Several xenobiotic chemicals are known to play a role in destroying the primordial and pre-antral follicles with resultant chemical-induced damage to the oocytes. A recent review has reported that environmental, pharmaceutical, and occupational chemical exposures can lead to premature ovarian failure, amenorrhea, and infertility.

Connie J Mark-Kappeler from the Department of Physiology, University of Arizona, USA, and coworkers, evaluated the impact of xenobiotic chemicals on the reproductive health of women and noted the following findings that have been published in the Biology of Reproduction:

• Environmental and genetic factors determine the rate at which the primordial follicles are destroyed; certain toxins can hasten this destruction.
• Chemotherapeutic agents, such as cyclophosphamide and cisplatin, as well as ionizing radiation lead to loss of ovarian function in an irreversible manner
  • The effect depends on the dosage and age of the patient.
  • The reactivity and type of agent used also influence the outcome, with bifunctional alkylating drugs noted to cause DNA damage
• Complete body irradiation or radiation therapy to the abdominal/pelvic region is more likely associated with loss of menstrual cyclicity and/or fertility. A fractionated radiation protocol is found to be safer compared to a single higher dosage.
• Cigarette smoking is related to an earlier onset of menopause (of 1-4 years); polycyclic aromatic hydrocarbons/smoke components can result in the depletion of follicles.
• Occupational exposure to various chemicals is also related to damage to the ovaries.
  • 2-bromopropane has been implicated with infertility in both sexes.
  • Butadiene, 4-vinylcyclohexene, and their diepoxides can result in the depletion of specific pre-antral follicles. It was observed that 4-vinylcyclohexene and its diepoxide metabolites cause a variation in survival factors like KIT/Kit Ligand, apoptosis, and/or cellular signaling, which maintain the dormancy of primordial follicles.
• Estrogenic endocrine disruptors, such as genistein, diethylstilbestrol (DES), and bisphenol-A (BPA), may modify the formation/development of follicles and thereby damage fertility or normal offspring development.

The researchers noted that an extensive loss in the number of primordial follicles leads to early menopause (irreversible ovarian failure), and the detection of such a loss is difficult due to the lack of known biomarkers derived from primordial follicles. Damage to the primordial follicles results in delayed cyclicity, and the complete depletion of follicles from the primordial pool can be detected only after damage to the larger follicles.

Although the findings of various studies indicate the negative impact of toxins on ovarian follicles, their identification is arduous owing to the lack of techniques for calculating the number of pre-antral follicles in living persons. Further research is essential for better understanding of the mechanism involved in ovarian toxicity, and recognition of the different ovotoxicants for both screening of such chemicals and evaluating their toxicity.

References

1. Mark-Kappeler CJ, Hoyer PB, Devine PJ. Xenobiotic effects on ovarian pre-antral follicles. Biol Reprod. 2011 Nov;85(5):871-83.

2. Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst. 2006 Jul 5;98(13):890-6.