Zelieann R Craig
Assistant Professor, BIO5 Institute
Assistant Professor, Physiological Sciences - GIDP
Associate Professor, Animal and Comparative Biomedical Sciences
Primary Department
Department Affiliations
(520) 621-9965
Work Summary
We investigate how the chemicals in our daily lives interact with the female reproductive system and influence fertility. We hope that our discoveries will help reduce the incidence of infertility and improve women's health.
Research Interest
Infertility is the inability to produce life offspring. Several factors increase a female’s risk for infertility including aging, stress, and exposure to chemicals. Unfortunately, fertility in women and animals has declined significantly over several decades. Therefore, understanding how these factors influence human and animal fertility are of great health and economic importance. A group of chemicals collectively known as phthalates have been classified as endocrine disruptors based on their ability to interact with the reproductive system. Phthalates have been detected in human urine, animal tissues, and feed. Despite these observations, knowledge about how phthalates interact with the female reproductive system is currently very limited. Dr. Craig's work focuses on understanding how phthalates affect the function of the ovary, the major reproductive organ in females. Thus, work in her laboratory is focused on using animal models to help us understand the mechanisms by which phthalates exert their effects on the ovary, determine whether phthalates cause female infertility, and examine whether the effects of phthalates on female reproduction can be prevented or reversed. Using this knowledge she hopes to inspire and guide future work aimed at reducing, preventing, and/or reversing chemical-related adverse reproductive outcomes in humans and animals. Keywords: Infertility, Toxicology, Endocrine Disruptors, Phthalates, Reproduction

Publications

Barton, J. K., Connolly, D. C., Craig, Z. R., Chambers, S. K., Hutchens, G. V., Dominguez Cooks, J. P., Koevary, J. W., Howard, C. C., Rice, P. F., & Hoyer, P. (2018). Comparison of Markers of Reproductive Function in Female C57Bl/6 versus TgMISIIR-TAg Transgenic Mice: Effect of VCD exposure on Ovarian Failure.. Comparative Medicine.
BIO5 Collaborators
Jennifer Kehlet Barton, Zelieann R Craig
Craig, Z. R., Davis, J. R., Marion, S. L., Barton, J. K., & Hoyer, P. B. (2010). 7,12-Dimethylbenz[A]Anthracene Induces Sertoli-Leydig-Cell Tumors in the Follicle-Depleted Ovaries of Mice Treated with 4-Vinylcyclohexene Diepoxide. COMPARATIVE MEDICINE, 60(1), 10-17.
BIO5 Collaborators
Jennifer Kehlet Barton, Zelieann R Craig
Rivera, Z., Christian, P. J., Marion, S. L., Brooks, H. L., & Hoyer, P. B. (2009). Steroidogenic capacity of residual ovarian tissue in 4-vinylcyclohexene diepoxide-treated mice. Biology of reproduction, 80(2), 328-36.
BIO5 Collaborators
Heddwen L Brooks, Zelieann R Craig

Menopause is an important public health issue because of its association with a number of disorders. Androgens produced by residual ovarian tissue after menopause could impact the development of these disorders. It has been unclear, however, whether the postmenopausal ovary retains steroidogenic capacity. Thus, an ovary-intact mouse model for menopause that uses the occupational chemical 4-vinylcyclohexene diepoxide (VCD) was used to characterize the expression of steroidogenic genes in residual ovarian tissue of follicle-depleted mice. Female B6C3F1 mice (age, 28 days) were dosed daily for 20 days with either vehicle or VCD (160 mg kg(-1) day(-1)) to induce ovarian failure. Ovaries were collected on Day 181 and analyzed for mRNA and protein. Acyclic aged mice were used as controls for natural ovarian senescence. Relative to cycling controls, expression of mRNA encoding steroidogenic acute regulatory protein (Star); cholesterol side-chain cleavage (Cyp11a1); 3beta-hydroxysteroid dehydrogenase (Hsd3b); 17alpha-hydroxylase (Cyp17a1); scavenger receptor class B, type 1 (Scarb1); low-density lipoprotein receptor (Ldlr); and luteinizing hormone receptor (Lhcgr) was enriched in VCD-treated ovaries. In acyclic aged ovaries, mRNA expression for only Cyp17a1 and Lhcgr was greater than that in controls. Compared to cycling controls, ovaries from VCD-treated and aged mice had similar levels of HSD3B, CYP17A1, and LHCGR protein. The pattern of protein immunofluorescence staining for HSD3B in follicle-depleted (VCD-treated) ovaries was homogeneous, whereas that for CYP17A1 was only seen in residual interstitial cells. Circulating levels of FSH and LH were increased, and androstenedione levels were detectable following follicle depletion in VCD-treated mice. These findings support the idea that residual ovarian tissue in VCD-treated mice retains androgenic capacity.

Basavarajappa, M. S., Craig, Z. R., Hernández-Ochoa, I., Paulose, T., Leslie, T. C., & Flaws, J. A. (2011). Methoxychlor reduces estradiol levels by altering steroidogenesis and metabolism in mouse antral follicles in vitro. Toxicology and applied pharmacology, 253(3), 161-9.

The organochlorine pesticide methoxychlor (MXC) is a known endocrine disruptor that affects adult rodent females by causing reduced fertility, persistent estrus, and ovarian atrophy. Since MXC is also known to target antral follicles, the major producer of sex steroids in the ovary, the present study was designed to test the hypothesis that MXC decreases estradiol (E₂) levels by altering steroidogenic and metabolic enzymes in the antral follicles. To test this hypothesis, antral follicles were isolated from CD-1 mouse ovaries and cultured with either dimethylsulfoxide (DMSO) or MXC. Follicle growth was measured every 24 h for 96 h. In addition, sex steroid hormone levels were measured using enzyme-linked immunosorbent assays (ELISA) and mRNA expression levels of steroidogenic enzymes as well as the E₂ metabolic enzyme Cyp1b1 were measured using qPCR. The results indicate that MXC decreased E₂, testosterone, androstenedione, and progesterone (P₄) levels compared to DMSO. In addition, MXC decreased expression of aromatase (Cyp19a1), 17β-hydroxysteroid dehydrogenase 1 (Hsd17b1), 17α-hydroxylase/17,20-lyase (Cyp17a1), 3β hydroxysteroid dehydrogenase 1 (Hsd3b1), cholesterol side-chain cleavage (Cyp11a1), steroid acute regulatory protein (Star), and increased expression of Cyp1b1 enzyme levels. Thus, these data suggest that MXC decreases steroidogenic enzyme levels, increases metabolic enzyme expression and this in turn leads to decreased sex steroid hormone levels.

Ziv-Gal, A., Craig, Z. R., Wang, W., & Flaws, J. A. (2013). Bisphenol A inhibits cultured mouse ovarian follicle growth partially via the aryl hydrocarbon receptor signaling pathway. Reproductive toxicology (Elmsford, N.Y.), 42, 58-67.

Bisphenol A (BPA) is an endocrine disruptor that inhibits growth of mouse ovarian follicles and disrupts steroidogenesis at a dose of 438μM. However, the effects of lower doses of BPA and its mechanism of action in ovarian follicles are unknown. We hypothesized that low doses of BPA inhibit follicular growth and decrease estradiol levels through the aryl hydrocarbon receptor (AHR) pathway. Antral follicles from wild-type and Ahr knock-out (AhrKO) mice were cultured for 96h. Follicle diameters and estradiol levels then were compared in wild-type and AhrKO follicles ± BPA (0.004-438μM). BPA inhibited follicle growth (110-438μM) and decreased estradiol levels (43.8-438μM) in wild-type and AhrKO follicles. However, at BPA 110μM, inhibition of growth in AhrKO follicles was attenuated compared to wild-type follicles. These data suggest that BPA may inhibit follicle growth partially via the AHR pathway, whereas its effects on estradiol synthesis likely involve other mechanisms.