Effects of Maternal and Lactational Exposure to 2‐Hydroxy‐4‐Methoxybenzone on Development and Reproductive Organs in Male and Female Rat Offspring

Abstract

BACKGROUND 2-hydroxy-4-methoxybenzophenone (HMB) is an ultraviolet (UV)-absorbing compound used in many cosmetic products as a UV-protecting agent and in plastics for preventing UV-induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential. METHODS To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time-mated female Harlan Sprague-Dawley rats were dosed with 0, 1,000, 3,000, 10,000, 25,000, or 50,000 ppm HMB (7-8 per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23. RESULTS AND CONCLUSION Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats.

Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data

“…Finally, other toxicants such as alcohol [73, 110], flame retardants [111], diesel [112] or anti-UV protectors [113] seem to influence the ovarian reserve but we have not found sufficient data to conclude this. Indeed, only animal studies are available for flame retardants [111], diesel [112] and anti-UV protectors [113] and discrepancies exist between the two human cross-sectional studies for alcohol [73, 110].…”

“…Activation of the AhR system.Pocar et al, 2012 [105]Exposure of mice to a mixture of PCB 0, 1, 10 or 100 mg/kg/day during pregnancy and lactationPCB level significantly ⇗ in exposed newborns compared to the controls.Decrease in ovary weight ( p  < 0.05),⇗ follicular atresia ( p  < 0.0001) in the F1 generation onlyPerfluorinated compoundsKnox et al, 2011 [108]Cross-sectional study on 25,957 womenStart of menopause was earlier by several months in exposed patientsTaylor et al, 2014 [107]Cross-sectional study of the NHANES cohort, 3011 women were studied for the association between exposure to perfluorinated compounds and the age at menopause onsetWomen with elevated perfluorinated compound serum levels were younger at menopause than women with lower levels.AlcoholPeck et al, 2016 [73]Analysis of primordial follicle stock in 133 patients having underwent hysterectomy. Evaluation of behavioral habits using a questionnaireLight to moderate alcohol consumption is associated with a higher follicle count.Flame retardantsLefèvre et al, 2016 [111]Exposure of pregnant rats to bromine flame retardants for 2 to 3 weeks⇗ 50% in the number of antral and pre-antral follicles = Alteration of folliculogenesisHMB = 2-hydroxy-4methoxybenzone, anti-UV protectorNakamura et al, 2015 [113]Rats exposed to different doses of HMB (7–8 per group) from the 6th gestational day until the 23rd postnatal day. Effects on offspringDelayed follicular development in the group receiving the highest dose.…”

“…Indeed, only animal studies are available for flame retardants [111], diesel [112] and anti-UV protectors [113] and discrepancies exist between the two human cross-sectional studies for alcohol [73, 110]. …”

Transcript profiling in the testes and prostates of postnatal day 30 Sprague-Dawley rats exposed prenatally and lactationally to 2-hydroxy-4-methoxybenzophenone

“…Previous studies in mice and rats have reported effects of HMB exposure on the male reproductive system [7–10]. Rats and mice exposed to 50000 ppm of HMB in the diet had significant declines in body weight and sperm production [9].…”

“…Rats and mice exposed to 50000 ppm of HMB in the diet had significant declines in body weight and sperm production [9]. Reduced serum testosterone levels were also observed in postnatal day (PND) 23 rats treated with HMB; however, reductions were not dose-dependent [10]. We have previously reported on the estimated plasma HMB concentration in humans that were obtained from females exposed topically to 2 mg/cm 2 HMB for 4 days [10, 11]; where levels were comparable to those seen after exposure to 3000–10000 ppm HMB in rats.…”