation in ovary).
Uncertainties and Inconsistencies
Chemicals may be found to interfere with reproductive function in the female. This interference is commonly expressed as a change in normal morphology of the reproductive tract or a disturbance in the duration of particular phases of the estrous cycle. However, menstrual cyclicity is affected by many parameters such as age, nutritional status, stress, exercise level, certain drugs, and the use of contraceptive measures that alter endocrine feedback. In nonpregnant females, repetitive occurrence of the four stages of the estrous cycle at regular, normal intervals suggests that neuroendocrine control of the cycle and ovarian responses to that control are normal. Even normal, control animals can show irregular cycles. However, a significant alteration compared with controls in the interval between occurrence of estrus for a treatment group is cause for concern. Generally, the cycle will be lengthened or the animals will become acyclic. Therefore changes in cyclicity should be interpreted with caution and not judged adverse without a comprehensive consideration of additional relevant endpoints in a weight-of-evidence approach.
Two generation studies by Tyl et al with Butyl benzyl phthalate (BBP) did not observe effects in F0 females on any parameters of estrous cycling, mating, or gestation. However, F1 females carrying F2 litters at and reduced number of total and live pups/litter at birth, with no effects on pre- or postnatal survival (Tyl et al., 2004).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
In many instances, human female reproductive toxicity of an agent is suspected based on studies performed in experimental animals. The neuroendocrinology, steroid biochemistry, and other physiologic events in the females of most small experimental species often used (mouse, rat, hamster) are similar in their susceptibility to disruption by toxicants (Massaro, 1997).
Although the assessment of the human ovarian cycle may have a variety of biomarkers distinct from those in rats, many of the underlying endocrine mechanisms associated with successful follicular development, ovulation, pregnancy, and parturition are homologous between the two (for review see (Bretveld et al., 2006). For this reason, a toxicant-induced perturbation of ovarian cycles in female rats suggest that a compound may function as a reproductive toxicant in human females.
- environmental air pollution (Mohallem et al., 2005)
- phthalates (DEHP)
- abortion rate of 100% in F0 dams in the 500-mg/kg/day was observed, in F1 females found that the total number of F2 embryos (exposed to DEHP only as germ cells) was not impaired. However, in the 0.05- and 5-mg DEHP groups, 28% and 29%, respectively, of the blastocysts were degenerated, compared with 8% of controls (Schmidt et al., 2012).
- Lamb et al. studied fertility effects of DEHP in mice (both sexes) and found that DEHP caused dose-dependent decreases in fertility. DBP exposure resulted in a reduction in the numbers of litters per pair and of live pups per litter and in the proportion of pups born alive at the 1.0% amount, but not at lower dose levels. A crossover mating trial demonstrated that female mice, but not males, were affected by DBP, as shown by significant decreases in the percentage of fertile pairs, the number of live pups per litter, the proportion of pups born alive, and live pup weight. DHP in the diet resulted in dose-related adverse effects on the numbers of litters per pair and of live pups per litter and proportion of pups born alive at 0.3, 0.6, and 1.2% DHP in the diet. A crossover mating study demonstrated that both sexes were affected. DEHP (at 0.1 and 0.3%) caused dose-dependent decreases in fertility and in the number and the proportion of pups born alive. A crossover mating trial showed that both sexes were affected by exposure to DEHP. These data demonstrate the ability of the continuous breeding protocol to discriminate the qualitative and quantitative reproductive effects of the more and less active congeners as well as the large differences in reproductive toxicity attributable to subtle changes in the alkyl substitution of phthalate esters (Lamb et al., 1987).
Rat phthalates (DEHP)
- female rats exposed to a high dose of DEHP (3,000 mg/kg/day) had irregular estrous cycles and a slight decline in pregnancy rate (Takai et al., 2009). At 1,000 mg/kg bw/day over a period of 4 weeks did not disturb female fertility or early embryo development.
- There was significant evidence that 5, 15, 50, and 400 mg /kg/day females differed from the control females in the relative amount of time spent in oestrous stages, however no changes were revealed in the number of females with regular cycles, cycle length, number of cycles, and in number of cycling females across the dose groups as compared to the control females The litter size (number of live pups) produced by the P0 generation was significantly reduced in the 400 mg/kg/day dose group (Blystone et al., 2010).
Studies showing a correlation between decreased fertility and;
- professional activity (Olsen, 1994)
- phthalates (DEHP) In occupationally exposed women to high concentration of phthalates exhibit hypoestrogenic anovulary cycles and was associated with decreased pregnancy rate and higher miscarriage rates (Aldyreva,M.V.,Klimove,T.S.,Iziumova,A.S.,Timofeevskaia,L.A., 1975).
- smoking (Hull, North, Taylor, Farrow, & Ford, 2000)
- the use of certain drugs or radiation exposure (Dobson & Felton, 1983)
For the taxonomic applicability see also the Table 1.
Aldyreva,M.V.,Klimove,T.S.,Iziumova,A.S.,Timofeevskaia,L.A. (1975). The effect of phthalate plasticizers on the generative function. Gig.Tr.Prof.Zabol., (19), 25–29.
Bhattacharya, P., & Keating, A. F. (2012). Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity. Toxicology and Applied Pharmacology, 261(3), 227–35. doi:10.1016/j.taap.2012.04.009
Blasberg, M. E., Langan, C. J., & Clark, A. S. (1997). The effects of 17 alpha-methyltestosterone, methandrostenolone, and nandrolone decanoate on the rat estrous cycle. Physiology & Behavior, 61(2), 265–72.
Blystone, C. R., Kissling, G. E., Bishop, J. B., Chapin, R. E., Wolfe, G. W., & Foster, P. M. D. (2010). Determination of the di-(2-ethylhexyl) phthalate NOAEL for reproductive development in the rat: importance of the retention of extra animals to adulthood. Toxicological Sciences : An Official Journal of the Society of Toxicology, 116(2), 640–6. doi:10.1093/toxsci/kfq147
Bretveld, R. W., Thomas, C. M. G., Scheepers, P. T. J., Zielhuis, G. A., & Roeleveld, N. (2006). Pesticide exposure: the hormonal function of the female reproductive system disrupted? Reproductive Biology and Endocrinology : RB&E, 4(1), 30. doi:10.1186/1477-7827-4-30
Chao, H.-R., Wang, S.-L., Lin, L.-Y., Lee, W.-J., & Päpke, O. (2007). Placental transfer of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in Taiwanese mothers in relation to menstrual cycle characteristics. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association, 45(2), 259–65. doi:10.1016/j.fct.2006.07.032
Clark, A. S., Blasberg, M. E., & Brandling-Bennett, E. M. (1998). Stanozolol, oxymetholone, and testosterone cypionate effects on the rat estrous cycle. Physiology & Behavior, 63(2), 287–95.
Cooper, R. L., and Goldman, J. M. (1999). Vaginal cytology. In An Evaluation and Interpretation of Reproductive Endpoints for Human Health Risk Assessment. Washington. Davis, B. J., Maronpot, R. R., & Heindel, J. J. (1994). Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats. Toxicology and Applied Pharmacology, 128(2), 216–23. doi:10.1006/taap.1994.1200
Dobson, R. L., & Felton, J. S. (1983). Female germ cell loss from radiation and chemical exposures. American Journal of Industrial Medicine, 4(1-2), 175–90.
Gilmore, D. P., & McDonald, P. G. (1969). Induction of prolonged diestrus in the rat by a low level of estrogen. Endocrinology, 85(5), 946–8. doi:10.1210/endo-85-5-946 Herreros, M. A., Encinas, T., Torres-Rovira, L., Garcia-Fernandez, R. A., Flores, J. M., Ros, J. M., & Gonzalez-Bulnes, A. (2013). Exposure to the endocrine disruptor di(2-ethylhexyl)phthalate affects female reproductive features by altering pulsatile LH secretion. Environmental Toxicology and Pharmacology, 36(3), 1141–9. doi:10.1016/j.etap.2013.09.020
Herreros, M. A., Gonzalez-Bulnes, A., Iñigo-Nuñez, S., Contreras-Solis, I., Ros, J. M., & Encinas, T. (2013). Toxicokinetics of di(2-ethylhexyl) phthalate (DEHP) and its effects on luteal function in sheep. Reproductive Biology, 13(1), 66–74. doi:10.1016/j.repbio.2013.01.177
Hull, M. G., North, K., Taylor, H., Farrow, A., & Ford, W. C. (2000). Delayed conception and active and passive smoking. The Avon Longitudinal Study of Pregnancy and Childhood Study Team. Fertility and Sterility, 74(4), 725–33.
Lamb, J. C., Chapin, R. E., Teague, J., Lawton, A. D., & Reel, J. R. (1987). Reproductive effects of four phthalic acid esters in the mouse. Toxicology and Applied Pharmacology, 88(2), 255–69.
Laws, S. C. (2000). Estrogenic Activity of Octylphenol, Nonylphenol, Bisphenol A and Methoxychlor in Rats. Toxicological Sciences, 54(1), 154–167. doi:10.1093/toxsci/54.1.154
Li, X., Johnson, D. C., & Rozman, K. K. (1995). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on estrous cyclicity and ovulation in female Sprague-Dawley rats. Toxicology Letters, 78(3), 219–22.
Massaro, E. J. (Ed.). (1997). Handbook of Human Toxicology, Volume 236. Taylor & Francis.
Meerts, I. A. T. M., Hoving, S., van den Berg, J. H. J., Weijers, B. M., Swarts, H. J., van der Beek, E. M., … Brouwer, A. (2004). Effects of in utero exposure to 4-hydroxy-2,3,3’,4',5-pentachlorobiphenyl (4-OH-CB107) on developmental landmarks, steroid hormone levels, and female estrous cyclicity in rats. Toxicological Sciences : An Official Journal of the Society of Toxicology, 82(1), 259–67. doi:10.1093/toxsci/kfh251
Mohallem, S. V., de Araújo Lobo, D. J., Pesquero, C. R., Assunção, J. V., de Andre, P. A., Saldiva, P. H. N., & Dolhnikoff, M. (2005). Decreased fertility in mice exposed to environmental air pollution in the city of Sao Paulo. Environmental Research, 98(2), 196–202. doi:10.1016/j.envres.2004.08.007
NTP. (2005). Multigenerational Reproductive Assessment by Continuous Breeding when Diethylhexylphthalate (CAS 117-81-7).
OECD. (2008). No 43: Guidance document on mammalian reproductive toxicity testing and assessment.
Ogata, R., Omura, M., Shimasaki, Y., Kubo, K., Oshima, Y., Aou, S., & Inoue, N. (2001). Two-generation reproductive toxicity study of tributyltin chloride in female rats. Journal of Toxicology and Environmental Health. Part A, 63(2), 127–44. doi:10.1080/15287390151126469
Olsen, J. (1994). Is human fecundity declining--and does occupational exposures play a role in such a decline if it exists? Scandinavian Journal of Work, Environment & Health, 20 Spec No, 72–7.
Schilling, K., Deckardt. K., Gembardt, Chr., and Hildebrand, B. (1999). Di-2-ethylhexyl phthalate – two-generation reproduction toxicity range-finding study in Wistar rats. Continuos dietary administration.
Schmidt, J.-S., Schaedlich, K., Fiandanese, N., Pocar, P., & Fischer, B. (2012). Effects of di(2-ethylhexyl) phthalate (DEHP) on female fertility and adipogenesis in C3H/N mice. Environmental Health Perspectives, 120(8), 1123–9. doi:10.1289/ehp.1104016
Takai, R., Hayashi, S., Kiyokawa, J., Iwata, Y., Matsuo, S., Suzuki, M., … Deki, T. (2009). Collaborative work on evaluation of ovarian toxicity. 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats. The Journal of Toxicological Sciences, 34 Suppl 1(I), SP111–9.
Tyl, R. W., Myers, C. B., Marr, M. C., Fail, P. a, Seely, J. C., Brine, D. R., … Butala, J. H. (2004). Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. Reproductive Toxicology (Elmsford, N.Y.), 18(2), 241–64. doi:10.1016/j.reprotox.2003.10.006
Wolf, C., Lambright, C., Mann, P., Price, M., Cooper, R. L., Ostby, J., & Gray, L. E. (1999). Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p’-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differen. Toxicology and Industrial Health, 15(1-2), 94–118. doi:10.1177/074823379901500109