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theses

Diethylhexyl phthalate (DEHP) is present in medical devices, packaging and food containers, from where it leaches into the external environment and causes reproductive toxicity among others in humans and animals. DEHP is an endocrine-disrupting chemical (EDC) and in utero and lactational exposure of DEHP causes testicular dysgenesis syndrome in males. Studies in females, suggest that the ovary is the target of DEHP toxicity, however, its mechanism of action remains unknown. Therefore in our study, we exposed timed-pregnant Fischer CDF rats (F0) to DEHP (500 mg/kg/day) from embryonic day (E) 11 to 21 and their F1 pups from postnatal day (PND) 0 to PND 7, a developmental window that includes female gonadal differentiation, critical events in ovarian folliculogenesis and epigenetic reprogramming in females, to specifically study the effect of developmental exposure of DEHP on ovarian function in the F1 offspring. The present study also investigated a transgenerational effect, if any on the female reproductive function, specifically through either the maternal germline (maternal cross; MC) or both maternal and paternal germlines (double cross; DC). Various reproductive parameters such as puberty, estrous cyclicity, pregnancy rate, and litter size were examined. The results showed a significant delay in the onset of puberty, as monitored by vaginal opening, only in the DEHP-exposed F1 females but not in the F3 females. No effect on the regularity of the estrus cycle was seen despite reduced serum estradiol levels in the F1 offspring. Follicular composition was analyzed in adult ovaries and expressed as a percentage of total follicles. Significantly large number of growing follicles which seem to progress towards atresia were observed in the DEHP exposed F1 animals at young adulthood (PND 50-85). Therefore the data is suggestive of ‘premature ovarian failure’. Our study showed that altered follicular dynamics were accompanied by increased Mullerian inhibiting substance (MIS) and androgen receptor (AR) expression in growing follicles in F1 generation. Decreased estradiol levels, up-regulated AR and MIS expression inhibits progression of the early antral follicles, resulting in increased follicular atresia that reduced the number of total follicles per section in the F1 generation. Decrease in primordial follicles and an increase in early antral follicles accompanied by attenuated MIS production by both primary and antral follicles, reemphasized the possibility of disrupted follicular development in the DC group. Similarly, in MC group, there was an increase in CL without affecting the litter size which may be indicative of premature luteinization. These alterations in follicular dynamics are similar to those in the F1 generation, suggesting developmental DEHP exposure can have a delayed and transgenerational effect on female ovaries.

ETD_5967

M.S.

Includes bibliographical references

by Arpita S. Bhurke

doi:10.7282/T3348HTD

ETD graduate

The author owns the copyright to this work.